1521-0081/66/1/102–192$25.00
PHARMACOLOGICAL REVIEWS
Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/pr.113.008029
Pharmacol Rev 66:102–192, January 2014
ASSOCIATE EDITOR: DIANNE M. PEREZ
Purinergic Signaling and Blood Vessels in Health
and Disease
Geoffrey Burnstock and Vera Ralevic
Autonomic Neuroscience Centre, University College Medical School, London, United Kingdom and Department of Pharmacology, The
University of Melbourne, Australia (G.B.); and School of Biomedical Sciences, Queen’s Medical Centre, Nottingham, United Kingdom (V.R.)
V.R. was supported by the British Heart Foundation [Project Grant PG/11/45/28975 and BHF Studentship FS/12/7/29359].
Address correspondence to: Geoffrey Burnstock, Autonomic Neuroscience Centre, University College Medical School, Rowland Hill
Street, London NW3 2PF, UK; and Department of Pharmacology, The University of Melbourne, Australia. E-mail [email protected]
dx.doi.org/10.1124/pr.113.008029.
102
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Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
II. Dual Control of Vascular Tone by Perivascular Nerves and Endothelial Cells . . . . . . . . . . . . . . . . . 104
A. Perivascular Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
1. Sympathetic Nerves. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
2. Parasympathetic Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
3. Sensory-Motor Nerves. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
B. Endothelial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
1. P2Y Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
2. P2X Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
3. P1 (Adenosine) Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
III. Purinergic Signaling in Different Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
A. Aorta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
B. Rat Tail Artery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
C. Ear Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
D. Mesenteric Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
1. Mesenteric Veins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
2. Mesenteric Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3. Mesenteric Arterial Bed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
E. Coronary Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
F. Cerebral Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
G. Skin Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
H. Intestinal Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
I. Skeletal Muscle Microvasculature and Femoral Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
J. Pulmonary Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
K. Carotid Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
L. Splenic Vessels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
M. Uterine Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
N. Human Umbilical and Placental Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
1. Human Umbilical Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
2. Placental Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
O. Saphenous Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
1. Saphenous Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
2. Saphenous Vein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
P. Renal Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
1. Microcirculation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2. Renal Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
3. Juxtamedullary Afferent Arterioles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Q. Hepatic Artery and Portal Vein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Purinergic Signaling and Blood Vessels
103
1. Hepatic Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2. Portal Vein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
R. Other Blood Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
S. Lymphatic Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
IV. Long-Term Trophic Roles of Purines and Pyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
A. Vascular Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
B. Vascular Endothelial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
V. Vascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
A. Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
B. Atherosclerosis and Coronary Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
C. Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
1. Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2. Brain and Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3. Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4. Kidney. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
5. Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
6. Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
7. Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
8. Umbilical Cord. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
9. Testis and Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
10. Pancreas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
11. Skeletal Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
12. Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
D. Thrombosis and Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
E. Diabetic Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
F. Migraine and Vascular Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
G. Sepsis and Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
H. Hyperhomocysteinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
I. Calcific Aortic Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
J. Metabolic Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
VI. Conclusions and Future Directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Abstract——Purinergic signaling plays important
roles in control of vascular tone and remodeling.
There is dual control of vascular tone by ATP released
as a cotransmitter with noradrenaline from perivascular sympathetic nerves to cause vasoconstriction
via P2X1 receptors, whereas ATP released from endothelial cells in response to changes in blood flow
(producing shear stress) or hypoxia acts on P2X and
P2Y receptors on endothelial cells to produce nitric
oxide and endothelium-derived hyperpolarizing factor, which dilates vessels. ATP is also released from
sensory-motor nerves during antidromic reflex activity to produce relaxation of some blood vessels. In
this review, we stress the differences in neural and
ABBREVIATIONS: [Ca2+]i, intracellular Ca2+ concentration; 2-MeSADP, 2-methylthio ADP; 2-MeSATP, 2-methylthio ATP; 5-HT, 5hydroxytryptamine; a,b-meATP, a,b-methylene ATP; ACh, acetylcholine; ATL146e, 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydrofuran-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester; AMPK, AMP-activated protein kinase; Ang-II, angiotensin II;
ANP, atrial natriuretic peptide; Ap3A, diadenosine triphosphate; Ap4A, diadenosine tetraphosphate; Ap5A, diadenosine pentaphosphate; Ap6A,
diadenosine hexaphosphate; ATPgS, adenosine-59-(g-thio)-triphosphate; AZD6140, 3-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylsulfanyltriazolo[5,4-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; BBB, blood-brain barrier; BX 667, (4S)-5-(4-ethoxycarbonylpiperazin1-yl)-4-[[4-(1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy-7-methylquinoline-2-carbonyl]amino]-5-oxopentanoic acid; CGRP, calcitonin gene-related
peptide; COX, cyclooxygenase; DOCA, deoxycorticosterone acetate; EDCF, endothelium-derived contracting factor; EDHF, endothelium-derived
hyperpolarizing factor; EJPs, excitatory junction potentials; ET, endothelin; HIF, hypoxia-inducible transcription factors; HUVECs, human
umbilical vein endothelial cells; IL, interleukin; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NA, noradrenaline; NANC,
nonadrenergic, noncholinergic; NF, nuclear factor; NGF, nerve growth factor; NK, natural killer; NO, nitric oxide; NOS, nitric-oxide synthase; NPY,
neuropeptide Y; PAI-1, plasminogen activator inhibitor-1; PD-81723, 2-amino-4,5-dimethyl-3-thienyl-[3(trifluoromethyl)-phenyl]methanone; PEDF,
pigment epithelium-derived factor; PGI2, prostacyclin; PK, protein kinase; PPADS, pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic acid; PSB 0739,
1-amino-9,10-dihydro-9,10-dioxo-4-[-(phenylamino)-3-sulfophenyl]amino]-2-anthracenesulfonic acid; ROS, reactive oxygen species; RT-PCR, reverse
transcriptase-polymerase chain reaction; SHR, spontaneously hypertensive rats; siRNA, small interfering RNA; TNF-a, tumor necrosis factor-a;
TRPC, transient receptor potential channel; Tb4, thymosin b-4; Up4A, uridine adenosine tetraphosphate; VEGF, vascular endothelial growth factor;
WKY, Wistar-Kyoto.
104
Burnstock and Ralevic
endothelial factors in purinergic control of different
blood vessels. The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in
promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y
receptors during angiogenesis and vessel remodeling
during restenosis after angioplasty are described.
The pathophysiology of blood vessels and therapeutic potential of purinergic agents in diseases, including hypertension, atherosclerosis, ischemia,
thrombosis and stroke, diabetes, and migraine, is
discussed.
I. Introduction
discriminate between different P2X receptors and between P2Y2 and P2Y4 receptors (see Table 1). There is
considerable evidence showing the expression of P2X
mRNA and protein in endothelial cells, but little is
known about their function; the more widespread application of molecular biology techniques is clearly needed
to identify the possible roles of P2X subtypes in the
endothelium, as is discussed in section II.B.2). Commercially available ligands do not discriminate well
between P2Y2 and P2Y4 receptors, and the default
position is that one or both are expressed in tissues
where responses to UTP (P2Y2/4 agonist, weak P2Y6
agonist) are demonstrated. However, the use of P2Y6
receptor knockouts showed that the contractile response to UTP in mouse aorta was mediated via P2Y6
receptors and not via P2Y2 receptors, which were
shown by RT-PCR to be expressed in the smooth
muscle (Bar et al., 2008; Kauffenstein et al., 2010a).
Similarly, the use of knockouts and antisense oligonucleotides showed the functional expression of vasocontractile P2Y4 and P2Y6 but not P2Y2 receptors in
mouse mesenteric arteries and cerebral arterioles (Vial
and Evans, 2002; Bar et al., 2008; Kauffenstein et al.,
2010a; Brayden et al., 2013). In contrast, in rat mesenteric arteries, small interfering RNA (siRNA) knockdown of P2Y2 mRNA demonstrated the almost exclusive
involvement of P2Y2 receptors in contraction to UTP
(Morris et al., 2011). This demonstrates pronounced
species differences in the expression of vasocontractile
P2Y receptors, which were not detected through the use
of pharmacology alone. This is an area where the more
widespread application of molecular biology techniques
across species will help to clarify our interpretation of
the expression of vasocontractile P2Y receptors.
For information about purinergic peripheral and
central nervous control of the vascular system, several
articles are recommended (Spyer et al., 1997; Burnstock, 2007; Gourine et al., 2009; Cruz et al., 2010;
Passamani et al., 2011; Burnstock and Verkhratsky,
2012; Ichinose et al., 2012). Finally, the pathophysiology and therapeutic potential of purinergic agents to
treat vascular diseases will be reviewed.
Although it is clear that purinergic signaling plays
a pivotal role in the control of vascular tone and remodeling, there has been a tendency to extrapolate the
purinergic mechanisms involved in a particular vessel
to operate in all vessels. However, it has become clear
that there are significant differences in the purinergic
regulatory mechanisms in different blood vessels and
in different species related to the specific physiologic
roles of the particular vessel. Therefore, a detailed
analysis of the purinergic control mechanisms in different vessels follows. Common to most vessels is dual
control of vascular tone by ATP released as a cotransmitter with noradrenaline (NA) from sympathetic perivascular nerves causing constriction, whereas ATP
released from endothelial cells by shear stress (produced by changes in blood flow) and hypoxia acting on
endothelial cells releases endothelium-derived relaxing
factor(s) (EDRF) (see Burnstock, 1990a, 2007). The longterm (trophic) actions of purines in promoting migration
of endothelial cells and proliferation of both smooth
muscle and endothelial cells during angiogenesis also
appears to be a common feature of blood vessels (see
Teuscher and Weidlich, 1985; Burnstock, 2002).
The field lacks selective ligands for many of the
different P2 receptor subtypes, but the use of multiple
experimental approaches (e.g., RT-PCR, Western blotting) and commercially available ligands has, in general, provided good predictions of the P2 receptor
subtypes present in blood vessels. Where studies with
P2 receptor knockouts have been carried out, these
have largely confirmed and/or refined our existing interpretations of P2 receptor expression. For example,
mesenteric arteries from P2X1 receptor knockout mice
confirmed the involvement of P2X1 receptors in ATPmediated vasoconstriction and transient inward currents and in sympathetic neurogenic vasoconstriction
(Vial and Evans, 2002). P2Y6 receptor knockout mice
confirmed the involvement of these receptors in aortic
endothelium-dependent relaxation to UDP and smooth
muscle contraction to UDP (and UTP) (Bar et al., 2008).
P2Y2 knockout mice have confirmed an endotheliumdependent vasorelaxant function of P2Y2 receptors
(although unusually these were sensitive to ATP but
not UTP) (Guns et al., 2006). Native P2 receptor characterization is an area that would benefit from the
further use of molecular biology techniques. The main
challenges with regard to P2 receptor characterization
are the development of potent and selective ligands to
II. Dual Control of Vascular Tone by Perivascular
Nerves and Endothelial Cells
For many years, control of vascular tone was considered to be by antagonistic sympathetic noradrenergic
constrictor nerves and parasympathetic cholinergic dilator nerves. However, after recognition of the conceptual
105
Purinergic Signaling and Blood Vessels
TABLE 1
P2X and P2Y receptor agonists and antagonists
All of the ligands are commercially available, except for PPTN, 4-[(piperidin-4-yl)-phenyl]-7-[4-(trifluoromethyl)-phenyl]-2-naphthoic acid (Barrett et al., 2013).
Ion Channel/Principal Transduction
Agonists
Selective Agonists
P2X1
Ion channel
ATP
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7
Ion
Ion
Ion
Ion
Ion
Ion
ATP
ATP
ATP
ATP
ATP
ATP
P2Y1
Gq/11
ADP . ATP
2-MeSADP, ADPbS, MRS2365
P2Y2
P2Y4
P2Y6
Gq/11
Gq/11
Gq/11
UTP = ATP
UTP . ATP
UDP . . UTP . ATP
P2Y11
Gs, Gq/11
ATP . UTP
UTPgS, PSB1114
UTPgS, MRS4062
UDP, PSB 0474 ([ 3- phenacylUDP)
MRS2957
NF546, NAD+ NAADP+
P2Y12
P2Y13
P2Y14
Gi/o
Gi/o
Gi/o
ADP . . ATP
ADP . . ATP
UDP-glucose
UDP-galactose
channel
channel
channel
channel
channel
channel
advances about cotransmission (Burnstock, 1976) and
EDRFs (Furchgott, 1984), it is now clear that vascular
tone is under the dual control of cotransmitters released from perivascular nerves and various factors
released from endothelial cells (see Burnstock, 1987,
1988, 1989a, 1990a, 1993a, 2002, 2008c; Ralevic and
Burnstock, 1996a).
The possibility that ATP is released together with
NA from sympathetic nerves supplying the rabbit portal vein was raised early by Che Su (see Su, 1977,
1985), although the potent effects of ATP on venous
blood vessels was also recognized early (see Vanhoutte,
1978) and also the roles of adenosine and ATP in exercise
hyperemia of skeletal and cardiac muscle (see Forrester,
1981). Two types of receptors for purines were identified:
P1 receptors activated by adenosine and P2 receptors
activated by ATP and ADP (Burnstock, 1978), with P2 receptors further subdivided into P2X and P2Y (Burnstock
and Kennedy, 1985). P2 purinoceptors were later identified on both vascular smooth muscle and endothelial
cells (see Pearson and Gordon, 1989).
Release of ATP from endothelial cells in response to
changes in blood flow (due to shear stress) and hypoxia
has been demonstrated (Bodin et al., 1991; Burnstock,
1999; see Bodin and Burnstock, 2001b). Evidence has
been presented for the mechanism of ATP transport
from endothelial cells being vesicular exocytosis (Bodin
and Burnstock, 2001a), but also via connexin 43 hemichannels (Faigle et al., 2008). Pannexin hemichannels
and calcium homeostasis modulator 1 ion channels
are structurally and functionally related to connexins,
and there is increasing evidence for a widespread
involvement of these other ATP-conducting anion channels and ATP-binding cassette transporters in ATP
release from cells (Dubyak, 2009; Lazarowski, 2012;
a,b-meATP, L-b,g-meATP
—
A317491
ADP, 2-MeSADP
MRS2690
—
—
—
—
—
Selective Antagonists
NF023, NF449
Ro 0437626
—
Ro51, RO3
—
—
—
A839977, A740003
A438079, AZ 11645373
MRS2179
MRS2500
MRS2578
NF157
NF340
AR-C 66096
MRS2211
PPTN
Lohman et al., 2012a; Taruno et al., 2013). Further
studies using molecular approaches are warranted to
investigate further their potential role in purinergic
control of the vasculature. Reviews describing dual
control of local blood flow by nucleotides released by
nerves and endothelial cells are available (Burnstock
and Kennedy, 1986; Burnstock, 1990a, 2008a, 2010).
Ectonucleotidases are ectoenzymes associated with the
cell membrane that have an important role in determining extracellular concentrations of nucleotides and
nucleosides (Yegutkin, 2008; Zimmermann et al., 2012).
They include ectonucleotidase 59-triphosphate diphosphohydrolases (E-NTPDases), including E-NTPDase1/
ecto-ATPase/CD39, which hydrolyzes nucleoside triand diphosphates (found at the surface of endothelial
and vascular smooth muscle cells), and E-NTPDase2
(CD39L1) (expressed on the adventitial surface of blood
vessels), which hydrolyzes nucleoside triphosphates.
Ecto-59-nucleotidases (CD73) and alkaline phosphatases
catalyze the extracellular formation of adenosine from
AMP. Nucleotide sugars are resistant to hydrolysis by
ectonucleoside di- and triphosphohydrolases, but they
and other nucleotides are hydrolyzed by nucleotide
pyrophosphatase. Extracellular levels of nucleotides,
and consequently their actions at cell surface purine
receptors, are a balance between their release from cells
by the mechanisms discussed above and hydrolysis by
ectonucleotidases (Fig. 1). Studies on isolated vessels
from E-NTPDase1 knockouts and vessels in the presence of ecto-ATPase inhibitors have shown that ectonucleotidases can profoundly influence agonist potencies
(Crack et al., 1994; Kauffenstein et al., 2010a). This has
pharmacological and physiologic relevance for P1 and
P2 receptor activities in health and disease, which is
discussed in subsequent sections.
106
Burnstock and Ralevic
Fig. 1. Extracellular levels of nucleotides and consequent actions at cell
surface purine receptors are a balance between their release from cells
and hydrolysis by extracellular ectonucleotidases. Nucleotides can be
released from cells by connexin hemichannels, pannexin hemichannels,
ATP-binding cassette transporters (ABC), and anion channels. Sympathetic nerves release ATP (together with noradrenaline) by vesicular
exocytosis. Ectonucleotidase 59-triphosphohydrolases (ENTPDase) at the
surface of cells hydrolyze ATP, ADP, and UTP, whereas ecto-59-nucleotidase (CD73) further hydrolyzes the AMP formed to adenosine. The
nucleotides and adenosine can have auto- and paracrine effects at cell
surface P2X, P2Y, and adenosine A1, A2A, A2B, and A3 receptors.
A. Perivascular Nerves
1. Sympathetic Nerves. In many arteries, the mechanical and electrical responses to perivascular sympathetic
nerve stimulation are partially resistant to a-adrenoceptor antagonists. Many reports of sympathetic purinergic
excitatory cotransmission to various blood vessels are
available, although there is considerable variation in the
proportions of ATP and NA used (Burnstock, 1988,
1990b, 1995; Ralevic and Burnstock, 1998; Hill et al.,
2001; Lewis and Evans, 2001; Ralevic, 2009; Macarthur
et al., 2011). There appear to be separate stores of NA
and ATP in sympathetic nerve terminals, because N and
P/Q type calcium channels control NA release, whereas
only N-type channels control ATP release (Demel et al.,
2010; see also Ellis and Burnstock, 1989).
The vasocontractile actions of ATP released from
sympathetic nerves appear to be mediated principally
via P2X1 receptors (Fig. 2). There is evidence for the
expression of both P2X and P2Y receptors in vascular
smooth muscle from detection of mRNA, antibody recognition, electrophysiological and pharmacological studies, and the use of knockouts and siRNA knockdown.
The focus on P2X receptors in vascular smooth muscle,
at least with regard to control of vascular tone, is because it has been possible to identify a clear physiologic
role for these receptors as mediators of the response
to ATP released as a fast excitatory neurotransmitter
from sympathetic perivascular nerves (described below).
Sympathetic nerves in isolated blood vessel preparations can be selectively stimulated causing ATP (and
NA) release, and the pharmacological tools with which
to investigate P2X1 receptors are relatively good (a
number of selective antagonists are commercially available, see Table 1). P2X1 receptor knockout mice have
confirmed, in mesenteric arteries, the involvement of
P2X1 receptors in ATP-mediated vasoconstriction and
transient inward currents and in sympathetic neurogenic vasoconstriction (Vial and Evans, 2002). Moreover, P2X1 receptor clusters have been described on
vascular smooth muscle in regions adjacent to sympathetic nerve varicosities (Hansen et al., 1999; Vial and
Evans, 2005) and provide an explanation for why
smooth muscle P2X receptors, and not P2Y receptors,
are involved in ATP cotransmission.
P2X receptors are ionotropic receptors, and their
activation by ATP leads to a rapid response involving
calcium entry directly through the P2X cation channels, membrane depolarization, and calcium influx
through voltage-activated calcium channels, whereas
NA acts more slowly due to adrenoceptor coupling to G
proteins and the involvement of second messengers.
ATP and NA can act synergistically, resulting in a rapid
onset augmented contraction (Kennedy and Burnstock,
1986; Ralevic and Burnstock, 1990; Johnson et al.,
2001). In recent articles, evidence was presented that
activation of a1-adrenoceptors on vascular smooth muscle cells open pannexin 1 channels to release ATP,
leading to enhanced vasoconstriction, providing new
insights into the regulation of peripheral resistance
and blood pressure by sympathetic nervous stimulation (Billaud et al., 2011, 2012). The use of pannexin
knockout animals would be valuable to investigate the
extent of involvement of pannexins and smooth muscle
ATP release in sympathetic signaling throughout the
cardiovascular system and also in the myogenic response, because pannexin channels are activated by
distension.
By use of calcium confocal imaging in rat mesenteric
arteries, neurally released ATP was shown to produce
an early junctional calcium transient and this was
followed by calcium waves developing later due to the
actions of neurally released NA (Lamont et al., 2003;
Wier et al., 2009). Nifedipine, an L-type calcium channel blocker, inhibits the purinergic component of sympathetic vasoconstriction in dog (Omote et al., 1989)
and rat (Rummery et al., 2007) mesenteric arteries and
in rabbit ileocolic and saphenous arteries (Bulloch
et al., 1991), suggesting that ATP activation of P2X receptors on vascular smooth muscle evokes calcium entry
through voltage-activated L-type calcium channels.
However, in submucosal arterioles of guinea pig ileum,
P2X receptor-mediated vasoconstriction is nifedipine
insensitive (Galligan et al., 1995).
There is a substantial ATP component of sympathetic
neurotransmission in the rabbit saphenous artery
Purinergic Signaling and Blood Vessels
107
Fig. 2. Purinergic signaling at the sympathetic neuroeffector junction. Varicosities along the sympathetic nerve trunks are the sites of
neurotransmitter release. ATP, together with NA, is released by exocytosis from separate vesicles within sympathetic nerve varicosities. ATP acts
at smooth muscle P2X1 receptors, which have been localized in clusters in regions adjacent to the sympathetic nerve varicosities. Binding of ATP to
P2X1 receptors activates the receptors, allowing calcium (and other anion) influx leading to depolarization, further entry of calcium via voltage-gated
calcium channels (VGCC), and vasoconstriction. Some of the released ATP can act prejunctionally at inhibitory P2Y receptors. ATP is hydrolyzed via
cell surface ectonucleotidase 59-triphosphohydrolases (ENTPDase) to produce AMP, and ecto-59-nucleotidase (CD73) further hydrolyzes AMP to
adenosine, which can also act prejunctionally at inhibitory A1 adenosine receptors. Although contractile P2Y receptors are expressed on the vascular
smooth muscle there is little evidence for their involvement in perivascular sympathetic neurotransmission.
(Burnstock and Warland, 1987a; Warland and Burnstock,
1987). The mesenteric artery is another vessel where
there is a major ATP contribution of sympathetic cotransmission (Muir and Wardle, 1988; Ishikawa, 1985;
von Kügelgen and Starke, 1985; Muramatsu, 1986,
1987; Machaly et al., 1988; Muramatsu et al., 1989;
Ralevic and Burnstock, 1990). Notably, in the rabbit
jejunal artery and guinea pig submucosal arterioles,
ATP appears to be the predominant, if not the sole,
mediator of the contractile response to sympathetic
nerve stimulation, whereas coreleased NA acts as a
prejunctional modulator (Ramme et al., 1987; Evans
and Cunnane, 1992; Evans and Surprenant, 1992). Evidence has also been presented for a robust ATP component of adrenergic-purinergic cotransmission in rabbit
hepatic (Brizzolara and Burnstock, 1990) and ileocolonic arteries (Bültmann et al., 1991).
The depolarizations of smooth muscle arising from
the actions of excitatory neurotransmitter are known
as excitatory junction potentials (EJPs). Intra- and extracellular recordings in the rat femoral artery have
been used to demonstrate the intermittent release of
single quanta of ATP responsible for EJPs and to show
the similarity to the events occurring during sympathetic cotransmission in the vas deferens (Åstrand
and Stjärne, 1989). In the rat tail artery, EJPs are
resistant to prazosin (Cheung, 1982) but are blocked by
a,b-methylene ATP (a,b-meATP) (Sneddon and Burnstock,
1984a; Sedaa et al., 1986; Bao et al., 1989; Fig. 3, A–C)
and the P2 receptor antagonist suramin (Jobling and
McLachlan, 1992a; Fig. 3D). However, the ATP component appears to be smaller relative to NA in the sympathetic nerves supplying this vessel, so it is more
difficult to demonstrate a mechanical prazosin-resistant
(purinergic) component. Evidence has also been presented
for prazosin-resistant EJPs (Holman and Surprenant,
1980; Suzuki and Kou, 1983) and for cotransmission in
the rabbit ear artery involving ATP and NA (Head
et al., 1977; Saville and Burnstock, 1988; Leff et al.,
1990), but similar to the rat tail artery, it is difficult to
demonstrate a prazosin-resistant (purinergic) mechanical component of the response to perivascular nerve
stimulation, except with short bursts of pulses lasting
approximately a second, which appears to favor the
ATP component (Evans and Cunnane, 1992; Kennedy
et al., 1986; Bulloch and Starke, 1990). It has been
suggested that this might mean that NA may be the
most important component of sympathetic cotransmission during activities such as gentle exercise, whereas
ATP might be the more important component during
stress when short burst frequencies occur in sympathetic nerves (Burnstock, 1988). In the rat mesenteric
artery, EJPs and release of NA (measured by continuous amperometry) could be differentially modulated,
consistent with the possibility that ATP and NA are
nonuniformly stored in different classes of vesicles
108
Burnstock and Ralevic
Fig. 3. (A–C) Intracellular recording of the electrical responses of single
smooth muscle cells of the rat tail artery to field stimulation of the
sympathetic motor nerves (the pulse width was 0.1 ms at 0.5 Hz,
indicated by d). (Ai) Control response of the muscle. Note that to each
individual stimulus there was a rapid depolarization, and as the train of
pulses progressed, a slow depolarization developed. Similar responses
were obtained in (Bi) and (Ci), which are also control responses in Krebs
solution. (Aii) and (Aiii) show the effect of phentolamine (2 1026 M,
added to the bathing solution). The fast depolarizations produced by each
stimulus were not reduced, but there was a progressive reduction in the
size of the slow depolarization, which was almost abolished after
6 minutes. (Bii) The tissues have been in the presence of 1026 M
a,b-methylene ATP for over 15 minutes. The fast depolarizations produced by each stimulus were greatly reduced, but the slow depolarization
persisted. (Cii) shows the effect of a higher concentration of a,b-methylene
ATP. Here the fast depolarization was totally abolished, whereas the slow
depolarization persisted, although reduced to some extent. Subsequent
addition of phentolamine (2 1026 M), together with a,b-methylene
ATP, abolished the neurogenic response completely (Ciii). (Reproduced
from Sneddon and Burnstock, 1984b, with permission.) (D) Excitatory
junction potentials (EJPs) in the main tail artery of the rat. Inhibition of
the fast EJPs by suramin (1 mM). (Reproduced from Jobling and
McLachlan, 1992a, with permission of the Australian Physiological and
Pharmacological Society Inc.)
within sympathetic varicosities (Dunn et al., 1999;
Brock et al., 2000) and, hence, could be released in
different proportions according to the patterns of
stimulation.
The most direct way to demonstrate ATP sympathetic cotransmission is to measure and show its release from sympathetic nerves. Su (1975, 1978b) used
tritium-labeled adenosine and NA to indicate that ATP
is released together with NA from sympathetic nerves
supplying the rabbit aorta. The vessels were preloaded
with [3H]adenosine (which can be incorporated into
new ATP), and subsequent electrical stimulation of
perivascular nerves caused neurogenic [3H]purine release, including [3H]ATP (Su, 1975, 1978b). A similar
approach was used to demonstrate sympathetic cotransmission of NA and ATP in the dog basilar artery
(Muramatsu et al., 1979, 1981) and rabbit pulmonary
artery (Katsuragi and Su, 1980, 1982). In a follow-up
study in the dog basilar artery, desensitization of P2X
receptors with a,b-meATP was used in experiments to
further demonstrate sympathetic cotransmission of
ATP and NA (Muramatsu and Kigoshi, 1987). Release
of ATP from sympathetic nerves has been measured
directly, using the luciferin luciferase assay in guinea
pig vas deferens, and the ATP was shown to be coreleased with NA (Kirkpatrick and Burnstock, 1987);
however, this assay has had limited success in blood
vessels, probably because of the lower levels of ATP
released. More recently, overflow of ATP has been
measured using ATP biosensors from nerves in rat
skeletal muscle 1A arterioles (Kluess et al., 2010). The
fact that the bioprobes measure ATP in real time is a
particular advantage because ATP released from sympathetic nerves is rapidly metabolized by E-NTPDases
1 (CD39) expressed on vascular smooth muscle cells
and is also potentially metabolized by soluble ATPase
released from the sympathetic nerves themselves
(Westfall et al., 2000).
Evidence for adrenergic-purinergic cotransmission
has also been obtained from the vascular beds and
whole animals. Mean arterial pressure fluctuations in
conscious rats are evoked by NA and ATP released
from sympathetic nerves, but can be distinguished by
their frequency characteristics (Golubinskaya et al.,
1999). A contribution of ATP to sympathetic vasopressor responses of the pithed rat has also been demonstrated (Grant et al., 1985; Bulloch and McGrath,
1988a; Schlicker et al., 1989). As with the purinergic
neurogenic response in isolated mesenteric arteries
from rat and dog (Omote et al., 1989; Rummery et al.,
2007), the purinergic component of the vasopressor response to stimulation of the sympathetic outflow of
the rat can be blocked by nifedipine, indicating an
involvement of L-type calcium channels, whereas the
a-adrenoceptor-mediated responses to the cotransmitter NA are relatively resistant to nifedipine (Bulloch
and McGrath, 1988b). In urethane-anesthetized rats,
purinergic cotransmission was shown to play a major
role in the pressor sinocarotid reflex (Tarasova and
Rodionov, 1992).
Hypothalamic stimulation in anesthetized rabbits
produced skeletal muscle vasodilation, which has been
claimed to be mediated by ATP released from sympathetic nerves (Shimada and Stitt, 1984). Adenosine
was not involved in vasodilatation produced by exogenous ATP or hypothalamic stimulation. Stimulation of
the lumbar sympathetic nerve chains in the ganglionblocked rabbit produces hindlimb constriction that
apparently has no a-adrenergic component (Hirst and
Purinergic Signaling and Blood Vessels
Lew, 1987). A study of autoperfused intestinal circulation of anesthetized cats treated with atropine and
propanolol showed that the initial rapid phase of
prazosin-resistant vasoconstriction was abolished after
desensitization of P2X purinoceptors with a,b-meATP
(Taylor and Parsons, 1989). Schwartz and Malik (1989)
concluded from a study of rat isolated kidney that renal
vasoconstriction elicited by periarterial nerve stimulation was mainly due to release of a purinergic transmitter, probably ATP, and to a lesser extent NA. In the
rat mesenteric arterial bed, a purinergic (a,b-meATPsensitive) component of the contractile response to
sympathetic nerve stimulation was revealed when the
perfusion pressure was raised to a level closer to that
found in vivo, likely due to postjunctional enhancement
of the purinergic contractile response (Pakdeechote
et al., 2007b). This has important implications, suggesting that the purinergic component of sympathetic
cotransmission may have been underestimated in in
vitro vascular preparations studied at low tone/pressure,
a suggestion supported by the increase in ATP sympathetic cotransmission observed in the vasculature in
hypertension (see section V.A).
With exposure to a cold environment, blood flow to
the skin is reduced, preventing excessive heat loss. In
the dog, this is achieved by reflex increase in sympathetic tone of cutaneous veins, which is resistant to
adrenoceptor antagonism; it is, however, inhibited by
desensitization of P2X purinoceptors with a,b-meATP
(Flavahan and Vanhoutte, 1986). The possibility is
raised that this may be important for thermoregulation
and may explain why purinergic cotransmission is
more prominent in cutaneous compared with deep
blood vessels. NA and ATP act as vasoconstrictors
to most blood vessels via a-adrenoceptors and P2X1
purinoceptors; studies carried out on the rabbit coronary artery, where the predominant effect of NA is
vasodilation via b-adrenoceptors, have shown that the
cotransmitter ATP causes vasodilation via muscle P2Y
purinoceptors (Corr and Burnstock, 1991; Keef et al.,
1992).
2. Parasympathetic Nerves. Most blood vessels,
with the exception of those supplying salivary glands
and some cerebral blood vessels are not innervated by
parasympathetic nerves (Lundberg, 1996). It is not
known yet whether ATP is a cotransmitter in perivascular parasympathetic nerves.
3. Sensory-Motor Nerves. Many blood vessels are
innervated by sensory-motor nerves, both unmyelinated C fibers and myelinated Ad fibers. The principal
neurotransmitter in perivascular sensory-motor nerves
is calcitonin gene-related peptide (CGRP), which mediates vasorelaxation. There was early evidence that
ATP can be released during antidromic stimulation of
sensory nerves in the rabbit ear artery causing vasodilation (Holton, 1959). Reviews describing other examples where ATP appears to act as a cotransmitter in
109
sensory-motor nerves during vascular axon reflex
activity are available (Rubino and Burnstock, 1996;
Burnstock, 1993a, 2009b).
B. Endothelial Cells
Endothelial cells express P1 and P2 receptors, they
are a source of purines (which can activate P1 and P2
receptors in an autocrine manner), and they contribute
to the metabolism of purines through the actions of cell
surface ectonucleotidases. A fundamental role of endothelial cells is the mediation of vasodilatation and thus
they counterbalance the vasocontractile effects mediated by ATP and NA released from perivascular sympathetic nerves (Fig. 4). In addition to their autocrine
activation by purines, endothelial cells are also a target
of nucleotides and nucleosides released from myocytes
and blood cells by various stimuli, which act at endothelial P2 receptors to elicit vasodilatation (Fig. 5).
The dominant purine receptors on both animal and
human endothelial cells are A2A and A2B adenosine
receptors and P2Y1, P2Y2, and P2X4 nucleotide receptors (see Burnstock, 2009a), but vessel- and speciesspecific differences in receptor subtype expression exist
(discussed in the sections on individual blood vessels).
Endothelial cell activation by purines leads to release
of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin (PGI2) (Van
Coevorden and Boeynaems, 1984; Lückhoff and Busse,
1986; Bogle et al., 1991; Kelm et al., 1991), which can
cause vasorelaxation and inhibition of platelet aggregation. A recent study using the human forearm claims
that in addition to the vasodilator action of ATP via
endothelial cell release of NO and prostaglandins,
ATP-mediated relaxation also occurs via activation of
inwardly rectifying potassium channels (Crecelius
et al., 2011, 2012). The importance of the endothelium
is evident from the fact that endothelial cell dysfunction promotes platelet activation and leukocyte accumulation at the site of injury; the activated platelets
and leukocytes can release ATP, ADP, and UTP. With
an intact endothelium these nucleotides can elicit vasodilatation, but when there is endothelial damage they
may act as vasoconstrictors via P2 receptors on the
vascular smooth muscle, which may lead to local vasospasm (Figs. 5 and 6).
ATP is released during changes in flow (involving
shear stress) from primary cultures of endothelial cells
derived from animal and human blood vessels (Bodin
et al., 1991; see Burnstock, 1999; Bodin and Burnstock,
1996, 2001a), and ATP release was stimulated by hypotonic challenge (Schwiebert et al., 2002). Long-term
treatment with transforming growth factor b1 impairs
ATP release from bovine aortic endothelial cells in response to hypotonic stress (Watanabe et al., 2007).
Uptake of adenosine by endothelial cells and its conversion to ATP was described early (Pearson et al.,
1978) and ATP was released by neutrophil elastase
110
Burnstock and Ralevic
Fig. 4. Purinergic control of blood vessel tone is a balance between actions of ATP released from sympathetic nerves at the outer surface of the vessel
and purines released at its innermost layer, the endothelium. ATP released from sympathetic nerves (together with NA) acts at smooth muscle P2X1
receptors to cause vasoconstriction. Inside the blood vessel, nucleotides released principally from the endothelium and erythrocytes by shear stress and
hypoxia act at endothelial P2X4 and P2Y receptors to cause the release of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)
leading to vasorelaxation. Cell surface ectonucleotidase 59-triphosphohydrolases (ENTPDase) hydrolyze ATP, ADP, and UTP, whereas ecto-59nucleotidase (CD73) further hydrolyzes AMP to adenosine, which acts at endothelial and smooth muscle A2A and A2B receptors to elicit vasorelaxation.
(LeRoy et al., 1984). Increased shear stress leads to
release of ATP and endothelin (ET) from freshly isolated endothelial cells from 12-month, but not from
4-month-old rabbits (Milner et al., 1992). UTP and UDP
can also be released from endothelial cells of rabbit
thoracic aorta in response to shear stress (Saïag et al.,
1995). It has been reported that polyphenolic compounds contained in red wine induce release of ATP,
ADP, and UTP from endothelial cells in rat isolated
aorta to activate P2Y1 and P2Y2 receptors, leading to
vasodilation (Mendes et al., 2003).
The functional significance of ATP released from
endothelial cells by fluid shear stress is that it acts, via
P2 receptors, to permit local or spreading changes in
blood vessel contractility (vasodilatation) in response
to this stimulus. There is ATP-stimulated release of
ATP by human endothelial cells (Bodin and Burnstock,
1996), which would conduct the endothelial cells in a
coordinated response via paracrine signaling, via actions at endothelial P2Y and P2X4 receptors (discussed
in subsequent sections). ATP released from rat adrenomedullary endothelial cells after shear stress increases intracellular Ca2+ concentration Ca2+ and leads
to spread to neighboring cells of a Ca2+ wave (Hong
et al., 2006). The Ca2+ wave was blocked by suramin or
apyrase, which degrades extracellular ATP, suggesting
Fig. 5. Cellular sources of nucleotides and nucleosides relevant to the control of blood vessel contractility. In healthy blood vessels, vasoconstriction by
ATP released from sympathetic nerves and vasodilatation produced by purines and pyrimidines released from endothelial cells, myocytes, and
erythrocytes act in concert to regulate vascular tone. In healthy blood vessels, aggregating platelets release nucleotides that elicit endotheliumdependent vasodilatation. In vascular disease, platelets and white blood cells (WBC) adhere to the dysfunctional/damaged endothelium or the
underlying smooth muscle, and the released nucleotides may contribute to a shift in the balance toward vasoconstriction (as well as inducing vascular
remodeling).
Purinergic Signaling and Blood Vessels
111
Fig. 6. In blood vessels with a healthy endothelium, platelet aggregation is inhibited, but where there is endothelium damage or dysfunction, platelet
aggregation can occur, promoting smooth muscle constriction and proliferation. Activated platelets and endothelial cells release ATP, ADP, and UTP.
When the endothelium is healthy, these nucleotides act at endothelial P2Y receptors to release nitric oxide (NO) and endothelium-derived
hyperpolarizing factor (EDHF), leading to vasodilatation. Activation of endothelial P2Y receptors also leads to the release of prostacyclin (PGI2), which,
together with NO, inhibits platelet aggregation. Cell surface ectonucleotidase 59-triphosphohydrolases (ENTPDase) hydrolyze ATP, ADP, and UTP,
whereas ecto-59-nucleotidase (CD73) further hydrolyzes AMP to adenosine, which acts at platelet adenosine receptors to further inhibit aggregation.
Where there is endothelium damage or dysfunction, nucleotides released from platelets promote platelet aggregation via platelet P2Y1, P2Y12, and
P2X1 receptors. ATP, ADP, and UTP released from platelets may cause vascular smooth muscle constriction via P2Y and P2X1 receptors and smooth
muscle proliferation via P2Y receptors. Activation of smooth muscle P2X1 receptors may inhibit proliferation. Activation of endothelial P2Y2 receptors
increases endothelial expression of tissue factor (TF), a promoter of platelet aggregation. Activation of endothelial P2Y receptors can stimulate
secretion of endothelial von Willebrand factor, which would also lead to promotion of platelet aggregation.
that ATP released from endothelial cells is the mediator of the spreading Ca2+ responses of adjacent endothelial cells (Hong et al., 2006). The mechanism by
which ATP is released from endothelial cells is not fully
understood. Evidence that ATP release from endothelial cells during shear stress is vesicular was presented
(Bodin and Burnstock, 2001a). Later studies have suggested that connexin and pannexin 1 channels are also
involved in the mechanism of ATP release (Härtel and
Noll, 2011; Lohman et al., 2012a, 2012b). Localized
release of ATP from endothelial cells was blocked by
caveolin-1 knockdown with siRNA, and the released
ATP triggers Ca2+ waves at caveolae in vascular endothelial cells (Yamamoto et al., 2011).
Adenosine 59-tetraphosphate is a highly potent
purinergic endothelium-derived vasoconstrictor in human microvessels acting predominantly through activation of smooth muscle P2X1 receptors (Tölle et al.,
2008). Uridine adenosine tetraphosphate (Up4A) has
also been claimed to be an endothelium-derived vasoconstricting factor (EDCF) in cultured endothelial cells
from human dermal microvessels (Jankowski et al., 2005)
and rat pulmonary artery (Gui et al., 2008).
Extracellular levels of nucleotides are tightly regulated by the actions of ectonucleotidases. Early studies
of the hydrolysis of ATP by ATPases on endothelial
cells of pig aorta showed rapid breakdown to ADP and
AMP but delay before further breakdown by 59-nucleotidase to adenosine (Gordon et al., 1986). Ectonucleoside triphosphate diphosphohydrolase 1 (E-NTPDase
1/CD39) is expressed by vascular endothelial cells
(Robson et al., 1997; Banz et al., 2008) and is the major
member of the E-NTPase family involved in hydrolyzing extracellular nucleotides at the endothelial cell surface. Soluble forms of adenylate kinase 1 and NTPDase1
(CD39) contribute in the active cycling of circulating
nucleotides (Yegutkin et al., 2012). E-NTPDase 1/CD39
regulates P2Y1 and P2Y2 receptor-dependent vasorelaxation and in Entpd1 knockout mice (lacking E-NTPDase
1/CD39) aortic relaxations mediated by these receptors were augmented (Kauffenstein et al., 2010b). Conversely, increased E-NTPDase activity within human
umbilical vein endothelial cells (HUVECs) inhibited the
P2Y receptor-mediated endothelial response (secretion
of von Willebrand factor) and the extent of apoptosis
triggered by high concentrations of ATP (likely via P2X7
receptors) (Goepfert et al., 2000). Systemic administration of E-NTPDase 1/CD39 minimized injury-induced
platelet deposition and leukocyte recruitment and abrogated neointimal hyperplasia (Drosopoulos et al., 2010).
The authors suggest that human E-NTPDase 1/CD39
can play an active role in suppressing thrombotic, inflammatory, and proliferative cellular responses after vascular injury.
112
Burnstock and Ralevic
Ecto-59-nucleotidase (CD73) catalyzes the hydrolysis
of extracellular AMP to adenosine and is highly expressed on the vascular endothelium. Interferon-a is
an upregulator of ecto-59-nucleotidase leading to adenosine production in HUVECs (Niemelä et al., 2004).
Atorvastatin, a cholesterol-lowering drug acting through
inhibition of 3-hydroxy-3-methylglutaryl coenzyme A
reductase, has been shown to accelerate extracellular
nucleotide degradation in human endothelial cells,
which may have a protective role in the early steps of
endothelial dysfunction, which precedes the development of atherosclerosis (Osman et al., 2008). There is
a loss of ecto-59-nucleotidase from porcine endothelial
cells after exposure to human blood, which may have
implications in xenograft rejection (Khalpey et al.,
2005). Two opposite ATP-generating (involving ectoadenylate kinase) and ATP-consuming pathways have
been identified in human cell-free serum, the balance
controlling the duration and magnitude of purinergic
signaling in the blood (Yegutkin et al., 2003; Quillen
et al., 2006).
A number of in vivo studies have shown cardiovascular effects of purines that are likely to involve the
endothelium. In the absence of selective antagonists
that can be used in vivo, the receptor subtypes involved
in these responses is not entirely clear. ATP introduced
into dogs or rats in vivo induced hypotension (Fukunaga
et al., 1982; Boarini et al., 1984; Ribeiro and Lima, 1985;
Kien et al., 1987). ATP-MgCl2 introduced intravenously
into anesthetized horses reduced systemic and colonic
vascular resistance (Tetens et al., 2001a). Regional differences in effects of P2 receptor agonists were described
in renal, mesenteric, cerebral, and coronary vascular
beds in anesthetized rats (Cox and Smits, 1996). Intravenous injection of ATP or UTP in the anesthetized
mouse caused a decrease in systemic arterial pressure
via a cAMP pathway, but it was claimed that P2X1,
P2Y1, and P2Y4 receptors played little or no role in
these effects (Shah and Kadowitz, 2002). Conducted dilations initiated by purines in arterioles in hamster cheek
pouch are endothelium dependent and require endothelial Ca2+ (Duza and Sarelius, 2003).
In cat in vivo it was shown that a,b-meATP, a P2X
receptor agonist, had potent pressor activity in the
pulmonary circulation [100-fold more potent than angiotensin II (Ang-II)], whereas it had minor pressor
activity in the systemic bed (1000-fold less potent than
Ang-II) (Bivalacqua et al., 2002b). It is most likely that
these pressor effects are mediated by the contractile
actions of purines on the vascular smooth muscle.
However, there was a report that after block of NO
production, ATP released an EDCF; neither ET nor
superoxide contributed to this EDCF, but prostanoids
appeared to be involved (Dominiczak et al., 1991).
1. P2Y Receptors. Most blood vessels express on
their vascular endothelium P2Y1 receptors, activated
by ADP and ATP, and P2Y2 receptors, activated
equipotently by UTP and ATP. P2Y4 receptors, activated by UTP, and P2Y6 receptors, activated by UDP, are
also expressed on the endothelium of some blood
vessels (Wang et al., 2002). Early studies were carried
out on bovine aortic endothelial cells and showed
distinct effects of ADP and UTP/ATP consistent with
actions at different P2 receptors, then called P2Y and
P2U receptors; it is now known that these correspond
to P2Y1 receptors and P2Y2 and/or P2Y4 receptors,
respectively (Kitazono et al., 1992; Wilkinson et al.,
1993; Motte et al., 1995). Coexpression of P2Y1 receptors and P2Y2 and/or P2Y4 receptors on the endothelium of different blood vessels has now been widely
reported (see sections on individual blood vessels). However, only P2Y1 receptors were identified in rat brain
microvascular endothelial cells (Webb et al., 1996).
Occupation of purinergic receptors on endothelial
cells leads to an increase in [Ca2+]i triggering the corelease of NO, EDHF, and PGI2 (Van Coevorden and
Boeynaems, 1984; Lückhoff and Busse, 1986, 1990;
Robertson et al., 1990; Kelm et al., 1991; Marrelli,
2001; Wei et al., 2003). The generation of NO and
EDHF by endothelial P2Y1 and P2Y2 and/or P2Y4 receptors causes vasorelaxation (Malmsjö et al., 2000b;
You et al., 2005). The involvement of PGI2 in purinergic,
endothelium-dependent, vasorelaxation is variable and
appears to depend on both the vessel and the purine
receptor subtype. For example, indomethacin, a cyclooxygenase inhibitor, blocked vasorelaxation to UTP
(P2Y2/4 receptors) in canine epicardial coronary artery
(Matsumoto et al., 1997a), blocked relaxations to ADP
(P2Y1 receptor), but not those to UTP (P2Y2/4 receptors) in bovine aortic collateral artery rings (Wilkinson
et al., 1994), but had no effect on relaxations to
2-methylthio ADP (2-MeSADP) (P2Y1 receptor) in rat
thoracic aorta (Dol-Gleizes et al., 1999) or relaxations
to ADP, ATP, and UTP (P2Y1 and P2Y2/4 receptors) in
the rat mesenteric arterial bed (Ralevic and Burnstock,
1996c). Endothelial NO and PGI2 inhibit platelet aggregation. However, ATP and ADP can also stimulate
release of von Willebrand factor from cultured human
endothelial cells (Palmer et al., 1994; Vischer and
Wollheim, 1998), which may promote hemostasis. Moreover, activation of P2Y2 receptors in human coronary
artery endothelial cells has been shown to increase the
expression within the endothelial cells of tissue factor,
an initiator of the coagulation cascade (Ding et al.,
2011). Hence, the actions of purines at their endothelial
receptors include pro- and anticoagulant effects, in addition to the important direct effects of ADP and ATP in
stimulating platelet aggregation via platelet P2Y1,
P2Y12 and P2X1 receptors (Gachet, 2008; Hechler and
Gachet, 2011).
The initial rise in [Ca2+]i in response to ATP in
bovine cultured endothelial cells caused mobilization of
Ca2+ from intracellular stores (indicating that a P2Y
receptor was involved), which activated K+ channels,
Purinergic Signaling and Blood Vessels
thereby inducing hyperpolarization (Lückhoff and Busse,
1990). It has been shown that Ca2+ waves within endothelial cells are induced by ATP via P2Y (P2Y1), but not
P2U (P2Y2 and/or P2Y4), receptors in guinea pig aortic
strips (Ohata et al., 1997). ATP stimulates L-arginine
uptake and NO release from porcine aortic endothelial
cells (Bogle et al., 1991). The mechanism of ATPinduced NO release from endothelial cells may involve
Ca2+-activated Cl2 channels (Wei et al., 2003). AMPactivated protein kinase (AMPK) may also be involved.
AMPK plays a key role in the regulation of energy homeostasis and is activated by cellular stress, including
hypoxia/ischemia and hyperglycemia; the stress events
are accompanied by rapid release of ATP from damaged
tissues, endothelial cells, and platelets. ADP signaling
to bovine aortic endothelial cells via P2Y1 receptors
has shown that expression of AMPK and calcium/
calmodulin-dependent kinase kinase-b is necessary for
signaling to endothelial nitric oxide synthase (NOS)
and NO release (Hess et al., 2009). ATP, ADP, and
UTP (but not UDP) induced phosphorylation and activation of AMPK in HUVECs via P2Y1, P2Y2, and/or
P2Y4 receptors (da Silva et al., 2006). In aortic endothelial cells, ATP activation of P2Y receptors produces
a sustained activation of phospholipase D involving
protein kinase (PK) C (Pirotton et al., 1990; Purkiss
and Boarder, 1992). A more recent study has shown
that extracellular nucleotide-mediated NOS phosphorylation involving P2Y1, P2Y2, and possibly P2Y4 receptors is calcium- and PKCd-dependent, and it was
suggested that the signaling pathway may offer new
therapeutic avenues for the treatment of endothelial
dysfunction (Da Silva et al., 2009).
FAD is released from cells during inflammation and
protects against ischemia-reperfusion injury in rat
myocardium. FAD elicits endothelium-dependent vasodilation in rat perfused mesenteric beds by activation of P2Y receptors (Ralevic et al., 1995b), perhaps by
an endothelium-derived relaxing or hyperpolarizing
factor other than NO and PGI2 (Hashmi-Hill et al.,
2007). Functional P2Y receptors are present on murine
aortic endothelium, but endothelium-dependent purinergic relaxation declines after plaque development,
which involves decreased availability of NO (Korda
et al., 2005). Endothelium-dependent vasodilation is
reduced with advancing age, but ATP-mediated, in
contrast to acetylcholine (ACh)-induced vasodilatation
is not impaired with age in healthy humans (Kirby
et al., 2010). Acyl derivatives of coenzyme A were
shown to act as antagonists of ADP-mediated vasodilatation at endothelial P2Y1 receptors and were
selective versus vasodilatation mediated by UTP
acting at endothelial P2Y2 receptors; coenzyme As
may be released from cells during certain conditions
such as ischemia and diabetes, raising the possibility
that they act as novel endogenous regulators of
purineric signaling (Alefishat et al., 2013).
113
A trophic role for P2Y receptors was suggested when
it was proposed that the size of endothelial cells is
regulated by P2Y receptors (Tanaka et al., 2003, 2004).
A comparative study of P2Y receptor endotheliummediated responses of single endothelial cells from
bovine retina and HUVECs showed different patterns
of P2Y2 receptor desensitization and roles of growth
factors (Sanabria et al., 2008). It has been reported
that ATP-mediated endothelial cell barrier enhancement is associated with cytoskeletal activation and is
dependent on both Rac activation and cortactin (Jacobson
et al., 2006). Extracellular ATP causes activation of
myosin light chain phosphatase in endothelial cells,
which is involved in regulation of endothelial barrier
function (Härtel et al., 2007). b-NAD has been shown to
promote the barrier function of endothelial cells cultured from human pulmonary artery, and this involved
P2Y1 and P2Y11 receptors and PKA- and EPAC1/Rac1dependent actin cytoskeleton rearrangement (Umapathy
et al., 2010).
2. P2X Receptors. Although the presence of P2Y
receptors in vascular endothelial cells is well established, there have also been reports about the presence
of P2X receptors on the endothelium of a number of
blood vessels. P2X1, P2X4, and P2X7, as well as P2Y2,
receptors were identified using immunohistochemistry
on endothelial cells of the human internal mammary
artery, radial artery, and saphenous vein; P2X4 receptors were strongly expressed on saphenous vein compared with the arteries (Ray et al., 2002). In a study of
P2 receptor expression in human mammary arteries
and HUVECs, the P2X1 receptor was dominant in
smooth muscle, but P2X4, P2Y1, and P2Y11 receptors
were the most abundant receptors on the endothelium;
P2Y2 and P2Y6 receptors were also expressed at lower
levels on both smooth muscle and endothelial cells
(Wang et al., 2002). Another study of endothelial cell
cultures from human coronary and pulmonary arteries
and aorta, as well as HUVECs, showed that these
expressed P2X4 and P2X5 receptors (Schwiebert et al.,
2002). Evidence was presented to show that P2X4 and
P2X6 receptors located on HUVECs are restricted to
areas of cell-cell contact, and it was suggested that
these receptors were associated with VE-cadherin, a
marker for cell adhesion, at HUVEC adherens junctions (Glass et al., 2002). P2X4 receptor expression has
been shown in endothelial cells of guinea pig cochlear
spiral ligament capillaries (Wu et al., 2011). Based
on P2X receptor immunostaining, it was claimed that
P2X receptors (P2X1, P2X2, and P2X4 subtypes) were
present on the endothelium of rat mesenteric artery,
aorta, and middle cerebral and coronary arteries (Nori
et al., 1998; Hansen et al., 1999). Electron microscopic
immunolabeling showed P2X2 receptors localized on
endothelial cells in rat brain (Loesch and Burnstock,
2000). P2X3 receptors were shown to be localized on
endothelial cells in blood vessels of the rat thymus
114
Burnstock and Ralevic
(Glass et al., 2000). Endothelial cells in the rat thyroid
immunostained for P2X3, P2X4, and P2X7 receptors,
and it was suggested that this unusually rich expression of endothelial P2X receptors may reflect the constant dynamic changes in thyroid activities and the
special need for regulation of vascular tone in endothelial barrier formation (Glass and Burnstock, 2001).
Relatively little is known about the function of endothelial P2X receptors. The most comprehensive evidence exists for P2X4 receptors, identifying them as
mediators of vasodilatation acting as mechanostransducers of the response to ATP released from endothelial cells. It was shown that P2X4 receptor knockout
mice do not have normal endothelial responses to changes
in flow, with reduced dilation; the animals have higher
blood pressure and excrete smaller amounts of NO
(Yamamoto et al., 2006). It was further shown that
adaptive remodeling (decrease in vessel size in response to a decrease in blood flow) was also decreased.
It was suggested that hypertension in the P2X4 receptor knockouts may have been caused by the removal
of ATP-induced vasodilatation involving P2X4 receptors and NO and by removal of the negative influence
of NO on smooth muscle proliferation (Yamamoto
et al., 2006). P2X4 receptors were claimed to mediate
the ATP-induced vasodilatation of guinea pig cochlear
spiral ligament (Wu et al., 2011). P2X4 receptors were
shown, using antisense oligonucleotides designed to
knockout P2X4 expression, to mediate ATP-induced
Ca2+ influx in primary cultures of HUVECs (Yamamoto et al., 2000). However, a recent study measuring
ATP- and UTP-induced Ca2+ mobilization, membrane
hyperpolarization, and NO production in HUVECs
failed to find any evidence of functional P2X receptors
and concluded that P2Y2 receptors are the predominant isoform underlying these responses in HUVECs
(Raqeeb et al., 2011).
mRNA was shown to be expressed for P2X4, P2X5,
and P2X7 receptors on bovine aortic endothelium, and
whole-cell and outside-out patch electrophysiological
studies suggested that there are different roles for
these P2X receptor subtypes (Ramirez and Kunze,
2002). a,b-MeATP, presumably acting via P2X1 or P2X3
receptors, caused production of NO by microvascular
endothelial cells from rat cremaster muscle; unlike the
actions of 2-methylthio ATP (2-MeSATP) at coexpressed endothelial P2Y1 receptors, NO production by
a,b-meATP was unaffected by melatonin, indicating
distinct sites of action (Silva et al., 2007). It was reported that P2X1 receptors are expressed in the endothelium of rat mesenteric arteries and that their
activation leads to vasodilation largely via EDHF
(Harrington and Mitchell, 2004). Experiments with
P2X1 receptor knockout mice showed that endothelial
P2X1 receptors may mediate vasodilation of mesenteric
arteries, and it was suggested that this may be of
particular importance at the sites of inflammation or
vascular insult (Harrington et al., 2007). The more
widespread application of molecular biology techniques
is clearly needed to identify the possible roles of other
P2X subtypes in the endothelium.
When HUVECs were subjected to laminar shear
stress, P2X4 receptor mRNA levels began to decrease
within 1 hour and further decreased in time, reaching
60% at 24 hours (Korenaga et al., 2001). HUVEC
expression of P2X4 and P2X7 receptors was upregulated under inflammatory conditions (Wilson et al.,
2007); activation of the P2X7 receptors resulted in
release of both pro- and anti-inflammatory interleukin
(IL)-1 receptor ligands, the balance of which may provide a means for altering the inflammatory state of the
vessel wall. Selective upregulation of P2X4 receptor
gene expression by interferon-g in endothelial cells of
human umbilical vein and aorta and microvascular
endothelial cells has been reported (Tang et al., 2008).
The density of expression of the P2X4 receptor on
endothelial cells in rabbit aorta was increased by
approximately 10-fold after balloon injury, resulting in
intima proliferation (Pulvirenti et al., 2000). Expression levels of P2X4 were significantly higher in endothelium of the human saphenous vein than in the radial
and internal mammary arteries, and given that P2X4
modulates vascular contractility and is upregulated in
situations involving intima proliferation, it was suggested that vein grafts used in coronary bypass surgery
are more susceptible to developing atherosclerosis (Ray
et al., 2002). Stimulation of P2X7 receptors on bovine
pulmonary artery endothelial cells enhances lipopolysaccharide (LPS)-induced apoptosis via caspase-8 activation (Sylte et al., 2005).
3. P1 (Adenosine) Receptors. There is a review of
the early literature describing the role of adenosine in
local regulation of blood flow after its release during
hypoxia or ischemia (Berne et al., 1983). One role for
adenosine is to inhibit the release of sympathetic neurotransmitters via prejunctional receptors (Sollevi and
Fredholm, 1983); another is to dilate vessels via the
endothelium and smooth muscle (Sparks and Gorman,
1987; Collis, 1989; Tabrizchi and Bedi, 2001). These
actions of adenosine would lead to an increase in blood
flow to the hypoxic or ischemic tissue. All four subtypes
of P1 adenosine receptors, A1, A2A, A2B, and A3, have
been identified on the vascular endothelium (and smooth
muscle), with A2A and A2B receptors being most commonly expressed.
There was early evidence of the functional expression of P1 (adenosine) receptors in endothelial cells.
Removal of the endothelium decreased relaxation of
canine coronary arteries to adenosine (Rubanyi and
Vanhoutte, 1985). The vasodilator effect of adenosine
in rat aorta was similarly shown to be partly endothelium dependent (Yen et al., 1988). Endothelial release of NO was claimed to contribute to the vasodilator
effect of adenosine in humans (Smits et al., 1995) and
Purinergic Signaling and Blood Vessels
in human iliac artery (Li et al., 1998) and pig carotid
artery (Li et al., 1995). A2 receptors were identified on
cultures of guinea pig coronary endothelial cells (Nees
et al., 1987), bovine pulmonary artery endothelial cells
(Legrand et al., 1989), and rat renal artery endothelial
cells (Martin and Potts, 1994). The adenosine receptor
on guinea pig microvascular coronary endothelial cells
was identified as the A2A subtype (Schiele and Schwabe,
1994). Both A2A and A2B receptors were described on
human aortic endothelial cells (Iwamoto et al., 1994).
A2A and A2B receptors were also shown to be present on
porcine coronary artery endothelial cells (Olanrewaju
et al., 2000). An A1 receptor on bovine pulmonary artery
endothelial cells was shown to mediate Cl2 efflux
(Arima et al., 1994), and an A1 receptor was shown to
mediate release of NO from the endothelium of rat
aorta (Ray and Marshall, 2006). An A3 receptor was
shown to mediate endothelium-dependent contractions
in mouse aorta; contractions to an A3 selective agonist
were abolished by endothelium removal, were absent
in A3 receptor knockout mice, and appeared to involve
cyclooxygenase-1 (Ansari et al., 2007b).
Analysis of the mechanisms underlying adenosineevoked release of NO from rat aortic endothelium suggested that A1 receptor-mediated NO release requires
extracellular Ca2+, phospholipase A2, and ATP-sensitive
K+ channels, whereas A2A receptor-mediated NO release requires extracellular Ca2+ and Ca2+-activated K+
channels (Ray and Marshall, 2006). Cyclic nucleotidegated channels are claimed to play a key role in A2B
receptor-induced endothelial Ca2+ influx in vasorelaxation
of mouse aorta strips (Cheng et al., 2008).
In addition to a role of adenosine in hypoxic vasodilatation there is evidence that adenosine may promote angiogenesis during ischemia/hypoxia, with the
new blood vessels helping to maintain tissue oxygenation (see Auchampach, 2007; see also section IV). A2B
receptors on human microvascular endothelial cells
modulate expression of angiogenic factors (Feoktistov
et al., 2002). Activation of A2B receptors on human and
bovine retinal endothelial cells increases vascular endothelial growth factor (VEGF) production and cell proliferation, and A2B receptors may be involved in hypoxic
induction of VEGF (Takagi et al., 1996; Grant et al.,
1999). Given this important role of A2B receptors, it
seems fitting that hypoxia modulates adenosine receptor expression in human endothelial cells by shifting
expression of A2A receptors to A2B receptors (Feoktistov
et al., 2003). Differences between human micro- and macrovessel endothelial cell responses to adenosine receptors and b-adrenoceptors in hypoxia have been reported
(Wiktorowska-Owczarek et al., 2007).
It has been suggested that adenosine may exert
anticoagulant activity on vascular endothelial cells via
A2A and A3 receptors by downregulating endothelial
cell tissue factor expression, particularly during ischemic and atherosclerotic processes, known to be associated
115
with increased purine levels (Deguchi et al., 1998). It
has also been suggested that cytokines modulate the
expression of A2A and A2B receptors in human microvascular endothelial cells (Khoa et al., 2003). Regulation of Ang-II-induced reactive oxygen species (ROS)
production and redox-signaling by A2A receptors on
endothelial cells has been reported; inhibition of A2A
receptors protects endothelial cells from acute Ang-IIinduced oxidative stress and endothelium dysfunction
(Thakur et al., 2010). Adherent leukocytes prevent
adenosine formation and consequently impair endothelial barrier function by an ecto 59-nucleotidase
(CD73)-dependent mechanism (Henttinen et al., 2003).
Adenosine has been shown to have important vasoactive effects in vivo, some of which appear to involve
the endothelium. Adenosine introduced into artificially
ventilated dogs caused a profound decrease in systemic
vascular resistance (Lagerkranser et al., 1984). NO
participates in the hypotensive effect induced by A2
receptor stimulation in anesthetized rats (Stella et al.,
1995). Femoral vasodilation induced by intra-arterial
adenosine in rabbits was mediated by A1 and A2 receptors (Sakai et al., 1998). A3 receptors mediate hypotension in the pithed rat (Fozard and Carruthers, 1993),
but this was later shown to be due to activation of A3
receptors on mast cells, leading to mast cell degranulation (Hannon et al., 1995; Fozard et al., 1996). Intravenous infusion of adenosine or a selective A2A receptor
agonist in conscious mice lacking endothelial NOS
(knockouts for eNOS) produced a reduction in mean
arterial blood pressure (Andersen et al., 2011). Intravenous injection of uridine in conscious rats decreases
arterial pressure by activating A1 receptors (Yilmaz
et al., 2008).
A recent report claims that adenosine is a major
regulator of endothelial progenitor cells (Devaux et al.,
2012). Adenosine upregulates the chemokine receptor
CXCR4 and stimulates their recruitment in the infarcted heart and enhances repair. Another group has
identified A2A and A3 receptors as mediators of human
endothelial progenitor cell migration (Fernandez et al.,
2012).
There have been reviews concerned with purinergic
signaling in endothelial cells over the years (Nees and
Gerlach, 1983; Pearson and Gordon, 1985; Boeynaems
and Pearson, 1990; Boeynaems et al., 1990; Pirotton
et al., 1993; Adair, 2005; Burnstock, 2008a).
A schematic is shown in Fig. 7, which illustrates the
receptors involved in the dual control of vascular tone.
III. Purinergic Signaling in Different Vessels
The distribution of purinoceptor subtypes on both
smooth muscle and endothelial cells mediating vasoconstriction and vasodilation in different vessels in the
body are summarized in Tables 2 and 3.
116
Burnstock and Ralevic
A. Aorta
The aorta has been the target vessel of many studies
of purinergic signaling following the original discovery
of EDRF in this vessel (Furchgot and Zawadzki, 1980).
Studies carried out in the aorta have contributed to our
understanding of endothelial P2 receptors, of the role
of the endothelium as a source of purines, which can be
released by various stimuli including hypoxia and
shear stress, as well as the role of the endothelium in
regulating extracellular levels of purines through the
actions of cell surface ectonucleotidases.
ATP was shown to be released from endothelial cells,
as well as nerves, after transmural stimulation and in
response to methoxamine (a-adrenoceptor agonist) in
the rabbit aorta (Sedaa et al., 1990). Hypotonic stress
induces ATP release from bovine aortic endothelial
cells, and this may involve the volume-regulated anion
channel, a nucleotide-permeable channel (Hisadome
et al., 2002). Polyphenolic compounds contained in red
wine may also induce release of ATP, ADP, and UTP
from endothelial cells in rat isolated aorta to activate
P2Y1 and P2Y2 receptors, leading to vasodilation (Mendes
et al., 2003). Extracellular levels of purines are tightly
regulated by ATP-dephosphohydrolase (apyrase), localized in both intima and media of bovine aorta (Côte
et al., 1991, 1992), and by E-NTPDase 1/CD39, also
localized on both the endothelium and smooth muscle.
E-NTPDase 1/CD39 was shown to be the major ectoenzyme regulating nucleotide metabolism at the surface of mouse aortic smooth muscle (Kauffenstein et al.,
2010a). Gadolinium, which blocks stretch-activated
calcium channels, blocked ATP and ADP hydrolysis by
ectonucleotidases and thereby increased vascular reactivity of rat aortic rings (Angeli et al., 2011). After
release from endothelial cells, purines can act on P2
receptors on the same or adjacent endothelial cells in an
Fig. 7. Schematic diagram illustrating the main receptor subtypes for purines and pyrimidines present in blood vessels involved in control of vascular
tone. ATP is released as a cotransmitter with NA and NPY from sympathetic nerves in the adventitia to act at smooth muscle P2X1 receptors and, in
some vessels, P2X2, P2X4, P2Y1, P2Y2, and P2Y6 receptors, resulting in vasoconstriction (and rarely vasodilation); ATP is released with calcitonin generelated peptide (CGRP) and substance P (SP) from sensory-motor nerves during “axon reflex” activity to act on smooth muscle P2Y receptors, resulting
in either vasodilatation or vasoconstriction. P1 (A1) receptors on nerve terminals of sympathetic and sensory nerves mediate adenosine (arising from
ectoenzymatic breakdown of ATP) modulation of transmitter release. P2X2/3 receptors are present on a subpopulation of sensory nerve terminals.
P1 (A2) receptors on vascular smooth muscle mediate vasodilatation. Endothelial cells release ATP and UTP during shear stress and hypoxia to act on
P2Y1, P2Y2, and sometimes P2Y4, P2Y11, P2X1, P2X2, P2X3, and P2X4 receptors, leading to the production of nitric oxide (NO) and subsequent
vasodilatation. Adenosine tetraphosphate (AP4) activates P2X1 receptors to excite smooth muscle. ATP, after its release from aggregating platelets,
also acts, together with its breakdown product ADP, on these endothelial receptors. Blood-borne platelets possess P2Y1 and P2Y12 ADP-selective
receptors as well as P2X1 receptors. Immune cells of various kinds possess P2X7 as well as P1, P2X1, P2Y1, and P2Y2 receptors. ATP released from red
blood cells, which express P2X7 and P2Y13 receptors, is also involved in some circumstances. The additional involvements of uridine adenosine
tetraphosphate (Up4A) are indicated. (Figure is modified from Burnstock, 1996b, with permission from Blackwell Science Ltd, UK).
117
Purinergic Signaling and Blood Vessels
TABLE 2
Summary of the P1 receptors on smooth muscle and endothelial cells mediating vasoconstriction (+) and vasodilatation (2) in different vessels
and species
Smooth Muscle
Endothelial Cells
Vessel
R
Aorta
References
R
+
Stoggall and Shaw, 1990
A1 (rat)
2
A2 (rat)
2
A1 (SHR)
+
A2B (guinea pig)
P1 (frog)
2
2
Grbovic and Radenkovic,
2003
Balwierczak et al., 1991
Martin, 1992; Martin
et al., 1993; Fozard
et al., 2003
Knight and Burnstock, 1996
A1 (mouse)
A2A (rat)
+
2
Prentice et al., 2001
Lewis et al., 1994; Prentice and
Hourani, 1996
A2A (mouse)
2
A2A (hamster)
A2B (rat)
A2B (mouse)
2
2
2
A3 (mouse)
+
P1 (A1/A2A)
P1 (rabbit)
2
2
A2A
2
Ponnoth et al., 2009 (see also
Prentice et al., 2002)
Prentice and Hourani, 2000
Prentice and Hourani, 1996
Talukder et al., 2003; Ansari et al.,
2007a (see also
Prentice et al., 2002)
Ansari et al., 2007b; El-Awady
et al., 2011
Ke˛ dzior et al., 2009
Kennedy and Burnstock, 1985a;
Headrick et al., 1992
Hiley et al., 1995
A1 (guinea pig)
A2A (porcine)
A2A (guinea pig)
2
2
2
Rubio and Ceballos, 2003
Hasan et al., 2000
Rubio and Ceballos, 2003
A3 (guinea pig)
P1 (rat)
A2A (rat)
A2B (rat)
2
2
2
2
Rubio and Ceballos, 2003
Lynch et al., 2006
Coney and Marshall, 1998
Shin et al., 2000b; Ngai et al., 2001
P1 (human)
A1 (rat)
A2 (rat)
A2 (young rabbit)
2
2
2
2
Mortensen et al., 2009c
Danialou et al., 1997
Abiru et al., 1995
Steinhorn et al., 1994
A2A (rat)
A2A (rat)a
A2A (rabbit)
2
2
2
Grbovic et al., 2000
Carroll et al., 2006
Prior et al., 1999
A2B (human)
+
Donoso et al., 2005
Rat Tail Artery
Ear Artery
P1 (rabbit)
2
Mesenteric artery
A2A (rat)
2
A2B (rat)
2
A1 (porcine)
A2A (human)
A2A (porcine)
2
2
2
A2B (human)
A2B (porcine)
A2A (rat)
2
2
2
A2 (dog)
A2 (rabbit)
A1 (cat)a
2
2
+
A1 (guinea pig)
+
A2B (guinea pig)
A2 (rabbit)
2
2
A2 (cat)
2
De Mey and Vanhoutte, 1981
Cassis et al., 1987
Neely et al., 1991; Cheng
et al., 1996
Wiklund et al., 1987;
Szentmiklósi et al., 1995
Szentmiklósi et al., 1995
Steinhorn et al., 1994; El-Kashef
et al., 1999)
Cheng et al., 1996
A1 (mouse)
A1 (rabbit)a
A2 (rat)a
A2B (human)
A3 (human)
+
+
2
+
2
Hansen et al., 2003, 2007
Weihprecht et al., 1992
Telang et al., 2003
Donoso et al., 2005
Donoso et al., 2005
Coronary Vessels
Cerebral Vessels
Skeletal Muscle
Femoral artery
Pulmonary Vessels
Renal artery
Afferent arteriole
Arcuate artery
Hepatic Portal Vein
Chorionic artery
and vein
References
A1 (guinea pig)a
Kennedy and Burnstock,
1985a; Headrick et al., 1992
Hiley et al., 1995; Radenkovic
et al., 2005
Rubino et al., 1995; Prentice
et al., 1997
Merkel et al., 1992
Sato et al., 2005
Arif Hasan et al., 2000; Teng
et al., 2005; Rayment
et al., 2007b
Kemp and Cocks, 1999
Teng et al., 2005
Ngai and Winn, 1993;
Coney and Marshall, 1998;
Shin et al., 2000a
Nakhostine and Lamontagne,
1993; Ray et al., 2002
Fahim and Mustafa, 2001
R, response.
a
Effects of endothelium removal not investigated.
auto- and paracrine manner. Purines released locally
from erythrocytes or platelets can also regulate aortic
function via endothelial purine receptors.
Early articles reported that ATP relaxed porcine isolated aorta, provided the endothelial cells were present
(Gordon and Martin, 1982). Endothelium-dependent
relaxation of porcine aorta by ATP was shown to be mimicked by ADP, but AMP and adenosine were approximately 120 times less potent (Gordon and Martin, 1983).
2-MeSATP was shown to be 50 times more potent than
ATP, whereas UTP was 100 times less potent in relaxing the isolated aorta of newborn pig (Martin et al.,
1985), suggesting in retrospect that P2Y1, but not P2Y2
and/or P2Y4 receptors were involved. It was claimed
that ATP mediates endothelial PGI2 release via a P2Y
receptor in porcine aortic endothelial cells (Needham
et al., 1987). ADP also induced the release of PGI2 from
bovine cultured aortic endothelial cells (Van Coevorden
and Boeynaems, 1984). The first evidence that there
was more than one P2Y receptor subtype mediating
NO and PGI2 release from bovine aortic endothelial
cells (Motte et al., 1993) was followed by the proposal
that P2Y and P2U receptors were coexpressed on bovine aortic endothelial cells (Communi et al., 1995).
118
Burnstock and Ralevic
TABLE 3
Summary of the P2 receptors on smooth muscle and endothelial cells mediating vasoconstriction (+) and vasodilatation (2) in different vessels
and species
Note that the P2X1 receptor subtype identification in this table is based on agonist selectivity (usually a,b-meATP) and thus does not exclude the possible involvement of
other homomeric or heteromeric P2X receptors.
Smooth Muscle
Endothelial Cells
Vessel
Aorta
Receptor
R
References
P2X1 (rat)
P2X1 (mouse)
P2X1/5a
P2X5 (pig)b
P2Y1 (rabbit)
+
+
+
+
2
White et al., 1985; Li et al., 2011b
Bény, 2004
Sugihara et al., 2009
Chin and Chueh, 2000
Payne et al., 2002
P2Y2/4 (mouse)
P2Y6 (mouse)
+ Bény, 2004
+ Bar et al., 2008;
Kauffenstein et al., 2010a
Rat tail artery
P2X1
Ear artery
P2X4 (in early
development)
P2Y1
P2Y2/4
P2X1 (rabbit)
P2Y2/4 (rabbit)
P2Y (pig)
Mesenteric: artery P2X1 (rat)
P2X1 (rabbit)
P2X1 (guinea pig)
Coronary vessels
Cerebral vessels
R
(pig)
(rabbit)
(rat)
(guinea pig)
(mouse)
2
2
2
2
2
P2Y2/4 (rabbit)
P2Y4 (guinea pig)
2
2
P2Y2 (mouse)
2
P2Y2/4 (rat)
2
P2Y6 (mouse)
2
P2Y1
P2Y1
P2Y1
P2Y1
P2Y1
References
Martin et al., 1985
Payne et al., 2002
Dol-Gleizes et al., 1999
Kaiser and Buxton, 2002
Bény, 2004; Guns et al.,
2005, 2006; Kauffenstein
et al., 2010b; Payne
et al., 2002
Kaiser and Buxton, 2002
Bény, 2004; Guns et al.,
2005, 2006; Kauffenstein
et al., 2010b
Bültmann et al., 1997;
Dol-Gleizes et al., 1999
Guns et al., 2005, 2006;
Bar et al., 2008
+ Evans and Kennedy, 1994;
McLaren et al., 1998; Fukumitsu
et al., 1999; Wallace et al., 2006;
Li et al., 2011b
+ Wallace et al., 2006
+ Wallace et al., 2006
+ Saïag et al., 1990
+ O’Connor et al., 1990; Leff et al.,
1990; von Kügelgen and Starke,
1990a; Ziganshin et al., 1994;
Ren and Zhang, 2002
+ von Kügelgen et al., 1987
+ Rayment et al., 2007a
+ Ralevic and Burnstock, 1988, 1991; P2X1 (rat)
Ohara et al., 1998; Lewis et al.,
1998; Vial and Evans, 2002
+ Ren and Zhang, 2002
P2X1 (mouse)
+ Mutafova-Yambolieva et al., 2000
P2Y1 (rat)
P2X1 (hamster)
+ Ralevic and Burnstock, 1996b;
Thapaliya et al., 1999
P2Y2 (rat)
P2X1 (mouse)
+ Koltsova et al., 2009
P2Y2/4 (hamster)c
2 Mathieson and Burnstock, 1985;
Burnstock and Warland, 1987b;
+ Ralevic and Burnstock, 1991;
P2Y2 (rat)
Morris et al., 2011
P2Y6 (rat)
+ Malmsjö et al., 2000a
P2Y6 (mouse)
+ Vial and Evans, 2002;
Koltsova et al., 2009
P2X1
+ Mutafova-Yambolieva et al., 2000
P2Y1 (guinea pig)
+ Mutafova-Yambolieva et al., 2000
P2Y2/4 (rat)
+ Ohara et al., 1998
P2Y2/4 (guinea pig) + Mutafova-Yambolieva et al., 2000
P2X1 (human)
+ Malmsjö et al., 2000c
+ Matsumoto et al., 1997b
P2X1 (dog)
P2Y (rabbit)
Mesenteric vein
Receptor
P2Y2 (human)
P2Y2 (pig)
P2Y (rabbit)
P2Y (guinea pig)
P2X1 (human)
+
2
2
2
+
P2X1 (rat)
+ Lewis et al., 2000a; Malmsjö
et al., 2003b;
Dietrich et al., 2009
Malmsjö et al., 2000c
Rayment et al., 2007a
Keef et al., 1992
Keef et al., 1992
Malmsjö et al., 2003a
P2Y4 (rat)
P2Y1 (pig)
P2Y1 (rat)
P2Y2/4 (guinea pig)
P2Y (lamb)
P2Y1 (rat)
P2Y1 (rabbit)
2 Harrington and
Mitchell, 2004
2 Harrington et al., 2007
2 Ralevic and Burnstock,
1996c; Malmsjö et al.,
1998, 2000a; Buvinic
et al., 2002
2 Ralevic and Burnstock,
1996c; Malmsjö et al.,
1998, 2000a; Buvinic
et al., 2002
2 Ralevic and Burnstock,
1996b; Thapaliya
et al., 1999
2 Malmsjö et al., 2000a
2 Olivecrona et al., 2004
2 Vials and Burnstock,
1994b; Korchazhkina
et al., 1999; van der
Giet et al., 2002
Vials and Burnstock, 1993
2 Simonsen et al., 1997
2
2 Mayhan, 1992; You et al.,
1997; Horiuchi et al., 2003
2 Brayden, 1991
(continued )
119
Purinergic Signaling and Blood Vessels
TABLE 3—Continued
Smooth Muscle
Endothelial Cells
Vessel
Receptor
R
References
Receptor
+ Torregrosa et al., 1990a
P2Y2 (rat)
P2X (rabbit)
P2Y2 (rat)
P2Y2/4 (human)
P2Y2/4 (bovine)
2 You et al., 1997, 1999a;
Horiuchi et al., 2003
2 Hardebo et al., 1987b
2 Miyagi et al., 1996
P2Y6 (human)
2 Hardebo et al., 1987b
P2Y1 (rabbit)
P2Y2 (human)
2 Brayden, 1991
2 Rosenmeier et al., 2008;
Mortensen et al., 2009a
2 Koller et al., 1991
2 De Mey and Vanhoutte, 1981
2 Cassis et al., 1987
2 Liu et al., 1989; Hasséssian
and Burnstock, 1995;
Rubino et al., 1999
2 Qasabian et al., 1997
2 Greenberg et al., 1987;
Dinh Xuan et al., 1990
2 Rubino et al., 1999
Skeletal muscle
P2X1 (dog)
P2X (rabbit)
Femoral artery
P2X1 (rabbit)
+ Li et al., 2011b
P2Y2/4 (bovine)
P2Y2/4 (rabbit)
P2Y6 (human)
P2Y6 (rat)
Pulmonary vessels P2X1 (rat)
+ Rubino and Burnstock, 1996
+ Rubino and Burnstock, 1996
P2Y2/4 (rabbit)
P2Y (human)
P2Y (rabbit)
2 Qasabian et al., 1997
P2X1 (human)
P2X1 (rat)
+ von Kügelgen et al., 1995
+ Inscho et al., 1991, 1992, 2008;
Eltze and Ullrich, 1996; Knight
et al., 2003; Tölle et al., 2010
+ Vonend et al., 2005b
+ Weihprecht et al., 1992
+ Inscho et al., 1998;
Knight et al., 2003
+ Eltze and Ullrich, 1996
+ Vonend et al., 2005b
+ Brizzolara and Burnstock, 1991;
Mathie et al., 1991b;
Ralevic et al., 1991
2 Brizzolara and Burnstock, 1991
+ Kennedy and Burnstock, 1985b
+ Reilly et al., 1987;
Reilly and Burnstock, 1987
2 Kennedy and Burnstock, 1985b
+ Dobronyi et al., 1997;
Ralevic et al., 1997
+ Buvinic et al., 2006
+ Buvinic et al., 2006
UTP and
UDP inactive (rat)
P2Y1 (rat)d
P2Y2 (rat)d
P2Y6 (rat)
P2Y6 (mouse)
Hepatic artery/bed P2X1 (rabbit)
Placental vessels
P2Y (rabbit)
P2X1 (rabbit)
P2X1 (rat)
P2Y (rabbit)
P2X1 (human)
P2Y1 (human)
P2Y2/4 (human)
Intestinal vessels
P2X (cat)
P2X (guinea pig)
Skin vessels
P2X (human)
P2X1 (dog)
P2X1 (rat)
Carotid artery
+ Liu et al., 1989; McCormack
et al., 1989a; Li et al., 2011b
P2Y (rat)
P2Y (dog)
P2Y (rabbit)
P2Y1 (rat)
P2Y2/4 (rat)
P2Y6 (rat)
P2X1/3 (mouse)
P2X1 (rabbit)
P2Y2/4 (rat)
Portal vein
References
P2X1 (goat)
+ von Kügelgen and Starke, 1990b
+ Lewis et al., 2000a;
Malmsjö et al., 2003b
+ Miyagi et al., 1996
+ von Kügelgen and Starke, 1990b
+ Malmsjö et al., 2003a
+ Lewis et al., 2000a;
Malmsjö et al., 2003b
+ Buckwalter et al., 2003, 2004
+ Dézsi et al., 1990
Renal vessels
R
+ Taylor and Parsons, 1991
+ Evans and Surprenant, 1992;
Galligan et al., 1995
+ Martin et al., 1991
+ Okamura et al., 1999
+ Li et al., 2011b
2 Tölle et al., 2010
2 Tölle et al., 2010
2 Knight et al., 2003
No relaxation to
ATP, 2-MeSADP
and UTP in endotheliumintact renal artery
P2Y (rabbit)f
2 Mathie et al., 1991b
P2Y (rat)
2 Takemura et al., 1998
P2Y1 (human)e
2 Buvinic et al., 2006
e
P2Y2 (human)
No relaxation to
2-MeSADP and
UTP in
endothelium-intact
umbilical and
chorionic vessels
2 Buvinic et al., 2006
2 Buvinic et al., 2006
P2Y (dog)
2 Okamura et al., 1999
P2Y1 (rat)
P2Y2/4 (rat)
2 Malmsjö et al., 1998
2 Malmsjö et al., 1998
a
Patch clamp studies.
Measurement of changes in cytosolic calcium concentration.
Measurement of hyperpolarization.
d
Isolated perfused kidney (not renal artery).
e
Cotyledons (not umbilical cord and superficial chorionic vessels).
f
Hepatic bed (P2Y relaxations are endothelium-independent in hepatic artery).
b
c
The P2Y and P2U receptors involved were shown to be
pharmacologically similar to cloned P2Y1 and P2Y2
receptors, respectively (Hansmann et al., 1997). It is now
known that UTP activates P2Y4 receptors as well as
P2Y2 receptors (and is a weak agonist of P2Y6 receptors).
Hence, in the absence of selective antagonists, the
subtype identity of UTP-sensitive endothelial P2Y
receptors is not always apparent. Early studies showed
that there is a requirement for PKC in the stimulation
of PGI2 production by bovine aortic endothelial P2Y
(P2Y1) and P2U (P2Y2 and/or P2Y4) receptors (Patel et al.,
1996).
120
Burnstock and Ralevic
Different P2 receptors on endothelial cells mediating
vasodilation and on smooth muscle mediating vasoconstriction of rat aorta were described in 1985 (White
et al., 1985). Subsequent studies showed that vasorelaxant P2Y1, P2Y2/4, and more rarely P2Y6 receptors
are variously expressed on the endothelium in the
aortae of different species (Table 2). 2-MeSADP was
very effective in relaxing the rat thoracic aorta, indicating the presence of P2Y1 receptors, but not P2Y12
receptors (since the relaxant response was not affected
by clopidogrel); UTP also evoked relaxations, likely via
P2Y2 and/or P2Y4 receptors (Dol-Gleizes et al., 1999).
ADP and ATP-mediated endothelium-dependent relaxations in guinea pig aorta were inhibited by the P2Y1
receptor-selective antagonist MRS2179; UTP relaxations were insensitive to MRS2179 and UDP was inactive, suggesting an involvement of P2Y4 receptors (Kaiser
and Buxton, 2002). Ca2+ waves within endothelial cells
are induced by ATP, but not UTP, via P2Y receptors in
guinea pig aortic strips (Ohata et al., 1997), consistent
with a likely expression of P2Y1 and P2Y4 but not P2Y2
receptors in this vessel. In mouse thoracic aorta, P2Y1,
P2Y2, and P2Y6 receptors are present on endothelial
cells and mediate vasorelaxation (Bény, 2004; Guns
et al., 2005). In a study of mouse aorta, using P2Y2 knockout animals, it was concluded that ATP-evoked relaxation was mainly mediated by the P2Y2 receptor, but
that the vasodilator effect of UTP was probably mediated partly via a P2Y6 receptor because it was not
different in aortae from P2Y2- or P2Y4-knockout mice
(Guns et al., 2005, 2006). It was claimed that GTP and
guanosine 59-O-(3-thiotriphosphate) elicit endotheliumdependent relaxations in rat aorta via P2U (P2Y2 and/
or P2Y4) receptors (Bültmann et al., 1997).
Cold storage of rabbit thoracic aorta attenuates
P2Y2/4 receptor-mediated endothelium-dependent dilation, whereas P2Y1 receptor-mediated endotheliumindependent receptors were only partially reduced
(Payne et al., 2002). A decrease in ATP-induced
endothelium-dependent relaxation of thoracic aorta
in aging rats was reported (Ueda and Moritoki,
1991).
There is some evidence for endothelium-independent
purinergic vasorelaxations in aortae. In mouse freshly
isolated aortic smooth muscle cells, ATP activated a
delayed Ca2+-independent K+ current (this followed an
initial phase involving activation of Ca2+-dependent K+
and Cl2 currents), and it was suggested that this might
represent a novel vasorelaxant pathway in vascular
smooth muscle cells (Serir et al., 2006). Diadenosine
polyphosphates cause hyperpolarization and activate
a Ca2+ -dependent K + conductance in porcine aortic
smooth muscle, probably via P2Y receptors (Schlatter
et al., 2000).
ATP contracts the smooth muscle of rat aorta (White
et al., 1985), and in patch-clamp studies of rat cultured
aortic smooth muscle cells, it was shown that ATP
increased [Ca2+]i with subsequent activation of both
Ca2+-dependent K+ and Cl- currents (von der Weid
et al., 1993) and L-type and non–L-type Ca2+ channels
(Kitajima et al., 1993). ATP caused release of Ca2+ from
intracellular stores in pig cultured aortic smooth
muscle cells to increase [Ca2+]i, which activated Cl2
currents, leading to depolarization and contraction
(Droogmans et al., 1991). ATP can initiate Ca2+ waves
in pig cultured aortic smooth muscle cells (Mahoney
et al., 1993). ATP triggered cytosolic [Ca2+]i oscillations, accompanied with K+ and Cl2 oscillations, via
gap junctions in mouse freshly isolated aortic smooth
muscle cells (Fanchaouy et al., 2005). UTP was also
able to elicit oscillatory currents due to activation of Clchannels in rat aortic myocytes (Muraki et al., 1998).
P2Y receptor subtypes P2Y1, P2Y2, P2Y4, and P2Y6
evoke different Ca2+ signals in cultured rat aortic smooth
muscle cells (Govindan and Taylor, 2012).
In rat aorta, a,b-meATP was more potent than ATP
in eliciting vasoconstriction, and these responses were
antagonized by arylazido amino propyl-ATP, suggesting an involvement of P2X1 receptors (White et al.,
1985). Studies of isolated smooth muscle cells from the
rat aorta (as well as cerebral and mesenteric arteries)
indicated that the heteromeric P2X1/5 receptor, as well
as the P2X1 receptor, was functionally expressed (Sugihara
et al., 2009). P2X5 receptors on porcine aortic smooth
muscle cells were claimed to be responsible for ATPinduced Ca2+ influx (Chin and Chueh, 2000). Evidence
for both P2X receptors (mediating Ca2+ influx) and P2Y
(P2Y2 and/or P2Y4) receptors (mediating release of Ca2+
from intracellular stores) in rat aortic smooth muscle
was presented (Kitajima et al., 1994; Muraki et al.,
1998). Sauzeau et al. (2000) and Govindan et al. (2010)
claimed that rat aortic myocytes express P2Y1, P2Y2,
P2Y4, and P2Y6 receptors that are coupled to activation
of Rho and Rho kinase and consequent stimulation of
actin cytoskeleton reorganization. Northern blot analysis showed that rat aortic smooth muscle cells express
mRNA for P2Y1, P2Y2, and P2Y6 receptors (Bouchie
et al., 2000). It was suggested that during the course of
culturing rat aortic myocytes there was a loss of P2X
receptors, which were replaced by P2Y2 receptors (Pacaud
et al., 1995; Kumari et al., 2003). In a study of purine
receptors in mouse thoracic aorta, it was concluded
that, as in rat thoracic aorta, P2X and P2Y receptors
(sensitive to UTP) can mediate contraction of the smooth
muscle (Bény, 2004). H2O2-induced phasic contractions
of rat aorta involve, at least in part, activation of
smooth muscle P2 receptors (Shen et al., 2000).
NADP-induced contractions of mouse aorta appear
to be mediated by two P2X receptor populations, one
located on the endothelium and the other on smooth
muscle, both of which lead to contraction (Judkins
et al., 2006). Up4A, reported to be an endotheliumderived vasoconstrictor, caused a moderate endotheliumdependent relaxation of rat aortic rings contracted with
Purinergic Signaling and Blood Vessels
phenylephrine, but in preparations that had not been
preconstricted caused contraction that was potentiated
by endothelium removal or NOS inhibition and was
mediated by P1 and P2X receptor activation (Linder
et al., 2008). Hansen et al. (2010) claimed that Up4A
had biphasic effects on mouse aortic vascular smooth
muscle, but vasoconstriction dominated at low concentrations. In the same study it was shown further that,
in conscious rodents, step-up infusions of Up4A elicited
hypotension and electrolyte retention.
ATP stimulates release of matrix metalloproteinase-2
from human aortic smooth muscle. Matrix metalloproteinase2 degrades elastin and type IV collagen and has been
implicated in the development of abdominal aortic aneurysms (Robinson et al., 2006). Extracellular inorganic pyrophosphate (PPi) is a potent suppressor of
pathologic calcification in blood vessels. Ectonucleotide pyrophosphatase/phosphodiesterases generate
PPi via the hydrolysis of ATP released from rat cultured aortic smooth muscle (Prosdocimo et al., 2009).
Plasminogen activator inhibitor-1 (PAI-1) is the primary regulator of plasminogen activation, and elevated
levels shift the fibrolytic balance toward thrombosis.
Treatment of rat aortic vascular smooth muscle cells
with UTP increased PAI-1 mRNA expression and
extracellular PAI-1 protein levels by 21- and 7-fold,
respectively, whereas UDP stimulated a 5-fold increase
in PAI-1 mRNA expression, suggesting that P2Y2/4 and
P2Y6 receptors might be involved (Bouchie et al., 2000).
They showed further that ADP produced an inhibitory
effect, probably via P2Y1 receptors.
Nonadrenergic, noncholinergic (NANC) nerve vasodilation mediated by ATP in rat thoracic aorta has
been shown, which was blocked by capsaicin, suggesting that the ATP was released from sensory nerves
(Park et al., 2000). It was claimed that the ATP acted
on P2Y receptors on the endothelium to mediate vasodilatation via release of NO (Park et al., 2000), although
it is hard to see how ATP released from perivascular
nerves can reach the endothelial cells without being
inactivated during its passage through hundreds of
micrometers of smooth muscle and connective tissue. It
would rapidly be metabolized by ectonucleotidases present on the endothelium and vascular smooth muscle
(Côte et al., 1991, 1992; Kauffenstein et al., 2010a).
P1 (adenosine) receptors have been shown to be
present on rabbit aortic smooth muscle (Ghai and
Mustafa, 1982). In guinea pig aorta, both A1 and A2
receptor subtypes were identified (Stoggall and Shaw,
1990), with some evidence for the expression of A2B
receptors (Martin, 1992). A2 receptors are involved in
endothelium-dependent relaxation of rat thoracic aorta
(Moritoki et al., 1990; Rose’Meyer and Hope, 1990).
Later articles have identified adenosine A2A receptors
as the mediators of rat aortic endothelium-dependent
vasodilation (Lewis et al., 1994; Ray and Marshall,
2006; Nayeem et al., 2008), although A2B receptors
121
have also been implicated (Ansari et al., 2007a). A2A
receptor endothelium-dependent aortic relaxation was
significantly reduced in A2A receptor knockout mice
(Ponnoth et al., 2009). High-salt diet enhances mouse
aortic relaxation through A2A receptors (Nayeem et al.,
2009).
Endothelium-mediated contraction via A3 adenosine
receptors has been described in mouse aorta, probably
involving prostaglandins (Ansari et al., 2007b). Immunohistochemical studies of the localization of P1 receptor subtypes revealed differences in the localization
of A1, A2A, A2B, and A3 receptors in rat aorta (elastic)
and tail artery (muscular) (Leal et al., 2008).
B. Rat Tail Artery
Stimulation of sympathetic nerves supplying the rat
tail artery produced EJPs and a slow depolarization;
the slow depolarization was due to NA, whereas the
EJPs were not blocked by adrenoceptor antagonists
(Cheung, 1982). The EJPs were later shown to be due
to ATP released as a cotransmitter from sympathetic
nerves, because they were blocked by desensitization of
P2X receptors by a,b-meATP (Sneddon and Burnstock,
1984b; Neild and Kotecha, 1986). Suramin, a P2 receptor antagonist, was also shown to block the ATP component of sympathetic neurotransmission of the rat tail
artery (Bao and Stjärne, 1993). Coreleased NA and ATP
from sympathetic nerves supplying the rail artery have
synergistic postjunctional contractile actions on the
smooth muscle (Johnson et al., 2001; Johnson, 2010).
Prejunctional a2-adrenoceptors mediate autoinhibition of the release of both NA and ATP from sympathetic nerves supplying the rat tail artery (Bao et al.,
1991; Msghina et al., 1999), whereas prejunctional
b-adrenoceptors mediate facilitation of NA and ATP
release (Brock et al., 1997). Differential modulation of
NA and ATP release by a2-adrenoceptors has been reported (Brock and Tan, 2004). There is modulation of
NA release from sympathetic nerves in rat tail artery
by inhibitory P2Y1 and P2Y12 receptors and facilitatory
A2A receptors (Gonçalves and Queiroz, 1996; Fresco
et al., 2007; Quintas et al., 2009). ET-1 inhibited NA and
ATP release from sympathetic nerves in the rat tail
artery, whereas high concentrations of ET-3 potentiated
the release of both transmitters (Mutafova-Yambolieva
and Westfall, 1998). Ca2+ channel blockers reduced the
release of both NA and ATP from sympathetic nerves in
the rat tail artery (Brock and Cunnane, 1999).
a,b-MeATP had potent contractile actions on the smooth
muscle of the rat tail artery (Evans and Kennedy,
1994), suggesting that P2X1 and/or P2X3 receptors
were involved. Evidence that ATP acts at two sites to
evoke contraction of rat tail artery was presented,
i.e., P2X1 receptors and G protein–coupled P2Y receptors (McLaren et al., 1998; Fukumitsu et al., 1999).
Contraction of the smooth muscle of rat tail arteries
was induced by UTP as well as ATP (Saïag et al., 1990),
122
Burnstock and Ralevic
suggesting that P2Y2 and/or P2Y4 receptors were
present as were P2X receptors. Decentralization of the
sympathetic outflow to the rat tail artery led to hypersensitivity to a,b-meATP, and it was suggested that
the enhanced response of the tail artery after spinal
cord transection may contribute to the hypertensive
episodes of autonomic dysreflexia in spinally injured
patients (Yeoh et al., 2004).
The amplitude of purinergic EJPs and a-adrenoceptor-mediated depolarizations declined significantly
with age, the former to a greater degree than the latter
(Jobling and McLachlan, 1992b). Long-term supplementation with a high cholesterol diet decreases the
release of ATP from the tail artery of aged rats
(Hashimoto et al., 1998b). Both purinergic and adrenergic components are present in reinnervating sympathetic fibers after denervation of rat tail arteries
(Tripovic et al., 2011). The rat tail artery is important
for both balance and temperature control. In a study of
the changes in purinergic signaling in developing and
aging rat tail arteries (Wallace et al., 2006), it was
shown that functional (contractile) expression of P2X1,
P2Y1, and P2Y2 and some P2Y4 receptors on smooth
muscle appears postnatally but then decreases with
age. P2X4 immunoreactivity was seen on both muscle
and endothelial cells at 4–6 weeks, but not later in
development; P2Y1 receptors on endothelial cells also
decreased with age (Wallace et al., 2006). It was suggested that the presence of a large component of
purinergic vasoconstrictor control of vascular tone in
the tail artery, compared with mesenteric arteries, was
associated with the need for efficient thermoregulation
in young rats.
ATP and shear stress (known to release ATP from
endothelial cells, see Burnstock, 1999) release NO from
rat tail artery endothelial cells, resulting in vasodilatation (Kwon et al., 1999). Hypotonic stress increased
the [Ca2+]i and outflow of ATP from endothelial cells of
the rat tail artery, as well as increasing cell volume
(Shinozuka et al., 2001). It has been claimed that
stimulation of adrenoceptors on endothelial cells of the
rat tail artery leads to release of adenine nucleotides
(Hashimoto et al., 1997). Inhibition of an antispasmogenic response to hydralazine (a smooth muscle relaxant) in tail arteries by ATP and adenosine was
reported in 1981 (Chevillard et al., 1981). Adenosine,
acting via A 2A receptors, caused a concentrationdependent dilation of rat tail arteries precontracted
with NA (Manickavasagar et al., 2009). The contractile
responses of the rat tail artery to adenosine is probably
mediated by endogenous 5-hydroxytryptamine (5-HT)
(Brown and Collis, 1981).
C. Ear Artery
A seminal article showing release of ATP during
antidromic stimulation of sensory nerves to produce
vasodilatation of rabbit ear artery was published in
1951 (Holton and Perry, 1951; see Holton, 1959). The
first hint of sympathetic cotransmission to rabbit ear
artery came from experiments that showed that longterm denervation decreased both NA and ATP contents
of the artery (Head et al., 1977). The use of reserpine
and 6-hydroxydopamine (to deplete catecholamines
and damage sympathetic nerve endings, respectively)
produced supporting evidence for purinergic cotransmission in the rabbit ear artery (Saville and Burnstock,
1988). Short pulse bursts at low frequency (2–5 Hz)
favor the purinergic component of sympathetic nervous
control of rabbit ear artery, whereas higher frequencies
favor the adrenergic component (Kennedy et al., 1986).
Electrical field stimulation of the rabbit ear artery
produced release of NA and ATP in a ratio of 1:180, but
the ATP release was significantly reduced in endotheliumdenuded preparations (Ishii et al., 1996).
EJPs were also recorded in the smooth muscle of
guinea pig ear artery and phentolamine (a-adrenoceptor antagonist) enhanced their amplitude (Kajiwara
et al., 1981), perhaps indicating block of prejunctional
adrenoceptors that inhibit the release of ATP. A
combination of prazosin blockade of a1-adrenoceptors
and a,b-meATP desensitization of P2X receptors blocked
the constrictor responses of guinea pig ear artery to
sympathetic nerve stimulation (Morris, 1994). Regional
differences in sympathetic cotransmission in guinea
pig proximal and distal ear artery vessels were revealed, with the purinergic component greater in the
proximal compared with the distal segments (Morris
et al., 1998). It was suggested that these differences are
related to the responses to thermoregulatory stimuli,
which occur predominantly in the distal segments.
a,b-MeATP caused constriction of the rabbit perfused
ear artery via actions at P2X receptors, but vasodilatation was elicited by ATP, presumably via P2Y receptors
expressed on endothelial cells because they could be
blocked by reactive blue 2 (Taylor et al., 1989; Xie et al.,
1997). Although there is a lack of consensus about the
P2Y versus P2X selectivity of reactive blue 2, it
consistently does not block vasorelaxations to adenosine
(Reilly et al., 1987; Rump et al., 1998; Glänzel et al.,
2003). a,b-MeATP was the most potent agonist of a
series of analogs producing contractions of the rabbit
ear artery (O’Connor et al., 1990), suggesting that the
receptor involved is the P2X1 (or P2X3) subtype. The
responses to a,b-meATP were antagonized by the P2
selective antagonists suramin (Leff et al., 1990; von
Kügelgen and Starke, 1990a) and pyridoxalphosphate6-azophenyl-2’,4’-disulfonic acid (PPADS) (Ziganshin
et al., 1994). Ionophoretic application of ATP to single
smooth muscle cells dispersed from rabbit ear artery
induced cation conductance (Benham et al., 1987;
Benham, 1989). UTP, equipotent with ATP, produced
vasoconstriction of the rabbit ear artery (von Kügelgen
et al., 1987), indicating the presence of P2Y2 and/or
P2Y4 receptors on the smooth muscle.
Purinergic Signaling and Blood Vessels
ATP produces vasodilatation via P1 receptors located on both smooth muscle and endothelial cells and
vasoconstriction via P2 receptors on the smooth muscle
of the rabbit ear artery (Kennedy and Burnstock,
1985a). A significantly greater dilator response to adenosine applied luminally compared with that applied at
the adventitial surface in experiments with rabbit
perfused ear artery was reported (Headrick et al.,
1992). Adenosine inhibited nerve-mediated contractions
of both rabbit ear and mesenteric arteries; however, the
amplitude of EJPs was increased by adenosine in the
ear artery, but decreased in the mesenteric artery,
perhaps indicating postjunctional events in the ear
artery and prejunctional events in the mesenteric artery
(Zhang et al., 1989). CGRP, a neurotransmitter in
sensory-motor nerves, attenuated sympathetic vasoconstrictor cotransmission in the rabbit isolated ear artery,
and this involved a postjunctional mechanism (Maynard
et al., 1990). ET-1 enhances vasoconstrictor responses to
exogenously administered and neurally released ATP in
rabbit perfused ear arteries (La and Rand, 1993).
D. Mesenteric Vessels
1. Mesenteric Veins. EJPs have been recorded in
the dog mesenteric vein, and isoprenaline, acting prejunctionally, increased the amplitude of the EJP but
decreased the evoked released of NA (Seki et al., 1990),
suggesting that ATP may be released as a cotransmitter from sympathetic nerves. The different effects of
isoprenaline on the ATP and NA components of sympathetic neurotransmission is consistent with the suggestion that ATP and NA are nonuniformly stored in
different classes of vesicles within sympathetic varicosities (Dunn et al., 1999; Brock et al., 2000). The
purinergic component of sympathetic vasoconstriction
of guinea pig mesenteric veins was greater than that of
mesenteric arteries (Smyth et al., 2000). However,
release of ATP from sympathetic nerves in canine mesenteric vessels was equal in arteries and veins (Bobalova
and Mutafova-Yambolieva, 2001). In a study using the
perfused mesenteric bed of the rat, it was claimed that
although ATP elicited arterial constriction predominantly via P2X receptors, venous constriction was via
P2U (P2Y2 and/or P2Y4) receptors (Ohara et al., 1998).
It has been claimed that multiple P2Y receptors (P2Y1
and P2Y2/4) mediate contraction of the guinea pig mesenteric vein in addition to P2X1 receptors (MutafovaYambolieva et al., 2000). NTPDase activity has been
described in guinea pig mesenteric veins as well as
arteries (Duval et al., 2003). Modulation of transmitter
release from sympathetic nerves is mediated by prejunctional P2Y as well as P1 receptors in mesenteric
veins, in contrast to mesenteric arteries, where prejunctional modulation is mediated largely by P1 receptors (Talaia et al., 2011).
2. Mesenteric Arteries. In early studies, EJPs were
recorded in the dog mesenteric artery in response to
123
field stimulation, although these were considered
erroneously to be due to release of NA (Inoue et al.,
1983). Studies of rabbit and guinea pig mesenteric
arteries led to the conclusion that ATP was likely to be
responsible for the generation of EJPs and fast initial
transient contraction, whereas NA produced the later
sustained contraction (Ishikawa, 1985; Rhee and Wier,
2007). EJPs were shown to be blocked by a,b-meATP
desensitization of P2X receptors in guinea pig mesenteric artery (Angus et al., 1988; Nagao and Suzuki,
1988; Meehan et al., 1991). Corelease of NA and ATP
from sympathetic nerves supplying the rabbit and dog
mesenteric artery was reported (Illes and Nörenberg,
1987; Muramatsu, 1987). Bradykinin facilitates sympathetic purinergic neurotransmission of rat mesenteric arteries (Kansui et al., 2012).
An elegant study of purinergic signaling in small and
larger diameter hamster mesenteric arteries confirmed
that EJPs in response to nerve stimulation were mediated by P2X receptors (Thapaliya et al., 1999). They
also showed that ATP released from perivascular sympathetic nerves activated P2Y2 receptors on the endothelium of the small (but not larger) arteries to act via
EDHF. The relaxant action of ATP released by electrical field stimulation of rabbit small mesenteric arteries was similarly claimed to be partially endothelium
dependent, but was resistant to inhibition of NOS
(Kakuyama et al., 1998). An electrophysiological study
of the longitudinal smooth muscle of the chicken
anterior mesenteric artery showed that electrical field
stimulation produced excitatory membrane responses
mediated by ATP acting largely via P2Y receptors (Khalifa
et al., 2005).
b-NAD has been claimed to be a sympathetic cotransmitter in the canine mesenteric artery (Smyth et al.,
2006). N-type and P/Q-type calcium channels regulate
differentially the release of NA, ATP, and b-NAD from
sympathetic nerves supplying canine mesenteric blood
vessels; N-type channels are equally expressed by
arteries and veins, whereas P/Q-type channels are
more pronounced in veins (Smyth et al., 2009).
Prejunctional modulation of NA release from sympathetic nerves supplying rabbit and guinea pig mesenteric arteries by ATP and adenosine was reported
(Kuriyama and Makita, 1984; Lautt et al., 1988),
largely involving A1 receptors (Illes et al., 1988).
Prejunctional a2-adrenoceptor activation inhibits
sympathetic cotransmitter release from rabbit and
dog mesenteric arteries (Illes and Nörenberg, 1987;
Muramatsu et al., 1989). Prejunctional a2-adrenoceptors
inhibit ATP release during low-frequency, brief duration sympathetic nerve stimulation in guinea pig mesenteric artery (Mutafova-Yambolieva and Keef, 2001).
Exogenous and locally generated Ang-II enhanced the
purinergic component of sympathetic neurotransmission in the guinea pig mesenteric artery (Onaka et al.,
1997).
124
Burnstock and Ralevic
Pressure is an important determinant of the size of
the purinergic component of the response to sympathetic neurotransmission, and it has been shown that
ATP is the predominant sympathetic neurotransmitter
in rat mesenteric arteries at physiologic pressure; at
low pressure the ATP component was significantly
reduced (Rummery et al., 2007). An important implication is that the purinergic component of sympathetic
neurotransmission may have been underestimated in
experimental studies in which the pressure has been
kept relatively low. Low- and high-frequency stimulation of sympathetic nerves in rat mesenteric arteries
favors the purinergic and noradrenergic components
respectively (Sjöblom-Widfeldt and Nilsson, 1990;
Lamont and Wier, 2002). Nerve-evoked P2X1 receptormediated contractions dominated in rat small and
medium sized mesenteric arteries, whereas the noradrenergic component dominated in large (first order)
mesenteric arteries (Gitterman and Evans, 2001). Spontaneous release of ATP and NA from sympathetic
nerve terminals in rat mesenteric arteries appears to
be from different vesicles (Brock et al., 2000). It was
claimed recently that breast feeding increases the
contractile response of rat mesenteric arteries to sympathetic nerve stimulation, due mainly to increased
release of the cotransmitter ATP (Blanco-Rivero et al.,
2013).
The main P2 receptor mediating EJPs and contractile responses to ATP is the P2X1 receptor expressed on
the vascular smooth muscle. RT-PCR studies of P2X
purinoceptor mRNA expression in rat mesenteric artery showed strong expression of P2X1 and P2X4 receptors, less of P2X7, and only weak expression of P2X2,
P2X3, and P2X5 receptors (Phillips and Hill, 1999).
Immunohistochemical studies showed a dominance of
P2X1 receptors on rat mesenteric arterial smooth muscle but also some expression of P2X4 and P2X5 receptor
proteins in small and medium-sized arteries (Gitterman and Evans, 2000). The dominance of P2X1 receptors in mediating currents in smooth muscle cells of the
rat mesenteric artery was confirmed, and no evidence
for an involvement of P2X4, P2X5, or P2X1/5 receptors
was found (Lewis and Evans, 2000). 2’,39-O-(2,4,6Trinitrophenyl)-ATP blocked the responses of rat mesenteric arteries to a,b-meATP (Lewis et al., 1998), whereas
in mouse mesenteric arteries, the contractile response
to a,b-meATP was blocked by the P2X 1 receptorantagonist NF023 (1,3,5-trisodium 8-{[3-({[3-({4,6,8tris[(sodiooxy)sulfonyl]naphthalen-1-yl}carbamoyl)phenyl]carbamoyl}amino)benzene]amido}naphthalene1,3,5-trisulfonate) (Koltsova et al., 2009), suggesting that
P2X1 receptors were involved. Studies with P2X1 receptor knockout mice established that P2X1 and P2Y6-like
receptors mediate sympathetic neurogenic vasoconstriction of mouse mesenteric arteries (Vial and Evans, 2002).
A spliced isoform of the P2X1 receptor, P2X1a, was cloned
from rat mesenteric arteries (Ohkubo et al., 2000).
Contractile P2Y receptors (P2Y2 and P2Y6) are coexpressed with P2X receptors on the mesenteric arterial
smooth muscle. Both ATP and UTP increase [Ca2+]i in
smooth muscle cells of rat small mesenteric arteries
(Juul et al., 1992). Low concentrations of ATP were shown
to activate P2X receptors, whereas high concentrations
additionally activated P2Y receptors (Lagaud et al.,
1996). Contractile responses to UTP, mediated by P2Y2
receptors, were significantly more potent in small compared with medium and larger rat mesenteric arteries
(Gitterman and Evans, 2000). Contractile responses of
the smooth muscle of the rat mesenteric artery were
elicited by stimulation of P2Y6 as well as P2X1
receptors (Malmsjö et al., 2000a). Similarly, in mouse
mesenteric arteries, there was evidence for contractile
responses mediated by both P2Y6 and P2X1 receptors,
because responses to UTP and UDP were reduced by
a selective P2Y6 antagonist, and a contractile response
to a,b-meATP was blocked by the P2X1 receptor antagonist NF023 (Koltsova et al., 2009). G protein–
coupled receptor kinase 2 and arrestin-2 regulate UTPstimulated P2Y2 receptors mediating constriction of
rat mesenteric artery smooth muscle (Morris et al.,
2011). Whole-cell voltage clamp studies of guinea pig
mesenteric terminal arterioles have suggested that
ATP activation of Ca2+ currents was mediated by P2Y1and P2Y11-like receptors (Morita et al., 2002).
In the developing rat mesenteric artery, contractile
responses to UTP were greatest at 4–6 weeks postnatal
and then declined (Wallace et al., 2006). In rat mesenteric arteries, ATP-induced contraction decreased
with age (Konishi et al., 1999). Excitatory innervation
of the longitudinal smooth muscle of the chicken
anterior mesenteric artery develops during the early
postnatal period; cholinergic excitatory neurotransmission precedes purinergic neurotransmission, although
purinoceptors are already expressed in the smooth muscle (Alkayed et al., 2011).
An early study showed that ATP dilated the rabbit
perfused mesenteric artery (Krishnamurty and Kadowitz, 1983). In this vessel, ATP acts on purinergic receptors on smooth muscle to produce contraction via P2X
receptors and additionally endothelium-independent
relaxation via P2Y receptors (Mathieson and Burnstock, 1985; Burnstock and Warland, 1987b). Striking
evidence for species differences between rabbit and rat
mesenteric arterial purinergic signaling was presented
in later studies, with the observation that ATP relaxation of rat mesenteric arteries was elicited largely via
the endothelium (Vuorinen et al., 1992). Similarly, hyperpolarizations to ATP in hamster mesenteric arteries
were endothelium dependent (Thapaliya et al., 1999),
as were relaxations to ATP, ADP, and UTP in the hamster mesenteric arterial bed (Ralevic and Burnstock,
1996b).
ATP and UTP both elicit endothelium-dependent
vasodilation of rat mesenteric arteries; the ATP effects
Purinergic Signaling and Blood Vessels
are via P2Y1 receptors and release of NO and EDHF,
whereas the UTP effects are via P2U (P2Y2 and/or
P2Y4) receptors by a non-NO mechanism, perhaps
involving EDHF (Malmsjö et al., 1998, 1999b). Subsequent studies showed that endothelium-dependent
relaxation of the rat mesenteric artery was mediated
by P2Y1, P2Y2, and P2Y4 (but not P2Y6) receptors
(Malmsjö et al., 2000a). Direct luminal perfusion of
ATP and UTP in rat small mesenteric arteries leads to
spreading dilatation via P2Y receptor activation of
EDHF (Winter and Dora, 2007). Luminal application of
the P2Y1 receptor agonists ADP and ADPbS to rat
pressurized small mesenteric arteries induced EDHFtype dilatations and endothelial cell Ca2+ increases,
which rapidly desensitize by mechanisms involving
PKC (Rodríguez-Rodríguez et al., 2009). In contrast, in
hamster mesenteric arteries only ATP and UTP, but
not 2-MeSATP (P2Y1 receptor agonist), elicited endothelial cell hyperpolarization, suggesting an involvement
of P2Y2 receptors (Thapaliya et al., 1999). Diadenosine
pentaphosphate, Ap5A, caused constriction of rat small
mesenteric arteries via P2X1 receptors and vasodilation via P2Y1 receptors (Steinmetz et al., 2000; Lewis
et al., 2000b).
It has been claimed that P2X1 receptors on the
endothelium of rat mesenteric arteries mediate vasodilation, which is unaffected by the NOS inhibitor
G
L-N -nitroarginine methyl ester or the prostaglandin
inhibitor indomethacin (Harrington and Mitchell, 2004).
Vasorelaxant P2X1 receptors mediating endotheliumdependent vasorelaxation to ATP have also been
claimed on mouse mesenteric arteries (Harrington
et al., 2007). In chicken small mesenteric vessels, ATP
mediates endothelium-dependent hyperpolarizations
of circular smooth muscle cells via P2Y1 receptors
(Draid et al., 2005) and endothelium-dependent hyperpolarization of longitudinal smooth muscle via P2X receptors (Alkayed et al., 2009). Endothelium-dependent
and -independent relaxations to GTP and guanosine in
rat mesenteric arteries do not appear to involve P1 or
P2 receptors (Vuorinen et al., 1994).
In rat isolated mesenteric artery, adenosine receptor
agonists elicit vasodilatation via A2B receptors located
on the smooth muscle and via a second undefined site
(possibly intracellular) (Prentice et al., 1997). In contrast, studies carried out in rat small mesenteric arteries showed that smooth muscle relaxation by adenosine
may involve A2A receptors that inhibit store-operated
Ca2+ entry-mediated increases in cytosolic Ca2+ levels
enhanced by the emptying of the stores (Wang et al.,
2009c). A2B receptors are the prominent P1 receptor
subtype in mouse mesenteric arterial smooth muscle,
whereas A1 receptors play a modulatory role (Teng et al.,
2013).
Congestive heart failure is accompanied by enhanced
peripheral sympathetic nerve activity, increased vascular resistance, and impaired peripheral blood flow.
125
Congestive heart failure induces downregulation of
P2X1 receptor-stimulated contraction in the mesenteric
artery, whereas P2Y receptor-mediated contractile activity remains unchanged (Malmsjö et al., 1999a).
3. Mesenteric Arterial Bed. ATP acts as an important functional sympathetic neurotransmitter constricting the rat perfused mesenteric vascular bed under
raised tone conditions, where the perfusion pressure is
closer to that found in vivo (Pakdeechote et al., 2007b).
The purinergic neurogenic responses were characterized using a,b-meATP, indicating a likely involvement
of P2X1 receptors; at basal tone (unconstricted preparations), responses to nerve stimulation were mediated
solely by activation of a1-adrenoceptors, but at a raised
tone, the responses were partly sensitive to a,b-meATP
(Pakdeechote et al., 2007b). As with rat isolated mesenteric arteries at physiologic pressures (Rummery et al.,
2007), this suggests that the purinergic component of
sympathetic neurotransmission may have been underestimated in studies in which cotransmission has been
investigated under relatively low pressures. In the rat
perfused mesenteric bed, neuropeptide Y (NPY), released together with NA and ATP from sympathetic
nerves (Donoso et al., 1997), enhanced the postjunctional actions of both cotransmitters (Westfall et al.,
1995). Cannabinoids inhibit both noradrenergic and
purinergic components of sympathetic cotransmission
in the rat mesenteric arterial bed (Pakdeechote et al.,
2007a). Prejunctional inhibition of sympathetic vasoconstriction of the hamster mesenteric arterial bed is
mediated by A1 (but not A2) receptors (Ralevic, 2000a).
Smooth muscle P2X receptors mediating contractile
responses to ATP have been described in mesenteric
arterial beds of both the rat (Ralevic and Burnstock,
1988, 1991) and golden hamster (Ralevic and Burnstock, 1996b). Contractile responses were also evoked
by a,b-meATP, which blocked responses to purine nucleotides, indicating likely actions at P2X 1 receptors
(Ralevic and Burnstock, 1988, 1991, 1996b). Selective
inhibition by PPADS of contraction mediated by P2X
receptors in the perfused rat mesenteric bed was
reported (Windscheif et al., 1994). P2X1 receptormediated vasoconstriction of the rat mesenteric arterial bed was unaffected by reduction of pH (to 6.9), but
contractions to NA were greatly attenuated (Ralevic,
2000b).
The effects of purines and pyrimidines were studied
on the rat mesenteric arterial bed, and it was shown
that, in addition to ATP acting via P2X receptors to
mediate vasoconstriction, receptors responsive to UTP
mediated both vasoconstriction of smooth muscle and
vasodilation via endothelial cells (Ralevic and Burnstock, 1991), possibly involving P2Y2 and/or P2Y4 receptors. mRNA encoding for P2Y 1, P2Y 2, and P2Y 6
receptors, but not P2Y4 receptors, was detected in the
rat arterial mesenteric bed and, after endothelium removal, which abolished nucleotide-evoked relaxations,
126
Burnstock and Ralevic
only P2Y6 mRNA was found; this shows a possible involvement of the P2Y1 and P2Y2 receptors in endotheliummediated vasodilation, whereas the P2Y6 receptors
expressed on the smooth muscle may be involved in
vasoconstriction (Buvinic et al., 2002). PPADS antagonized P2Y1-mediated ADP vasodilation of the rat
mesenteric arterial bed, but not UTP-evoked vasodilatation at P2U (P2Y2 and/or P2Y4) receptors (Ralevic
and Burnstock, 1996c). A selective P2Y1 receptor antagonist, MRS2179 ([2-[(hydroxy-oxidophosphoryl)oxymethyl]-5-(6-methylaminopurin-9-yl)oxolan-3-yl] hydrogen phosphate), also inhibited endothelium-dependent
relaxations to 2-MeSATP but not those to UTP in the
rat mesenteric arterial bed, showing distinct sites of
action of the two nucleotides (Buvinic et al., 2002). It
has been shown that diadenosine triphosphate (Ap3A)
and NADP mediate vasodilation via P2Y receptors,
whereas vasodilation to diadenosine diphosphate is mediated partly via P1 and possibly also via P2U (P2Y2
and/or P2Y4) receptors (Ralevic et al., 1995b). Nucleotide vasodilation of the rat mesenteric arterial bed via
P2Y1 and P2Y2/P2Y4 receptors on endothelium is mediated primarily by EDHF, with only a small involvement of NO (Malmsjö et al., 2002). In the mesenteric
arterial bed of the golden hamster, ATP elicited vasoconstriction via P2X receptors on smooth muscle and
vasodilation via P2U (P2Y 2 and/or P2Y 4 ) receptors
located on endothelium; in contrast to the rat mesenteric arterial bed, there was minimal expression of
vasorelaxant endothelial P2Y1 receptors (Ralevic and
Burnstock, 1996b).
ATP has been shown to stimulate vasodilation in
the rat mesenteric arterial bed by two different mechanisms producing a biphasic vasorelaxant response
(Ralevic, 2001; Stanford et al., 2001). The first, rapid,
phase involves the endothelium and NO (Stanford
et al., 2001; Ralevic, 2002) and likely involves endothelial P2Y1, P2Y2, and/or P2Y4 receptors (described
above). The second, prolonged, relaxation was blocked
by a,b-meATP, suggesting an involvement of P2X receptors (Ralevic, 2002). It has been claimed that the
second phase involves P2X1 receptors expressed on the
endothelium and generation of EDHF (Stanford et al.,
2001; Harrington and Mitchell, 2004). However, in rat
isolated mesenteric arteries, EDHF-mediated relaxations to ATP were enhanced after a,b-meATP desensitization of P2X1 receptors, and it was suggested
that depolarization produced by ATP activation of
smooth muscle P2X1 receptors normally counteracts
EDHF produced by concomitant ATP activation of endothelial P2 (P2Y) receptors (Malmsjö et al., 2000b).
In addition to P2 receptor control of mesenteric microvascular tone, adenosine elicits mesenteric vasodilator actions via A2B receptors located on the smooth
muscle cells (Rubino et al., 1995), although another
study showed that vasodilation produced by adenosine
in the rat perfused mesenteric arterial bed is mediated
partly via the endothelium (Tabrizchi and Lupichuk,
1995). There is a more recent review of purinergic receptors in the splanchnic microcirculation (Morato
et al., 2008).
E. Coronary Vessels
AMP has been known to be a potent dilator of coronary vessels since 1929 (Drury and Szent-Györgyi,
1929), and ATP, ADP and adenosine were later also
shown to relax coronary vessels (Green and Stoner,
1950; Berne, 1963; Toda et al., 1982).
Berne (1963) hypothesized that adenosine was the
physiologic regulator of blood flow during reactive
hyperemia, and this hypothesis dominated the field for
the next decade, although clear supporting evidence
was lacking (see Nees et al., 1985; Zucchi et al., 1989).
For example, an adenosine receptor antagonist, theophylline, failed to block reactive hyperemia, although
it blocked the vasodilator actions of exogenously applied adenosine (Afonso et al., 1972; Bünger et al., 1975).
Intracoronary adenosine and ATP increased coronary
blood flow, but reactive hyperemia in the dog heart
after occlusion was not blocked by the adenosine receptor antagonist aminophylline (Eikens and Wilcken, 1973a,b;
Giles and Wilcken, 1977; Clemens et al., 1985a). ATP
appeared early in the coronary sinus effluent from
isolated working rat hearts in response to hypoxia
(Clemens and Forrester, 1981). Also, adenosine was not
collected in the effluent until long after the hyperemic
response occurred, because ADP, after breakdown of
released ATP, acts as an inhibitor of 59-nucleotidase
breakdown of AMP to adenosine (Ishibashi et al., 1985).
Years later, after the seminal studies of Robert Furchgott
and others showed that ATP acted on endothelial P2
receptors to release NO, resulting in vasodilation, and it
was shown that ATP was released from endothelial cells
by hypoxia and increased flow (Bodin et al., 1991; Vials
and Burnstock, 1996), Burnstock (1993b) proposed that
reactive hyperemia was due to ATP release from endothelial cells during hypoxia acting to release NO. This
took place rapidly, and only later, after ATP was broken
down by ectoenzymes to adenosine, did coronary vasodilation of vascular smooth muscle via P1 receptors contribute to the hyperemic response.
In addition to hypoxia, ATP release from cardiac
endothelial cells has been shown in response to ACh,
bradykinin, 5-HT, and ADP (Yang et al., 1994). ATP, and
especially ADP (after breakdown of ATP by ectoenzymes)
released from aggregating platelets, causes endotheliumdependent relaxation of canine coronary arteries (Houston
et al., 1985). Maximal coronary vasodilatation can be
obtained safely with intracoronary ATP (Kato et al.,
1999) and also adenosine (Wilson et al., 1990) administration in humans. Indeed, ATP and sodium nitroprusside have been administered to patients to induce
and control hypotension during anesthesia (Hashimoto
et al., 1982).
Purinergic Signaling and Blood Vessels
Intracoronary adenosine, ATP, and ADP elicit their
dilating effects largely via the endothelium (Nees, 1989),
implying that both P1 and P2 receptors are expressed
by coronary endothelial cells. ATP and adenosine hyperpolarized guinea pig cultured coronary endothelial
cells; the adenosine hyperpolarization, but not that to
ATP, was antagonized by theophylline (Mehrke and
Daut, 1990), indicating that both P1 and P2 receptors
are present. Keef et al. (1992) presented evidence for
the presence of P2Y receptors on endothelial cells mediating hyperpolarization and P1 and P2 receptors on
smooth muscle mediating relaxation in guinea pig and
rabbit coronary arteries. It was suggested that ATP
may be a more significant relaxant of canine large coronary arteries than adenosine, but that adenosine may
be a more significant relaxant than ATP in canine small
coronary arteries (White and Angus, 1987). Endotheliumdependent vasodilation evoked by ATP has also been
demonstrated in human isolated coronary arteries
(Hansmann et al., 1998; Kato et al., 1999). However,
direct smooth muscle (endothelium-independent) relaxation to ATP and UTP of human epicardial coronary
arteries was also reported (Saetrum Opgaard and
Edvinsson, 1997), and ATP was shown to hyperpolarize smooth muscle cells of the guinea pig coronary artery (Takata and Kuriyama, 1980).
In perfused guinea pig heart, vasodilatation by ATP
was reported to involve NO (Vials and Burnstock, 1994a;
Matsumoto et al., 1997b), although another study concluded that ATP-induced vasodilation of guinea pig
heart did not depend on NO production but may be
partially dependent on the production of vasodilator
prostaglandins (Brown et al., 1992). Adenosine contributes very little to coronary vasodilation in guinea
pig hearts from bolus injection of ATP and ADP (Brown
et al., 1992; Gorman et al., 2003). ATP infusion in rat
heart was associated with large increases in myocardial blood flow (Hoffman et al., 1982). P2Y1 and P1
receptors were identified as the receptor subtypes
involved in purinergic endothelium-dependent vasodilation in rat (Vials and Burnstock, 1994b; Korchazhkina
et al., 1999) and dog (Bender et al., 2011) heart microvessels. P2Y1 and P2Y2 receptors were described in primary cultures of rat cardiac microvascular endothelial
cells (Moccia et al., 2001). There is evidence for UTPsensitive P2U receptors (P2Y2 and/or P2Y4), as well as
P2Y receptors, on human, canine, and guinea pig cardiac endothelial cells (Yang et al., 1996; Matsumoto
et al., 1997a; Zünkler et al., 1999). ATP and adenosine
have opposing effects on barrier function of the rat coronary microvasculature (Gündüz et al., 2012).
Studies of purine receptors in human, porcine, rabbit, and rat hearts have shown that, in addition to the
vasorelaxant, predominantly endothelial P2Y and P1
receptors described above, P2X and P2Y receptors mediating vasoconstriction are expressed on the coronary
artery smooth muscle (Fleetwood and Gordon, 1987;
127
Hopwood and Burnstock, 1987; Corr and Burnstock,
1994; Malmsjö et al., 2000c; Rayment et al., 2007a).
Evidence was presented that human coronary artery
smooth muscle cells express P2Y and P2U (P2Y2 and/or
P2Y 4) receptors, leading to increases in [Ca2+ ] i by
2-MeSATP and UTP, respectively (Strøbaek et al., 1996).
RT-PCR studies of P2 receptors in human coronary
arteries showed strong bands for P2X 1 and P2Y 2
receptors, with weaker expression of P2Y1, P2Y4, and
P2Y6 receptors (Malmsjö et al., 2000c). In the same study,
contractile responses of human coronary arteries to
a,b-meATP and the stable pyrimidine analog, uridine
59-O-3-thiotriphosphate, were consistent with activation of P2X1 and P2Y2 receptors, respectively (Malmsjö
et al., 2000c). Similarly, UTP-evoked contractions of porcine coronary artery smooth muscle appear to be predominantly P2Y2 receptor-mediated (Rayment et al.,
2007a). Coexpression of mRNAs for P2X1, P2X2, and
P2X4 receptors was shown on the smooth muscle of rat
coronary arteries (Nori et al., 1998). UTP was shown to
elicit depolarization of rat coronary artery smooth
muscle (Welsh and Brayden, 2001). The dinucleoside
polyphosphates [Ap5A and diadenosine hexaphosphate
(Ap6A)] vasodilate or vasoconstrict rat coronary vessels
via P2Y1 receptors on endothelial cells and P2X receptors on smooth muscle, respectively (van der Giet
et al., 2002). Up4A has been identified as a novel vasodilator of the coronary microcirculation of swine hearts,
acting, possibly through a breakdown product, via P1
but not P2 receptors (Zhou et al., 2013). Human epicardial coronary veins have been shown to contract in
response to ATP (Saetrum Opgaard and Edvinsson,
1997).
Transient depolarizations comparable to EJPs were
evoked in the smooth muscle of guinea pig circumflex
coronary artery by transmural stimulation (Keef and
Kreulen, 1988), suggesting that there may be a purinergic component of sympathetic nerve transmission.
ATP has been claimed to be the mediator of NANC
inhibitory transmission in lamb coronary small arteries via actions at P2Y receptors (Simonsen et al.,
1997).
Adenosine is a potent coronary dilator in all species
studied, including humans (Cobbin et al., 1974; Olsson
et al., 1979; Watt et al., 1987). It can arise directly from
cardiomyocytes after intracellular breakdown of ATP
and after extracellular breakdown of ATP released
from endothelial cells (Pekka Raatikainen et al., 1991).
It was suggested that the vasodilator actions of adenosine were mediated by A2 receptors (Leung et al., 1985;
Daly et al., 1986; Odawara et al., 1986; see Mustafa
et al., 2009), probably located on endothelial cells (Kroll
et al., 1987; Des Rosiers and Nees, 1987; Ramagopal
et al., 1988a; Balcells et al., 1992; King et al., 1990),
perhaps together with another P1 receptor subtype
(Nees et al., 1987). Methylxanthines antagonized A2
receptor-mediated coronary vasodilation (Ramagopal
128
Burnstock and Ralevic
et al., 1988b). Evidence was presented that A2B receptors mediate relaxation to adenosine in human
small coronary arteries, which is independent of the
endothelium and NO (Kemp and Cocks, 1999). However, Sato et al. (2005) claimed that, in human coronary arteriolar smooth muscle, it is A2A receptors that
mediate vasodilation. A review discusses the role of
adenosine in dilation of human coronary vessels (Heusch,
2010). A2A receptors also mediate relaxation of porcine
isolated coronary arteries (Rayment et al., 2007b);
although A2A receptors are the predominant subtype,
A2B receptors may play a role, possibly through the p38
mitogen-activated protein kinase (MAPK) pathway
(Teng et al., 2005). Adenosine A2A and A2B receptors
mediate NO production in porcine coronary artery
endothelial cells (Olanrewaju and Mustafa, 2000). Both
A2A and A2B receptors mediate coronary vasodilation in
mice (Flood and Headrick, 2001; Talukder et al., 2003)
and an involvement of KATP channels was demonstrated (Sanjani et al., 2011). Upregulation of A2B receptors in A2A receptor knockout mouse coronary artery
has been reported (Teng et al., 2008; Sanjani et al.,
2011).
An A1-selective agonist, N6-cyclopentyladenosine, was
shown to have vasorelaxant activity in porcine and
canine coronary arteries (Merkel et al., 1992; Cox et al.,
1994). A1 receptors were identified on smooth muscle
cells isolated from the porcine coronary artery (Dart
and Standen, 1993) as well as A2 receptors (Abebe
et al., 1994). Evidence for A3 receptors in the rat coronary circulation has also been presented (Hinschen
et al., 2003). In the guinea pig heart, endotheliumdependent coronary vasodilation was shown to be due
to multiple P1 receptor subtypes: A1 receptors releasing both NO and PGI2 and A2A and A3 receptors acting
mainly via NO (Rubio and Ceballos, 2003). There is
evidence for adenosine receptor-mediated hyperpolarization of bovine and porcine coronary artery smooth
muscle (Sabouni et al., 1989; Olanrewaju et al., 1995)
and of guinea pig cultured coronary endothelial cells
(Seiss-Geuder et al., 1992). Ticagrelor, a P2Y12 receptor
antagonist, enhances adenosine-induced coronary vasodilatory responses in humans (Wittfeldt et al., 2013).
NAD was shown to be a coronary vasodilator in 1971
(Afonso et al., 1971). Inosine transiently decreases coronary flow, but potentiates vasodilation by adenosine
(van der Meer and de Jong, 1990). Diadenosine tetraphosphate (Ap4A) elicited coronary vasodilation, probably via P1 receptors (Nakae et al., 1996). Diadenosine
polyphosphates are potent constituents of human coronary artery, radial artery, and saphenous vein bypass
grafts, and it was suggested that this may play a role in
postoperative contraction in these grafts (Conant et al.,
2008).
The rabbit heart requires a period of maturation
after birth before demonstrating an adult level of coronary responsiveness to exogenous adenosine (Buss
et al., 1987). It was suggested that several adenosine
receptor subtypes mediate coronary vasodilation in mature
rats, but a reduction in the response to adenosine with
age may be due to changes in the high-affinity receptor
site (Rose’Meyer et al., 1999) and/or a reduction in
adenosine receptor transduction (Hinschen et al., 2001)
and/or a reduction of A3 receptor-mediated activity
(Hinschen et al., 2003; Jenner and Rose’Meyer, 2006).
Long-term signaling by adenosine in cardiac microvascular cells has been described in vasculogenesis
(Ryzhov et al., 2008). Myocardial blood flow during
adenosine-mediated hyperemia was reduced in male
endurance athletes compared with untrained men, and
the fitter the athlete was, the lower was adenosineinduced myocardial blood flow, although A2A receptors
density was unchanged (Heinonen et al., 2008). ATP
appears to be one of the factors controlling coronary
blood flow during exercise (Farias et al., 2005; Gorman
et al., 2010, Gorman and Feigl, 2012). ATP (via P2Y
receptors) and insulin act synergistically to promote
proliferation of porcine cultured coronary artery smooth
muscle cells (Agazie et al., 2001). Sexual dimorphism
in the permeability response of coronary microvessels
to adenosine has been demonstrated (Huxley et al., 2005).
F. Cerebral Vessels
Adenosine dilates cerebral blood vessels (Berne et al.,
1974; Boisvert et al., 1978; Gregory et al., 1980) via P1
receptors (Beck et al., 1984; Palmer and Ghai, 1982;
Schütz et al., 1982). Adenosine caused dilation of rabbit
hypothalamic blood vessel smooth muscle at low concentrations, but constriction at high concentrations
(Livemore and Mitchell, 1983). Adenosine receptors
were described on capillaries in the rat brain (Palmer
and Ghai, 1982). A2 receptors were identified, mediating relaxation of cat cerebral arteries (Edvinsson and
Fredholm, 1983) and rabbit cerebral microvessels (Li
and Fredholm, 1985). It has been claimed that human
cerebral microvessels express A2, but not A1, receptors
(Kalaria and Harik, 1988). A2 receptors have also been
described in porcine basilar arteries (McBean et al.,
1988), goat cerebral vessels (Torregrosa et al., 1990b),
and rat pial arterioles (Ibayashi et al., 1991). Both A2A
and A2B receptors were later identified on vascular
smooth muscle, mediating vasodilation in rat cerebral
cortex (Coney and Marshall, 1998; Shin et al., 2000a).
In rat pial arteries, A2B receptors were present on
endothelial cells, mediating vasodilation via NO (Shin
et al., 2000b; Ngai et al., 2001). A2A receptors mediate
glutamate-evoked arteriolar dilation in the rat cerebral
cortex (Iliff et al., 2003).
A1 and A3 receptor subtypes have been identified on
endothelial cells in rat pial and intracerebral arteries
(Di Tullio et al., 2004) and human cerebral arteries
(Mills et al., 2011). An A1 receptor agonist was shown
to attenuate subarachnoid hemorrhage-induced cerebral vasospasm in rats (Lin et al., 2006). According to
Purinergic Signaling and Blood Vessels
Chang et al. (2007), the A2A receptor agonist ATL-146e
was shown to attenuate experimental posthemorrhagic
cerebral vasospasm in rats. Inosine potentiates adenosineevoked vasodilation in rat pial arterioles (Ngai et al.,
1989). Adenosine is taken up by bovine cortex capillaries
by a high-affinity uptake system (Wu and Phillis, 1982;
Stefanovich, 1983).
The blood-brain barrier (BBB) is composed of endothelial cells, pericytes, and astrocytes. mRNA for all the
P2Y receptor subtypes was present in astrocytes and
pericytes, but endothelial cells only expressed P2Y1,
P2Y2, and P2Y4 subtypes; NTPDase 1 and 2 were
expressed by all 3 cell types (Kittel et al., 2010). Efflux
transport of adenosine at the BBB has been described
(Isakovic et al., 2004; Murakami et al., 2005). Adenosine receptor-mediated endothelial cell signaling modulates the permeability of the BBB in vivo to facilitate
the entry of therapeutic compounds into the central
nervous system (Carman et al., 2011). Both mRNA and
protein for P2Y12 and GPR17 receptors are expressed
on endothelial cells of the BBB (Ceruti et al., 2010).
P2Y2 and P2Y4 receptors were strongly expressed at
the gliovascular interface and colocalized with glial
fibrillary acidic protein around larger vessels in cortex
(Simard et al., 2003). P2Y2 receptors were later
identified as the main P2 receptor subtype involved
in Ca2+ signaling in the human BBB endothelial cell
line hCMEC/D3 (Bintig et al., 2012). Tumor necrosis
factor-a (TNF-a) inhibits purinergic calcium signaling
in BBB endothelial cells by reducing gap junction
coupling and inhibiting ATP release (Vandamme et al.,
2004). ATP-binding cassette transporters, which are
localized at the surface of endothelial cells, play
important roles in the maintenance of BBB integrity
(ElAli and Hermann, 2011).
ATP was shown early to be more potent than adenosine as a dilator of cerebral vessels in the baboon and
cat (Forrester et al., 1975, 1979) and goat (Alborch and
Martin, 1980). Intracarotid infusion of ATP increased
cerebral blood flow in anesthetized baboons by about
90%, whereas adenosine increased it by less than 10%;
further application of ATP and adenosine produced
pial arteriolar dilations (Harper, 1985). In an important early study of pial arteries from the rabbit, cat,
and man, it was shown that ATP acting on P2 receptors
on smooth muscle elicited contraction, whereas adenosine acting via smooth muscle P1 receptors caused
relaxation; furthermore ADP and ATP acting on P2 receptors on endothelial cells caused relaxations (Hardebo
et al., 1987a).
Constriction of the rabbit basilar artery by ATP and
UTP occurred via actions at two distinct receptors (von
Kügelgen and Starke, 1990b), in retrospect by P2X and
P2Y2 and/or P2Y4 receptors. a,b-MeATP produced potent
contractions of goat middle cerebral artery (Torregrosa
et al., 1990a), suggesting mediation via P2X1 receptors.
UTP and UDP induced a long-lasting contraction of
129
isolated brain arteries in humans (Urquilla et al., 1978)
and dogs (Shirasawa et al., 1983). UTP also induced
a sustained contraction of the rat middle cerebral artery
(Laing et al., 1995). These early data suggested the
functional expression of contractile P2Y2 and/or P2Y4
receptors (sensitive to UTP) and contractile P2Y6 receptors (sensitive to UDP). A later study showed that
constriction of rat cerebral (pial) microvasculature is
mediated by smooth muscle P2X1, P2Y2, and P2Y6
receptors, a finding supported by both functional and
RT-PCR studies (Lewis et al., 2000a). P2X4 receptor
transcripts were not detected (Lewis et al., 2000a). The
P2Y6 receptor was described as the most potent receptor mediating constriction of the rat basilar artery,
with lesser contributions from P2X1 and P2Y2 receptors (Malmsjö et al., 2003b). P2Y4 and P2Y6 receptors
contribute substantially to myogenic mechanisms of
vasoconstriction of rat intraparenchymal cerebral arterioles (Brayden et al., 2013). Potent P2Y6 receptormediated contraction of human cerebral arteries has
also been demonstrated (Malmsjö et al., 2003a). Amyloid-b,
which may contribute to cerebrovascular dysfunction
in Alzheimer’s disease, enhanced ATP-induced cerebral arteriolar contractions (Dietrich et al., 2010).
The mechanism of UTP-induced cerebrovascular constriction in the rat appears to involve release of prostanoids (Lacza et al., 2001). All inositol trisphosphate
(InsP3) receptor isoforms are expressed in rat cerebral
artery smooth muscle cells, with inositol trisphosphate
type 1 dominant, which contributes to UTP-induced
vasoconstriction (Zhao et al., 2008). UTP released Ca2+
waves in smooth muscle cells of rat basilar artery; this
may underlie the tonic contractions produced by repetitive cycles of regenerative Ca2+ release from sarcoplasmic
reticulum through InsP3-sensitive receptors (Syyong
et al., 2009). Mammalian homologs of the Drosophila
transient receptor potential channel (TRPC) have been
identified in vascular smooth muscle cells. It has been
shown that TRPC3 mediates UTP-induced depolarization of smooth muscle cells in rat cerebral arteries
(Reading et al., 2005). ATP activated potassium channels and enhanced [Ca2+]i in cultured smooth muscle
cells of bovine cerebral arteries (Ikeuchi and Nishizaki,
1995). [Ca2+]i increase and membrane depolarization
caused by P2X receptor-mediated currents in rat cerebral artery smooth muscle cells may regulate the subsequent P2Y receptor responses (Kamishima and Quayle,
2004).
Most small arteries respond to an increase in intraluminal pressure by constricting, i.e., the “myogenic”
response. It was suggested that mechanical activation
may be a common feature of many Gq/11-coupled receptors, which may act as mechanosensors via subsequent
signaling to TRPC channels (Mederos y Schnitzler et al.,
2008). An involvement of direct mechanical activation
of UTP- and UDP-sensitive P2Y4 and P2Y6 receptors
(Gq/11 coupled, see Table 1) in the myogenic response
130
Burnstock and Ralevic
was shown in rat parenchymal arteriolar smooth
muscle cells (Brayden et al., 2013). The involvement
of TRPC channels in this effect is unclear because the
same group showed that TRPC3 channels (but not
TRPC6 channels) are involved in UTP-induced depolarization and constriction of rat cerebral arteries;
however, antisense oligodeoxynucleotide suppression
of TRPC3 had no effect on pressure-induced depolarization or the development of myogenic tone by
cerebral artery smooth muscle cells, but suppression
of TRPC6 decreased pressure-induced depolarization
of cerebral artery smooth muscle cells (Reading et al.,
2005). In contrast, in mouse mesenteric arteries the
myogenic response appears to involve activation of
P2Y receptors by endogenous nucleotides, because
myogenic tone was enhanced in arteries from ectonucleotidase (E-NTPDase 1/CD39) null mice (Kauffenstein
et al., 2010b). It is possible that different mechanisms
of P2Y receptor activation operate in central and peripheral arteries. If direct mechanical activation is
a feature of P2Y receptors, this has widespread implications for generation of the myogenic response and
more generally for the regulation of arterial contractility. If direct mechanical activation is a property of
P2Y receptors outside those in cerebral arteries, it is
likely to operate in addition to agonist-induced activation of P2Y receptors, because regulated nucleotide
release is a property of virtually all cells.
Relaxations of cerebral vessels by purine and pyrimidine nucleotides are generally endothelium dependent. UTP and UDP relax human pial arteries via the
endothelium (Hardebo et al., 1987b), suggesting that
P2Y2 and/or P2Y4 and P2Y6 receptors are involved. In
bovine middle cerebral arterial strips without endothelium, UTP induced contraction, but with intact
endothelium produced vasodilation via NO but not
PGI2, suggesting an involvement of P2Y2 and/or P2Y4
receptors (Miyagi et al., 1996). Relaxation of rabbit
small cerebral arteries to ADP was endothelium dependent (Brayden, 1991). ATP and ADP relaxation of
monkey temporal and cerebral arteries was endothelium dependent in temporal arteries, but largely endothelium independent in cerebral arteries (Toda et al.,
1991). In rat cerebral arterioles in vivo, microapplication of ATP produced a biphasic response consisting of
a transient constriction via smooth muscle P2X1 receptors and a subsequent dilation primarily due to endothelial P2Y receptor activation (Dietrich et al., 2009). It
was shown further that conducted vasomotor responses
travel along the vessel with a membrane hyperpolarization that precedes vessel dilation (Dietrich et al.,
2009). It has been suggested that in female rat pial
arterioles, ADP-induced dilation is the result of additive contributions from P2Y1 receptors present on
endothelium but also on the glia limitans, the underlying layer of astrocytic glial processes (Xu et al., 2005).
ATP interacts with astrocytes to induce enhanced
arteriolar dilation (Dietrich, 2012). The purinergic mechanisms involved in gliovascular coupling have been
reviewed (Pelligrino et al., 2011).
Endothelium-dependent cerebral artery vasodilatation via P2 receptors involves release of NO and EDHF
as in other blood vessels, with most of the evidence
coming from studies in rat blood vessels (see below).
Interestingly, endothelial TRPC1 and TRPC3 contribute to ATP-mediated relaxation in mouse cerebral
arteries (Kochukov et al., 2011), a mechanism thus far
not reported for P2 receptor-mediated vasodilatation in
other blood vessels. ADP-mediated dilatation of rat
cerebral arterioles was endothelium-dependent and
caused NO release (Mayhan, 1992), suggesting an
involvement of P2Y1 receptors. ATP dilated rat middle
cerebral arteries via endothelial P2Y1 and P2Y2 receptors, involving release of NO (You et al., 1997). EDHF,
in addition to NO, mediates vasodilation of rat middle
cerebral arteries via endothelial P2Y2 receptors by
opening an atypical calcium-activated K+ channel (You
et al., 1999b). In a more recent article (Geddawy et al.,
2010), it was shown that 2-MeSADP elicited EDHFtype relaxation via stimulation of endothelial P2Y1
receptors in monkey cerebral artery. In a comparative
study of rat middle cerebral arteries, third-order branches,
and penetrating arterioles, it was concluded that the
role of NO in purinoceptor-evoked dilations diminishes
along the cerebrovascular tree (artery to arterioles),
whereas the role of EDHF becomes more prominent
(You et al., 1999a). Horiuchi et al. (2003) showed that
dilation of rat intracerebral arterioles by low concentrations of ATP was via P2Y1 receptors, whereas high
concentrations activated P2Y2 receptors; NO was involved in P2Y1 but not P2Y2 receptor-mediated dilation.
Rat cultured brain capillary endothelial cells show
an increase in [Ca2+]i in response to ATP (Revest et al.,
1991). According to Frelin et al. (1993), two subtypes of
receptors were identified in these cells: an ADP-specific
receptor leading to release of intracellular Ca2+ (in
retrospect P2Y1 receptor) and a receptor that recognizes ATP and UTP that is positively coupled to phospholipase C (in retrospect a P2Y2 and/or P2Y4 receptor).
P2Y1 receptors were also identified on B10 cells, a
cloned cell line of rat brain capillary endothelial cells
(Webb et al., 1996). Another article claimed that in rat
brain capillary endothelial cells ATP activated P2Y2
receptors coupled to phospholipase C, Ca2+, and MAPK
and activated P2Y1 receptors linked to Ca2+ mobilization and a further unidentified receptor linked to an
increase in cAMP levels (Albert et al., 1997; Sipos et al.,
2000). ATP and UTP caused an increase in [Ca2+]i in the
immortalized rat brain endothelial cell line, RBE4,
perhaps via P2Y2 and/or P2Y4 receptors (Nobles et al.,
1995). P2Y6 receptor proteins were shown to be located
on endothelial, but not epithelial cells, in the lateral
ventricular choroid plexus of the rat (Johansson et al.,
2007). P2Y12 receptors were claimed to be present on rat
Purinergic Signaling and Blood Vessels
brain capillary endothelial cells as well as P2Y1 receptors (Simon et al., 2001, 2002). P2X2 receptors were
also localized with electron microscopy on vascular
endothelial cells in rat brain (Loesch and Burnstock,
2000). Diadenosine polyphosphates are antagonists at
P2Y1 receptors on rat brain capillary endothelial cells
(Vigne et al., 2000). P2Y1 and P2Y2 receptors were
identified on endothelial cells from bovine cerebral arteries (Zhang et al., 1997).
Sympathetic nerve stimulation constricted rabbit
basilar arteries via two components, one NA, the other
unknown at the time (Lee et al., 1980). ATP produced
contraction of canine basilar artery (Muramatsu et al.,
1980) and was later proposed to be released as a cotransmitter with NA from sympathetic nerve terminals
(Muramatsu et al., 1981). Perivascular nerve stimulation
of the guinea pig basilar artery elicited EJPs (Karashima
and Kuriyama, 1981; Fujiwara et al., 1982). Receptors for
ATP and adenosine were found at both pre- and postjunctional sites in canine cerebral artery (Muramatsu et al.,
1983). Prejunctional inhibitory effects of adenosine and
AMP on neuromuscular transmission in cat cerebral
arteries are mediated by A1 receptors (Rivilla et al., 1990).
Surprisingly, high concentrations of ATP were shown
to be released from brain tissue to affect local blood flow
(Forrester, 1978). ATP release from rat brain endothelial
cells was claimed to be via connexin hemichannels
(Braet et al., 2003). Its levels can be regulated by ADPases
present on rat brain capillary cells, which degrade ATP
to ADP, and ADP to adenosine (Vigne et al., 1998).
Indeed, adenosine, acting via A2 receptors, was shown
to contribute significantly to ATP-mediated pial arteriolar dilations in vivo in rats (Vetri et al., 2009, 2011).
Ca2+-ATPase was shown with electron microscopy to be
localized on rat cerebral endothelium (Nag, 1987).
In aging rat cerebral arteries, there is downregulation of P2X1 and upregulation of P2Y1 and P2Y2 receptor mRNA in smooth muscle cells and downregulation
of P2Y1 and P2Y2 receptor mRNA in endothelial cells
(Miao et al., 2001). Aging improves NOS-dependent
reactions of endothelial cells in rat cerebral arteries
produced by ADP (Mayhan et al., 2008).
In summary, vasoconstriction to ATP, UTP, and
UDP of cerebral arteries is mediated by smooth muscle
P2X1, P2Y2, P2Y4, and P2Y6 receptors. Adenosine mediates vasodilation predominantly by actions at A2A
and A2B receptors on the smooth muscle and endothelium. Endothelium-dependent vasodilation of cerebral
arteries is elicited by ADP via P2Y1 receptors, UTP via
P2Y2 and/or P2Y4 receptors, and UDP via P2Y6 receptors. Long-term effects of UTP include chemotactic,
mitogenic, and angiogenic actions on vascular endothelial cells (Satterwhite et al., 1999).
G. Skin Vessels
Thermally induced reflex changes in blood flow
through arteriovenous anastomoses in rabbit ear arteries
131
were shown to be mediated by sympathetic nerves, and
the possibility was raised that purinergic neurotransmission might be involved in these arteries (Hales
et al., 1978) and also in control of arteriovenous anastomoses in chicken foot (Hillman et al., 1982). Deep
lingual arteries in the monkey tongue are innervated
by adrenergic and purinergic components of sympathetic nerves, both producing vasoconstriction (Toda
et al., 1997). Transmural nerve stimulation caused contraction followed by vasodilation of the labial artery
close to the skin of the upper lip of dogs; the contraction
was abolished by a combination of prazosin and
a,b-meATP, indicating sympathetic cotransmission
involving NA and ATP, whereas the relaxation was
abolished by the NOS inhibitor L-NG-nitroarginine
methyl ester (Okamura et al., 1999).
Cold-induced neurogenic vasoconstriction of canine
cutaneous veins appears to be mediated largely by an
increase in the purinergic component of sympathetic
transmission (Flavahan and Vanhoutte, 1986). According to Koganezawa et al. (2006), it was suggested that
the cooling-induced reduction in skin blood flow was
due to the ATP released from sympathetic nerves
stimulating presynaptic P2 receptors on sympathetic
nerve terminals to facilitate release of NA, resulting in
constriction. Arteriolar contractile responses to nanomolar concentrations of topically applied adenosine
acting at A1 receptors in the skin microcirculation of
hamsters were enhanced when local skin temperature
was increased; vasodilator responses evoked by micromolar concentrations of adenosine were temperature
insensitive (Stojanov and Proctor, 1990). Adenosine
receptor inhibition with theophylline attenuated the
skin blood flow response to local heating in humans
(Fieger and Wong, 2010). Pharmacological evidence
has been presented for both high-affinity A1 receptors
mediating vasoconstriction and low affinity A2 receptors mediating vasodilation in hamster skin circulation
(Stojanov and Proctor, 1989).
The isolated perfused foot of ducks is a useful preparation for the study of skin circulation, and NANC
vasodilator nerves with responses mimicked by low
concentrations of ATP were identified early (McGregor,
1979). In cats, after pretreatment with guanethidine to
abolish the vasoconstrictor effects of sympathetic nerve
stimulation, a NANC vasodilator response to nerve
stimulation was revealed in the skin of the paw pad
(Bell et al., 1985); it remains to be determined whether
this involves ATP. There is evidence that degranulation of mast cells in the skin is produced by ATP released during antidromic impulses from sensory nerve
endings during axon reflexes, leading to vasodilation of
skin vessels (Kiernan, 1975). Human isolated subcutaneous resistance arteries were shown to dilate via
P2Y and P1 receptors and constrict via P2X receptors
(Martin et al., 1991). Intra-arterial infusion of ATP,
ADP, and AMP in canine facial and nasal vascular
132
Burnstock and Ralevic
beds caused vasodilation (Bari et al., 1993). Purinergic
agonists [ATP and adenosine-59-(g-thio)-triphosphate
(ATPgS)] induce release of inflammatory mediators
from human dermal microvascular endothelial cells
(Bender et al., 2008). ATP and NA synergize in
inducing IL-6 production by human dermal microvascular endothelial cells (Stohl et al., 2010).
Intradermal administration of ATPgS results in an
enhanced contact hypersensitivity response in mice,
and it was suggested that ATP, when released after
trauma or infections, may act as an endogenous adjuvant to enhance the immunoresponse and that P2 receptor agonists may augment the efficacy of vaccines
(Granstein et al., 2005). Intradermal administration of
ATP does not attenuate tyramine-stimulated vasoconstriction in human skin, in contrast to skeletal muscle
vessels (Wingo et al., 2010). Changes in purine receptor
expression (increase in P2Y1, P2Y2, and P2X5, decrease
in P2X7) on human lower leg epidermal keratinocytes
were shown in chronic venous insufficiency (Metcalfe
et al., 2006). Improvement of ischemic skin flap
survival used in surgery when exposed to ATP has
been described (Boss et al., 1984; Cikrit et al., 1984;
Zimmerman et al., 1987; Knight et al., 1989), perhaps
because of its vasodilator effects (Kuzon et al., 1985).
Direct Mg-ATP delivery to cutaneous wounds accelerates healing, perhaps by increasing synthesis of vascular endothelial growth factor (Chiang et al., 2007).
H. Intestinal Vessels
EJPs were recorded from smooth muscle in submucosal arterioles in the guinea pig small intestine
(Hirst and Neild, 1978), and these were later shown to
be produced by ATP released from sympathetic nerves
acting via P2X receptors. In this vessel, vasoconstriction was produced solely by ATP or a related purine
nucleotide acting through P2X receptors, whereas the
colocalized transmitter NA acted solely as a prejunctional modulator of ATP release (Evans and Surprenant, 1992; Vanner and Surprenant, 1996). ATP and NA
released from sympathetic nerve terminals mediate
contraction of rabbit isolated jejunal arteries (Evans
and Cunnane, 1992) and ileocolonic artery (Bulloch
and Starke, 1990). In general, the smaller the blood
vessel, the larger the purinergic component (McGrath
et al., 1990). Both substance P and CGRP decreased
the amplitude of neurally evoked EJPs in arterioles of
guinea pig small intestine (Coffa and Kotecha, 1999),
suggesting that purinergic neurotransmission can be
modulated by neurotransmitter released from sensory
nerves. Conversely, ATP released from sympathetic
nerve varicosities acts on prejunctional adenosine receptors (after ATP breakdown) on both extrinsic sensory
and submucosal vasodilator nerves to inhibit transmitter release (Lomax and Vanner, 2010). Reviews
describing neural purinergic control of intestinal vessels
are available (Burnstock, 2001a; Kotecha, 2002).
P2X receptors were shown to be present on both
arterial and venous blood vessels of the cat intestinal
circulation (Taylor and Parsons, 1991) and submucosal
arteries in the guinea pig ileum (Galligan et al., 1995).
ATP applied to equine colonic arterial and venous rings
induced a biphasic response, contraction followed by
sustained relaxation that was attenuated but not
eliminated by endothelium removal and did not involve
NO (Tetens et al., 2001b). Infusion of ATP into stomach, small intestine, and colon of cats caused vasodilation (Sjöqvist et al., 1985). Ca2+ signaling in rat gastric
microvascular endothelial cells is mediated by purinergic receptors, probably P2Y receptors, because increases in [Ca2+]i were due to release from intracellular
stores (Ehring et al., 2000). Superfusion of mouse
colonic submucosal vessels with ATP mediated large
vasoconstrictions in controls, but not in mice with 2,4,6trinitrobenzene sulfonic acid-induced colitis, and it was
concluded that reduced purinergic signaling to submucosal arterioles may be due to increased degradation
of ATP during colitis (Lomax et al., 2007).
Adenosine acting primarily via A1 receptors (but also
via A2A and A2B receptors) produces vasodilation of
arteries in rat jejunum (Li et al., 2007). Adenosine,
acting via A2 receptors, increases blood flow to the esophageal mucosa, antral mucosa, and small intestine of
rabbit (Pennanen et al., 1994). Adenosine is a vasodilator in the canine intestinal mucosa (Sawmiller and
Chou, 1991). Microvascular vasodilations to adenosine
were significantly greater in the duodenum than in the
terminal ileum of the rat; also, adenosine-induced
vasodilation was greater in the smaller compared with
the larger microvessels (Li et al., 2004). A study of
ethanol-induced arteriolar dilation in rat stomach led
to the conclusion that ethanol increases gastric mucosal blood flow via A2 receptors in submucosal arterioles (Nagata et al., 1996).
The beneficial effects of ATP on the treatment of
intestinal ischemia were claimed to be relatively small
(Van der Meer et al., 1982). However, adenosine is
effective in protecting the intestinal microvasculature
from the injurious effects of ischemia-reperfusion (Grisham
et al., 1989), perhaps via A1 receptors (Özaçmak and
Sayan, 2007). It was concluded in another study that
adenosine acts by modulating the inflammatory response evoked by intestinal reperfusion (Kaminski
and Proctor, 1992). Furthermore, gene deletion of 59nucleotidase/CD73 significantly enhanced intestinal
ischemia-reperfusion injury (Hart et al., 2008a). Beneficial effects of E-NTPDase1/CD39 against murine
intestinal ischemia-reperfusion injury have been reported
(Guckelberger et al., 2004).
I. Skeletal Muscle Microvasculature and
Femoral Artery
Adenosine was considered initially to be the major
purine to increase skeletal muscle blood flow in the dog
Purinergic Signaling and Blood Vessels
hindlimb (Dobson et al., 1971; Cotterrell and Karim,
1982). Later studies showed that ATP and ADP cause
strong vasoconstriction followed by vasodilation in the
rat hindlimb vascular bed (Sakai, 1978) as did UTP
and GTP (Sakai et al., 1979a), although it was postulated that they acted via release of 5-HT. Another
early study showed the relative vasodilator potency of
purines in the cat hindlimb as ADP . ATP . . AMP
(Gangarosa et al., 1979), suggesting activation of P2Y1
receptors.
An important article by Forrester (1981) reported
that ATP was the mediator of exercise hyperemia in
skeletal muscle. ATP release was investigated in pig
skeletal muscle during exercise (Wulf et al., 1984) and
release shown during exercise of human thigh muscle,
increasing both arterial and venous plasma ATP
concentration (Mortensen et al., 2011). During exercise, sympathetic nervous system activity increases
and this contributes to an increase in blood pressure,
the exercise pressor reflex. Data were presented to
suggest that P2 receptors on sensory nerves contribute
to this exercise pressor reflex in humans (Cui et al.,
2011). ATP released during cat skeletal muscle contraction acts on afferent C fibers to modulate cardiovascular responses (Li et al., 2008a). Short-term exercise
training augments sympathetic vasoconstrictor responsiveness and endothelium-dependent vasodilation in
resting skeletal muscle, perhaps related to enhanced
ATP release (Jendzjowsky and DeLorey, 2012). A
review that includes discussion of the involvement of
purinergic signaling in control of muscle blood flow
during exercise is available (Sarelius and Pohl, 2010).
The ability of contracting muscle and circulating
ATP to modulate sympathetic vasoconstriction is impaired in aging humans, and it was suggested that this
may be due to a reduction in circulating ATP with
advancing age (Kirby et al., 2011), perhaps due to
reductions in erythrocyte- and endothelium-mediated
ATP release (Kirby et al., 2012, 2013). A recent report
claims that aging does not alter the responsiveness of
postjunctional P2X1 and P2X4 receptors in the skeletal
muscle vasculature of the canine hindlimb at rest or
during exercise (DeLorey et al., 2012). Femoral artery
occlusion significantly increases the level of P2X3 receptors in lumbar dorsal root ganglion neurons, leading
to augmentation of the exercise pressor reflex pathways when blood supply to hindlimb muscles is insufficient, as seen in peripheral artery disease (Liu
et al., 2011). Functional sympatholysis refers to attenuation of sympathetic vasoconstrictor activity. Muscle
immobilization for two weeks impairs functional sympatholysis but increases exercise hyperemia and the
vasodilator responses to infused ATP (Mortensen et al.,
2012). In sympathetically denervated humans, this
vasodilation is facilitated (Puvi-Rajasingham et al.,
1997), suggesting involvement of the cotransmitters
NA and ATP.
133
ATP can be released from nerves in rabbit skeletal
muscle to cause skeletal muscle vasodilation via actions on P2 receptors; the ATP release was evoked after
hypothalamic stimulation (Shimada and Stitt, 1984).
Field stimulation of 1A arterioles from the red portion
of rat gastrocnemius muscle was shown to release ATP
in two phases from nerves, measured with real-time
biosensors (Kluess et al., 2010). They showed further
that endothelium removal resulted in an increase in
ATP overflow, indicating that endothelial cells attenuate ATP overflow from nerves and that changes in
ATP flow occurred during development and aging. Plasma
levels of ADP, as well as ATP, increase in strenuous
exercise in humans; the ADP significantly augmented
platelet activity but this prothrombotic response was
partially counteracted by concurrent upregulation of
soluble nucleotide-inactivating enzymes, providing insight into the mechanisms underlying the enhanced
risk of occlusive thrombus formation in exercising conditions (Yegutkin et al., 2007). Heat stress increases
limb blood flow in humans. The increased limb muscle
vasodilatation in these conditions of elevated muscle
sympathetic vasoconstrictor activity is closely related
to the rise in arterial plasma ATP and local tissue temperature (Pearson et al., 2011).
ATP, infused intravascularly, can induce pronounced
skeletal muscle vasodilatation, as shown in a number
of studies in humans. The combined inhibition of NO,
prostaglandins, and EDHFs was shown to inhibit ATPinduced vasodilatation in the human leg (Mortensen
et al., 2007). Endothelial P2Y2 receptors are involved
in ATP-induced vasodilation of human leg skeletal
muscle and are coupled to release of NO and prostaglandins; adenosine does not appear to be involved
(Mortensen et al., 2009a). In human contracting forearm and leg skeletal muscle, activation of ATP/UTPselective P2Y2 receptors on endothelial cells increases
blood flow and blunts sympathetic vasoconstriction
elicited via P2X and a1 receptors (Kirby et al., 2008;
Rosenmeier et al., 2008; Mortensen et al., 2009b). ATP
evokes vasodilation of human forearm skeletal microvessels (van Ginneken et al., 2004), but perhaps not via
NO (Shiramoto et al., 1997).
A role of the endothelium in mediating the dilator
actions of ATP via P2Y receptors on microvessels in the
rabbit hindlimb was suggested, and in addition there
was direct vasoconstriction via P2X receptors and vasodilation via P1 receptors (Dézsi et al., 1990). ADP
hyperpolarized and relaxed rabbit skeletal muscle
resistance arteries; the response was abolished by
removal of the endothelium (Brayden, 1991). ATP
dilated arterioles of skeletal muscle via the endothelium in rats (Koller et al., 1991) and rabbits (Pohl et al.,
1987). ATP and UTP dilate the cat hindlimb vascular
bed, but these effects were not blocked by NOS or
prostaglandin inhibitors or by inhibition of KATP channels (Champion and Kadowitz, 2000; Shah et al., 2001).
134
Burnstock and Ralevic
In the hamster cremaster microcirculatory preparation, ATP-mediated release of arachidonic acid metabolites from the vascular endothelium causes arteriolar
dilation (Hammer et al., 2001). ATP induces an increase in [Ca2+]i, which stimulates PGI2 synthesis in
endothelial cells of veins isolated from the hamster
hindlimb (Choi et al., 2002). In a subsequent study,
these authors showed that ATP, but not adenosine,
stimulates the release of PGI2 from the endothelium of
perfused veins isolated from the hamster hindlimb
(Hammer et al., 2003).
a,b-MeATP evokes reflex cardiovascular responses
in muscle microvessels, via P2X receptors, when injected into the arterial supply of the cat hindlimb vasculature (Li and Sinoway, 2002; Hanna et al., 2002;
Gao et al., 2006). P2X receptors can produce vasoconstriction in exercising canine skeletal muscle (Buckwalter
et al., 2003, 2004). Muscle acidosis was shown to attenuate
P2X receptor pressor responses but enhance TRPV1
pressor responses induced by femoral artery injection
of a,b-meATP and capsaicin, respectively, in rats (Gao
et al., 2007).
Adenosine and probably ATP contribute to blood flow
regulation in the exercising human leg by increasing
prostaglandin and NO formation (Mortensen et al.,
2009c; see Hellsten et al., 2012). Adenosine produced
prolonged vasodilation of arterioles after contraction or
exercise of canine skeletal muscle (Belloni et al., 1979;
Kille and Klabunde, 1984; Proctor, 1984). In addition,
adenosine acts on presynaptic receptors to inhibit
sympathetic nerve-mediated vasoconstriction (Fuglsang
and Crone, 1987). However, in studies of canine gracilis
muscle, it was concluded that, although released adenosine could contribute to exercise hyperemia, it is likely
not to be the main factor, particularly in the initial
stage (Ballard et al., 1987; Koch et al., 1990). Adenosine, acting via A2A receptors, contributes up to 30% of
the functional hyperemic response in the hindlimb of
anesthetized cats (Poucher, 1996). Both A1 and A2A
receptors were claimed to mediate adenosine-induced
vasodilatation of skeletal muscle of rat (Bryan and
Marshall, 1999) and cat (Bivalacqua et al., 2002a). It
was proposed that, although twitch contractions in rat
extensor digitorum long muscle produce a large hyperemia in femoral vessels, adenosine, acting via A2A
receptors, plays a greater role in the hyperemia associated with tetanic contractions (Ray and Marshall,
2009). A1 receptors play the predominant role in mediating adenosine-induced vasodilation of rat diaphragmatic arterioles via NO and ATP-dependent K+ channels
(Danialou et al., 1997). A2A receptors were shown to
modulate juvenile female rat skeletal muscle microvessel permeability (Wang and Huxley, 2006).
In femoral arteries of dog and rabbit, vasodilatation
evoked by ATP and ADP was endothelium dependent
in contrast to the dilatation produced by adenosine,
which acted directly on the vascular smooth muscle via
A2 receptors (De Mey and Vanhoutte, 1981; Cassis
et al., 1987). Säiag et al. (1990) showed vasoconstriction of femoral artery by ATP and UTP, suggesting
that both P2X and P2Y2 and/or P2Y4 receptors were
present. Sympathetic nervous control of femoral vasoconstriction involves ATP, released as a cotransmitter with
NA, playing the dominant role in response to lowfrequency stimulation (Bradley and Johnson, 2002;
Kluess et al., 2006). Acidosis attenuates P2X receptor
vasocontraction in rat isolated femoral (and iliac)
arteries (Kluess et al., 2005a), similar to the attenuation of P2X receptor-mediated pressor responses observed with acidosis in hindlimb skeletal muscle (Gao
et al., 2007). Elevated temperature decreases sensitivity of P2X receptors in femoral arteries (Kluess et al.,
2005b).
In human and rabbit skeletal muscle, erythrocytes
function as an O2 sensor, contributing to the regulation
of blood flow by releasing ATP (González-Alonso et al.,
2002; Ellsworth, 2004; Sprague et al., 2009; Ellsworth
and Sprague, 2012; González-Alonso, 2012). It was
suggested that the hemolysis of erythrocytes that
occurs after subarachnoid hemorrhage releases ATP
in concentrations that cause vasospasm in the rat femoral artery (Macdonald et al., 1998). ADP is involved in
photochemically induced thrombosis of the guinea pig
femoral artery (Hirata et al., 1993).
Adenosine appears to mediate fetal femoral arterial
vasoconstriction by its involvement in fetal carotid
chemoreflexes during hypoxemia (Giussani et al., 2001).
A2 receptor agonists were more potent at eliciting
vasodilation of the femoral vein than the femoral artery of rats; A2 receptor-induced vasodilatation is partially endothelium dependent in the femoral artery but
not in the vein (Abiru et al., 1995).
J. Pulmonary Vessels
Evidence for release of NA and ATP as cotransmitters from sympathetic nerves supplying rabbit pulmonary arteries was recognized (Katsuragi and Su, 1982;
Mohri et al., 1993). An important advance was made
when it was shown that EJPs recorded in the smooth
muscle of rat intrapulmonary arteries in response to
sympathetic nerve stimulation were mediated by ATP
(Inoue and Kannan, 1988). Adenosine, acting prejunctionally, inhibits release of transmitter from sympathetic nerves supplying the rabbit pulmonary artery
(Husted and Nedergaard, 1985). In guinea pig pulmonary vessels, inhibitory purinergic neurotransmission
has been described, and it was claimed that this was
endothelium dependent (Liu et al., 1992).
In the isolated, blood-perfused and ventilated rat
lung, P2X receptors activated by a,b-meATP caused
vasoconstriction, whereas P2Y receptors, probably
largely located on the endothelium, mediated a small
vasodilator response (Liu et al., 1989; McCormack
et al., 1989a). Vasoconstriction of the rat pulmonary
Purinergic Signaling and Blood Vessels
vascular bed was elicited equipotently by ATP, UTP,
and UDP; contractions to UTP and UDP were resistant
to suramin antagonism, whereas those to ATP were
blocked (Rubino and Burnstock, 1996) and so were
probably mediated by P2Y4 and P2Y6 receptors on
smooth muscle. In endothelium-denuded rat pulmonary arteries, P2Y2 receptors and a UDP-sensitive receptor (presumably P2Y6) were identified on myocytes
(Hartley et al., 1998). In a recent article (Mitchell et al.,
2012), P2Y1, P2Y6, and P2Y12 receptors were reported
to mediate contraction of rat intrapulmonary arteries.
An ATP-induced increase in [Ca2+]i in rat pulmonary
artery myocytes was mediated by P2X and P2U (P2Y2
and/or P2Y4) receptors (Guibert et al., 1996; Hartley
and Kozlowski, 1997). Regional variation in P2 receptor expression mediating constriction in the rat pulmonary arterial circulation was reported and, although
ATP was shown to be a potent constrictor in rat perfused lung (Rubino and Burnstock, 1996), it was only
a weak agonist in rat isolated intrapulmonary arteries;
in these arteries UTP and UDP were more potent than
ATP and were equipotent in inducing vasoconstriction
(Rubino et al., 1999). However, another report found
that P2Y receptor agonist potencies were similar in
large and small rat pulmonary vessels, but P2X receptor agonists were more potent in small arteries (Chootip
et al., 2002). However, in a more recent article from
this laboratory, it was reported that the pharmacological properties and mRNA and protein expression
profiles of P2X receptors in rat small and large
pulmonary arteries were very similar and that P2X1
receptors appeared to be the predominant subunit
involved (Syed et al., 2010). Rho kinase and PKC play
a role in P2X1-evoked contractions of small pulmonary
artery (Syed and Kennedy, 2010). In feline pulmonary
arteries ATP appears to elicit contraction in part
through A1 receptors after its breakdown to adenosine
(Neely et al., 1991). ATP and a,b-meATP induce
contraction of rabbit pulmonary artery (Baek et al.,
2008). Up4A has been identified as a novel endotheliumderived vasoconstrictor (Jankowski et al., 2005) and
has been shown to stimulate endothelium-independent
contraction of rat isolated pulmonary artery (Gui et al.,
2008).
Endothelium-dependent relaxation of human pulmonary arteries by ATP has been demonstrated
(Greenberg et al., 1987; Dinh Xuan et al., 1990). In rabbit
pulmonary arteries, relaxation to UTP was endothelium dependent, whereas relaxation to ATP was only
partially inhibited by removing the endothelium
(Qasabian et al., 1997). In contrast, ATP and 2-MeSATP
evoked endothelium-dependent vasodilatation in the
rat isolated pulmonary circulation, suggesting an
involvement of P2Y1 receptors; this involved NO but
there was no evidence for a role of prostanoids (Hasséssian
and Burnstock, 1995; Hakim et al., 1997). Similarly,
ATP and 2-MeSATP evoked endothelium-dependent
135
vasodilatation in rat isolated intrapulmonary arteries,
also indicating a likely action at P2Y1 receptors; UTP
and UDP lacked vasodilator activity (Rubino et al.,
1999), showing further species differences compared
with the rabbit pulmonary arteries described above.
ATP and UTP, acting via P2Y1 and P2Y2 and/or P2Y4
receptors, cause mobilization of intracellular Ca2+ and
subsequent PGI2 release in bovine pulmonary artery
endothelial cells (Lustig et al., 1992; Chen et al., 1996).
PKCbI mediates inhibition of P2Y1 and P2Y2 receptormediated phosphoinositide turnover in bovine pulmonary artery endothelial cells (Chen and Lin, 1999).
Porcine pulmonary vessels also express P2 receptors,
eliciting PGI2 release (Hellewell and Pearson, 1984).
Intercellular communication via Ca2+ waves upon mechanical stimulation of calf pulmonary artery endothelial
cells is mediated by nucleotides (Moerenhout et al., 2001).
Shear stress evokes release of ATP from endothelial
cells, which causes NO release and rat pulmonary
artery vasodilation (Hasséssian et al., 1993). ATP release
induced by NA from endothelial cells was greater in
the distal (smaller) compared with proximal pulmonary arteries of the rabbit (Takeuchi et al., 1995).
Shear stress stimulates human pulmonary artery
endothelial cells to release ATP, which then activates
Ca 2+ influx in endothelial cells via P2X 4 receptors
(Yamamoto et al., 2003). P2X4 receptor knockout mice
do not exhibit normal endothelial cell responses to
shear stress, showing reduced vasodilatation, impaired
[Ca2+]i influx and subsequent NO production, and
impaired vascular remodeling (Ando and Yamamoto,
2009). In addition to ATP released from endothelial
cells, ATP release from erythrocytes contributes to
release of NO and subsequent vasodilation (Sprague
et al., 1996; Kotsis and Spence, 2003). Distension of the
main pulmonary artery in anesthetized dogs stimulates vagal afferent activity (Moore et al., 2004), perhaps via purinergic mechanosensory transduction,
where ATP released in response to stretch acts on
P2X3 receptors expressed on sensory nerve terminals
in the vessel wall (see Burnstock, 2007). A previously
published article (Dieterle et al., 1978) described
hydrolysis of ATP to adenosine by cultures of porcine
pulmonary endothelial cells and uptake of adenosine,
which was rapidly phosphorylated by adenosine kinase. Inhibition of ecto-ATPase by ATPgS, a,b-meATP,
and 59-adenylylimidodiphosphate in endothelial cells
of bovine pulmonary artery has been reported (Chen
and Lin, 1997).
Adenosine mediates vasodilatation via P1 receptors
but does not mediate the vasodilator response to ATP
in the feline pulmonary vascular bed (Neely et al.,
1989). P1 receptors also mediate relaxation of bovine
bronchial arteries (Alexander and Eyre, 1985). In
human pulmonary arteries, the vasodilator effect of
adenosine is mediated by A2 receptors (McCormack
et al., 1989b). Adenosine markedly increases fetal ovine
136
Burnstock and Ralevic
pulmonary blood flow (Smolich et al., 2012). Adenosine,
acting via A2 receptors, dilates juvenile rabbit pulmonary arteries and veins (Steinhorn et al., 1994) and
adult rabbit perfused lung (Pearl, 1994); it is likely that
the A 2 receptors are located on the smooth muscle
because in rabbit isolated pulmonary artery the
vasodilator effect of adenosine is endothelium independent (El-Kashef et al., 1999). Adenosine also constricts
the pulmonary vasculature of a number of species
(Neely et al., 1991; Wiklund et al., 1987; Biaggioni
et al., 1989). In the feline pulmonary vascular bed this
involved A1 receptors (Neely et al., 1991; Cheng et al.,
1996); adenosine caused vasoconstriction via A1 receptors and vasodilation via A2 receptors but not by releasing NO (Cheng et al., 1996). Similarly, adenosine
elicits both contractile and relaxant effects on the
pulmonary artery of guinea pigs via A1 and A2B receptors, respectively (Szentmiklósi et al., 1995); the contractile effect was abolished by cyclooxygenase inhibition
with indomethacin (Biaggioni et al., 1989).
Compared with ovine pulmonary artery rings from
postnatal animals, ovine fetal pulmonary artery rings
have diminished endothelium-mediated relaxation to
ADP (Abman et al., 1991). ATP and adenosine increase
pulmonary blood flow in perinatal lamb via P1 and P2
receptors that are independent of PGI2 synthesis
(Konduri et al., 1992); these receptors were later identified as A2A and P2Y1 receptors, respectively (Konduri
et al., 2000), and shown to act via NO (Konduri and
Mital, 2000). An increase in ATP release during oxygen
exposure may contribute to birth-related pulmonary
vasodilation in fetal lambs (Konduri and Mattei, 2002).
ATP causes NO-mediated pulmonary vasodilation
predominantly via endothelial P2Y2 receptors in newborn rabbits (Konduri et al., 2004).
It has long been known that, unlike in most other
vascular beds, hypoxia induces pulmonary vasoconstriction (von Euler and Liljestrand, 1946), which may
lead to pulmonary hypertension. Hypoxia can also result in pulmonary vasodilation, and this was shown not
to be mediated by adenosine (Gottlieb et al., 1984). The
pulmonary hypertensive response to endotoxin was
first reported by Hinshaw and colleagues (1957), and
damage to the endothelium may play a role in the
development of pulmonary hypertension in humans
(Greenberg et al., 1987). ATP-MgCl2 has been shown to
reduce the vasoconstriction associated with hypoxic
pulmonary hypertension (Paidas et al., 1988). It was
subsequently proposed that ATP and adenosine may
have a beneficial role in the management of pulmonary
hypertension in children (Konduri, 1994). Adenosine
can decrease pulmonary artery pressure and vascular
resistance in patients with primary pulmonary hypertension who respond to calcium channel blockers (Inbar
et al., 1993). ATP-induced pulmonary vasodilation has
been described in patients with chronic obstructive
pulmonary disease (Gaba and Préfaut, 1990).
Extracellular nucleotides enhance leukocyte adherence to pulmonary artery endothelial cells via P2Y
receptors, and because adherence of leukocytes is an
important early step in acute vascular injuries, it was
speculated that nucleotide-induced leukocyte adherence could be important in mediating vascular injuries
in such conditions as respiratory distress syndrome
and septic shock (Dawicki et al., 1995). Permeability
edema is a life-threatening complication accompanying
acute lung injury. Extracellular ATP, produced during
inflammation, induces a rapid and dose-dependent
increase in transendothelial electrical resistance, and
restoration of endothelial barrier integrity is achieved
via ATP and adenosine acting on endothelial P2Y and
A2 receptors (Lucas et al., 2009). LPS binds to and
activates A1 receptors on human pulmonary artery
endothelial cells and thus may be involved in acute
lung injury because of Gram-negative septicemia and
endotoxemia (Wilson and Batra, 2002).
Extracellular ATP is a proangiogenic factor for pulmonary artery vasa vasorum endothelial cells, potentiating the effect of both vascular endothelial growth factor
and basic fibroblast growth factor (Gerasimovskaya
et al., 2008). Hypoxia, through the hypoxia-inducible
transcription factors (HIF)-1a and HIF-2a, induces
angiogenesis by upregulating cytokines. The adenosine
A2A receptor is an angiogenic target of HIF-2a in
human pulmonary endothelial cells and mediates increases in cell proliferation, cell migration, and tube
formation (Ahmad et al., 2009). The authors further
show that there is increased expression of A2A receptors in human lung cancer.
Dormant pulmonary vein conduction can be transiently
restored by ATP after extensive encircling pulmonary vein
isolation, and it has been claimed that radiofrequency
application for provoked ATP-reconnection may reduce
atrial fibrillation recurrence (Hachiya et al., 2007). Adenosine restores atriovenous conduction after ostial isolation
of pulmonary veins (Tritto et al., 2004). Spontaneous
ectopy arising from pulmonary veins is a trigger for atrial
fibrillation, and adenosine can induce pulmonary vein
ectopy (Cheung et al., 2012).
Reviews, which include discussion of the roles of
purines in control of pulmonary vascular tone, have
been published (Liu and Barnes, 1994).
K. Carotid Artery
ATP produced vasoconstriction that was more potent
than that produced by ADP in dog internal and external carotid arteries (Chiba et al., 1980). ATP vasoconstriction was via an increase in Ca2+ influx into the
smooth muscle cells of canine internal carotid artery
(Kawai et al., 1984). Endothelium-dependent hyperpolarizations in intimal smooth muscle cells were
elicited by ATP and ADP in rabbit carotid arteries,
whereas in adventitial smooth muscle cells the nucleotides produced depolarizations (Chen and Suzuki, 1991).
Purinergic Signaling and Blood Vessels
Abluminal application of ATP and ADP produced
vasoconstriction of rabbit carotid arteries via P2X
receptors, whereas intraluminal application of ADP
produced endothelium-mediated vasodilatation via
P2Y receptors (Kaul et al., 1992). The endotheliumdependent dilator effect of ATP via P2Y1 receptors was
via production of NO in rat carotid arteries, whereas
the endothelium-dependent dilations produced by UTP
mediated by P2U (P2Y2 or P2Y4) receptors did not
involve NO but probably EDHF (Malmsjö et al., 1998).
Adenosine produced vasodilation in dog internal and
external carotid arteries (Chiba et al., 1980). Adenosine is also a vasodilator in internal carotid arteries of
adult pigs but is less effective at eliciting vasodilatation in newborn pigs (Laudignon et al., 1990). The
ability of adenosine to release NO and cause vasodilation in the carotid artery and its circulation was shown
to be greater in mature than in juvenile or middle-aged
rats (Omar and Marshall, 2010). Adenosine acts as
a prejunctional inhibitory modulator of sympathetic
neurotransmission to the canine cavernous carotid artery (Fujiwara et al., 1986). In A2A receptor knockout
mice, there was enhanced homing ability of leukocytes
and increased formation of the neointima of injured
carotid arteries (Wang et al., 2010a).
L. Splenic Vessels
Adenosine was shown early to evoke mouse splenic
arteriolar dilation (Reilly and McCuskey, 1977). Later
ATP was shown to constrict canine perfused splenic
arteries (Ren et al., 1994). EJPs were recorded in arteriolar smooth muscle of splenic vessels of guinea pigs
and rats in response to sympathetic nerve stimulation
(Jobling, 1994). Later it was shown that ATP and NA
were cotransmitters in sympathetic nerves supplying
canine and rabbit splenic arteries, the purinergic component being predominant at low stimulation frequencies (Ren et al., 1996; Ren and Burnstock, 1997). a,b-MeATP
abolished the purinergic component of sympathetic
nerve-stimulated responses of canine splenic arteries
(Yang and Chiba, 1999b), consistent with activation of
P2X1 receptors. Yang and Chiba (2001) later showed
that activation of prejunctional NPY1 receptors enhanced the prolonged adrenergic vasoconstriction but
not the transient purinergic vasoconstriction. Prejunctional P1 receptors, a2 adrenoceptors, and Ang-II receptors can modulate the release of NA and ATP (Yang
and Chiba, 1999a, 2003). Precontraction with the
thromboxane-mimetic U46619 potentiated P2X receptormediated contractions in porcine isolated splenic arteries (Roberts, 2012).
M. Uterine Artery
EJPs were recorded in guinea pig uterine artery
smooth muscle cells in response to sympathetic nerve
stimulation, and there was a decrease in amplitude
of EJPs during pregnancy (Tare et al., 1998). ATP
137
released by sympathetic nerve stimulation to the
human uterine artery produced contractions via P2
receptors and inhibition of NA release via prejunctional A1 receptors (Neta et al., 1999). A study of purine
and pyrimidine receptors in human uterine artery led
to the conclusion that there are P2X1 (or P2X3) and
P2Y2 receptors on smooth muscle mediating contraction, whereas stimulation of P2Y2 receptors on endothelium produces NO, inducing relaxation (Fontes Ribeiro
et al., 1999).
Endothelial cells from ovine uterine arteries respond
to extracellular ATP via P2Y receptors, occupation of
which leads to Ca2+ release from the endoplasmic reticulum; a pregnancy-specific modulator role of mitochondria in this signaling mechanism has been described
(Yi and Bird, 2005). Pregnancy-enhanced gap junction
intercellular communication supports sustained phase
ATP-induced [Ca2+]i bursts in sheep uterine artery
endothelial cells (Yi et al., 2005). Studies of purinergic
signaling to uterine artery endothelial cells from pregnant and non-pregnant ewes identified pregnancyenhanced Ca2+ responses to ATP; P2Y2 receptors were
identified as the principal receptor subtype mediating
these effects in both pregnant and nonpregnant conditions, although expression of P2X1, P2X2, P2X7,
P2Y1, P2Y6, and P2Y11 receptors was also found on
uterine endothelial cells (Gifford et al., 2006).
N. Human Umbilical and Placental Vessels
1. Human Umbilical Vessels. Pharmacological and
histochemical evidence for P2X receptors on the smooth
muscle of both human umbilical artery and vein was
presented (Bo et al., 1998). On the basis of pharmacological experiments, P2X1, P2X4, and P2X7 receptors
were identified on the smooth muscle of human
umbilical cord and chorionic blood vessels (Valdecantos
et al., 2003). Calcium oscillations were induced by ATP
acting on P2Y receptors on human umbilical arterial
muscle cells (Meng et al., 2007). ATP, via P2X1 receptors, produced fast, transient cationic currents and increased [Ca2+]i in human umbilical artery smooth muscle
cells (Enrique et al., 2012). The expression of P2X
receptors on human umbilical cord lymphocyte CD34+
cells was significantly higher than that of adult human
blood cells, and it was suggested that this may reflect
early involvement of P2X receptors in differentiation of
human hemopoietic cells (Kazakova et al., 2011).
Because there are no nerves in umbilical vessels, this
implies an important role of locally released nucleotides in purinergic regulation of umbilical vascular
function. Thrombin, at physiologic concentrations, is
a potent stimulus of HUVEC ATP release involving
activation of the thrombin-specific, protease-activated
receptor 1, and intracellular calcium mobilization (Gödecke
et al., 2012). Reducing pannexin 1 expression reduced
ATP release, whereas downregulation of connexin 43
was ineffective (Gödecke et al., 2012). Hypoxia caused
138
Burnstock and Ralevic
ATP to be released from HUVECs (To et al., 2011). The
G protein agonist compound 48/80 also stimulated
release of ATP from HUVECs (Gruenhagen and Yeung,
2004). Because pannexin 1 is activated by anoxia and
ischemia (MacVicar and Thompson, 2010), it would be
interesting to investigate the possible involvement of
pannexins in ATP release from HUVECs during hypoxia and other stimuli.
ATP evokes hyperpolarization and NO synthesis in
endothelial cells cultured from human umbilical vein;
the pathway for NO synthesis was distinct from that
used by estrogen to produce NO (Sheng et al., 2008). A
more recent study showed that P2Y2 receptors are the
principal nucleotide receptors in HUVECs mediating
rapid Ca2+ mobilization, membrane hyperpolarization,
and NO production, events that underlie vasorelaxation to ATP and UTP via P2Y2 receptors (Raqeeb
et al., 2011). P2 receptors were characterized on the
HUVEC cell lines ECV304 (Conant et al., 1998) and
EAhy 926 (Graham et al., 1996) and both P2Y1 receptors, sensitive to Ap3A, and P2Y2 receptors, sensitive to
UTP but insensitive to diadenosine polyphosphates,
were identified. ATP acting on P2Y receptors on
HUVECs regulates PGI2 release via transient elevation of [Ca2+]i from intracellular bound stores (Carter
et al., 1988). Desensitization of PGI2 synthesis by ATP
is likely to be due to uncoupling of the P2Y receptor
from phosphoinositidase C but does not involve PKC
activation (Carter et al., 1990). Cultured HUVECs were
shown to synthesize platelet-activating factor as well
as PGI2 in response to ATP (McIntyre et al., 1985). P2Y
receptors activate MAPK/extracellular signal-regulated
kinase (ERK) through a pathway involving P13K/
PDK1/PKC-z in HUVECs (Montiel et al., 2006). In another HUVEC cell line (EAhy 926 cells), P2Y receptormediated inhibition of TNFa was demonstrated (Paul
et al., 2000).
HUVECs have high ATP synthesizing activity on
their cell surface, and this appears to be involved in the
proliferation of these cells in cancer (Arakaki et al.,
2003). ADP breakdown to adenosine by cultured HUVECs
was shown early (Dosne et al., 1979). Plasma membrane ATPases were first identified on the HUVEC cell
line ECV 304 (Meghji and Burnstock, 1995). Later ENTPDase 1/CD39 was shown to be present on HUVECs
(Koziak et al., 1999). Extracellular ATP formation in
cultured HUVECs is mediated by ectonucleotide
kinase activities via phosphotransfer reactions (Yegutkin et al., 2001). Perindopril, an angiotensin-converting
enzyme inhibitor, augments ecto-ATP diphosphohydrolase activity and platelet aggregation in HUVECs
(Kishi et al., 2003). LPS upregulates ecto-59-nucleotidase activity on HUVECs, and it was suggested that
because adenosine is an anti-inflammatory molecule,
59-nucleotidase upregulation may protect endothelial
cells against inflammatory damage (Li et al., 2008b).
Adenosine concentration in umbilical venous blood
increased significantly in anemic fetuses, suggesting
that the fetus responds to hypoxia by increasing blood
adenosine (Ross Russell et al., 1993). Functional A1
and A2B receptors were shown to be expressed on the
HUVEC-derived ECV304 cell line (Kobayashi et al.,
2005). A2B receptors have also been claimed to be
present on HUVECs (Fang and Olah, 2007).
2. Placental Vessels. Adenosine causes a biphasic
response, vasoconstriction followed by vasodilation, in
ovine fetal placental vasculature (Reid et al., 1990). In
human chorionic arteries A2B receptors, which are
normally vasorelaxant (see Table 2), caused contraction mediated by actions at both the endothelium and
smooth muscle and induction of the arachidonic acid
cascade (Donoso et al., 2005). It was suggested that A3
receptors mediate smooth muscle relaxation in human
chorionic arteries (Donoso et al., 2005).
ATP contracts human placental vascular smooth muscle via P2X receptors; UTP mediates weak vasoconstriction via P2Y2 (or P2Y4) receptors on smooth muscle;
ADP, ATP, and UTP dilate placental vessels, likely via
endothelial P2Y1 and P2Y2 receptors, and involve
release of NO (see Read et al., 1993; Ralevic et al., 1997;
Buvinic et al., 2006). Interestingly, contractile responses to ATP and a,b-meATP were sustained in human
perfused placental cotyledons and human placental
chorionic surface arteries (Dobronyi et al., 1997; Ralevic
et al., 1997) in contrast with the rapidly desensitizing
responses observed to a,b-meATP via P2X1 receptors
in most other blood vessels. Furthermore, responses to
ATP and a,b-meATP were blocked by suramin and
insensitive to PPADS (a P2 receptor antagonist that
blocks P2X1 responses in other vessels), whereas UTP
elicited little or no contraction, which might indicate
the involvement of heteromeric P2X receptors (Dobronyi et al., 1997; Ralevic et al., 1997). An elegant study
by Buvinic et al. (2006) showed that P2Y1 and P2Y2 (or
P2Y4) receptors were coupled to both contraction and
relaxation in human perfused placental cotyledons and
that these receptors were unevenly distributed along
the placental vascular tree; in the chord and chorionic
vessels P2Y1 and P2Y2 receptor distribution was
mainly in the smooth muscle, whereas in the cotyledon
vessel these receptors were equally distributed between the endothelium and smooth muscle cells (Buvinic
et al., 2006).
O. Saphenous Vessels
1. Saphenous Artery. The rabbit saphenous artery
exhibits a large purinergic component of the contractile
response to sympathetic nerve stimulation (Burnstock
and Warland, 1987a; Warland and Burnstock, 1987).
At a stimulation frequency of 2 Hz, the principal transmitter is ATP, while at higher frequencies both NA and
ATP are involved (Zhang and Ren, 2001). EJPs recorded in smooth muscle of the guinea pig saphenous
artery were inhibited by arylazido amino propyl ATP,
Purinergic Signaling and Blood Vessels
a P2 receptor antagonist (Cheung and Fujioka, 1986)
and also by suramin (Nally and Muir, 1992). The
purinergic contractile component of rabbit saphenous
(and ileocolic) arteries was antagonized by nifedipine,
a calcium channel blocker (Bulloch et al., 1991).
Prejunctional a2-adrenoceptors and P2 receptors were
suggested to play a role in the autoregulation of neuromuscular transmission in the guinea pig saphenous
artery (Fujioka and Cheung, 1987). NPY potentiates
the purinergic component of the neural response in
guinea pig saphenous artery (Cheung, 1991). ET-1
modulates cotransmission in the rabbit saphenous
artery by potentiating postjunctionally the purinergic
component of the contractile response to nerve stimulation and to exogenous ATP (Mutafova-Yambolieva
and Radomirov, 1994). NF023, a selective P2X1 receptor antagonist (Lambrecht, 1996), blocked the constrictor response of rabbit saphenous artery to a,b-meATP
but not the endothelium-dependent and -independent
responses mediated by P2Y receptors (Ziyal et al., 1997).
Substantial release of ATP from endothelial cells from
rat saphenous artery in response to a1-adrenoceptor
activation has been reported (Shinozuka et al., 1997).
2. Saphenous Vein. Sympathetic cotransmission
involving NA, ATP, and NPY has been described for
the human saphenous vein (Rump and von Kügelgen,
1994; Racchi et al., 1999; Loesch and Dashwood, 2009)
and dog saphenous vein, where an involvement of a1and a2-adrenoceptors and P2X receptors was shown
(Hiraoka et al., 2000). ATP elicited a transient inward
current and increased [Ca2+]i in freshly isolated
smooth muscle cells of human saphenous vein via
P2X receptors (Loirand and Pacaud, 1995). NPY, acting postjunctionally, potentiated the vasoconstriction
elicited by ATP as well as NA (Donoso et al., 2004).
Diadenosine polyphosphates are coreleased with ATP
into the blood stream from the dense granules of
platelets, and Ap3A was an effective agonist at eliciting
calcium responses at P2Y1 and P2Y2 receptors expressed on human cultured saphenous vein endothelial
cells; other diadenosine polyphosphates were largely
ineffective agonists (Conant et al., 2000). Downregulation of P2X1 receptors mediating contraction and
upregulation of P2Y1 and P2Y2 receptors has been demonstrated in human long saphenous vein during
varicose disease (Metcalfe et al., 2007).
P. Renal Vessels
1. Microcirculation. Adenosine was shown early to
increase vascular resistance in the kidneys of pigs,
dogs, rabbits, and rats, whereas it vasodilates most
other nonrenal blood vessels (Thurau, 1964; Scott
et al., 1965; Osswald, 1975; Sakai et al., 1981). Sympathetic nerve-mediated vasoconstriction results in
release of adenosine into the perfusate of the kidney
vascular bed (Fredholm and Hedqvist, 1978), in retrospect probably released from endothelial cells in
139
response to shear stress induced by changes in blood
flow. Ecto-59-nucleotidase controls the renal production
of adenosine (Ramos-Salazar and Baines, 1986). It was
suggested that the intrarenal vasoconstrictor effects of
adenosine were mediated by an angiotensin mechanism
(Spielman and Osswald, 1979; Dietrich et al., 1991),
and inhibition of adenosine A1 receptor-mediated glomerular vasoconstriction in angiotensin AT1A receptordeficient mice has been reported (Traynor et al., 1998).
Conversely, attenuated renovascular constrictor responses to Ang-II have been reported in A1 receptor
knockout mice (Hansen et al., 2003). However, one
article (Barrett and Droppleman, 1993) presented
evidence against an interaction between renovascular
A1 and angiotensin AT1 receptors. The vasoconstriction
elicited by intravenous infusion of adenosine acting via
A1 receptors is short lasting, being replaced within 1–2
minutes by vasodilation, probably mediated by A2
receptors on endothelial cells generating NO (Hansen
and Schnermann, 2003; Hansen et al., 2005).
ATP has a vasodilatory effect in the renal circulation, but only when given directly into the renal artery;
ATP is used clinically to induce hypotension, but is not
effective if administered intravenously (Hashimoto
et al., 1988). ATP dilates the rat perfused kidney via
endothelial release of NO (Radermacher et al., 1990).
In rat isolated perfused kidneys, it was shown that P2X
receptors, and perhaps also P2U (P2Y2 and/or P2Y4)
receptors mediating vasoconstriction, are located on
smooth muscle and that endothelial P2Y receptors
mediate vasodilation involving NO but not prostanoids
(Churchill and Ellis, 1993a; Eltze and Ullrich, 1996).
P2X1 receptors have been localized using autoradiography and immunochemistry on vascular smooth
muscle cells of rat intrarenal arcuate and interlobular
arteries and afferent (but not efferent) glomerular
arterioles (Chan et al., 1998). Renal periarterial (sympathetic) nerve stimulation induced vasoconstriction at
low frequencies and was primarily due to ATP release
in the rat perfused kidney (Schwartz and Malik, 1989).
Neuronal- and paracrine-released nucleotides evoke
renal vasoconstriction of mouse perfused kidney via
activation of P2X1, P2X3, and P2Y6 receptors (Vonend
et al., 2005b). a2A-Adrenoceptor activation inhibits
both NA and ATP release from mouse renal sympathetic nerves (Vonend et al., 2007). P2 receptor
antagonists enhanced noradrenergic pressor responses
of rat perfused kidney to sympathetic nerve stimulation by blocking prejunctional receptors (Bohmann
et al., 1997).
Diadenosine polyphosphates evoke transient constrictions of the rat renal microcirculation, which are
mediated by A1 and P2 receptors (Gabriëls et al., 2000).
Ap5A-induced vasoconstriction of human renal resistance vessels appeared to be mediated by P2X receptors, whereas vasodilation due to Ap4A appeared to
be mediated by P2Y receptors (Steinmetz et al., 2003).
140
Burnstock and Ralevic
Uridine, UMP, and UDP had vasoconstrictor actions in
the rat isolated perfused kidney (Macdonald et al.,
1984). Up4A was claimed to act as a potent vasoconstrictor of the rat isolated perfused kidney via P2X1
and P2Y2 receptors, whereas endothelium-dependent
vasodilation was mediated by P2Y1 and P2Y2 receptors
(Tölle et al., 2010).
2. Renal Arteries. Adenosine dilates rabbit renal
arteries, and it was suggested that this was via P1
receptors on the smooth muscle (Gagnon et al., 1980).
However, subsequent studies showed that adenosinemediated vasodilation of rabbit renal arteries is endothelium dependent, but independent of NO (Rump et al.,
1998, 1999). A2A receptors mediate vasodilation in
rabbit renal arcuate artery, and this has been claimed
to involve K+ channel activation (Prior et al., 1999). In
rat renal artery A2A receptors have been suggested to
mediate endothelium-dependent relaxation, which may
involve EDHF (Grbovic et al., 2000).
b,g-Methylene ATP, a P2X receptor agonist, produced weak vasoconstrictor responses of human renal
arteries (von Kügelgen et al., 1995). Extracellular ATP
increased cytosolic calcium in rat cultured renal artery
smooth muscle cells (Inscho et al., 1996). Freshly
isolated renal vascular smooth muscle cells from interlobular and arcuate arteries of rat kidney express genes
encoding P2X1 and P2X4 receptors (Harhun et al., 2009).
Sympathetic nerve stimulation releases both ATP and
NA in human renal arteries; ATP elicits vasoconstrictor responses via P2X receptors, whereas vasodilator
responses are mediated via P2Y receptors (Rump et al.,
1996). In the rat renal artery, P2X1, P2Y1, and P2Y2
receptors on the smooth muscle mediate vasoconstriction in response to ATP released as a cotransmitter
from sympathetic nerves (Knight et al., 2003). An unusual absence of endothelium-dependent or -independent vasodilation to purines and pyrimidines (but not
to ACh) was reported in the rat renal artery (Knight
et al., 2003). The authors speculated that the absence
of endothelium-mediated vasodilation may reflect
species variation, because in rabbits P2Y receptor
endothelium-mediated vasodilation via NO is present
(Rump et al., 1998).
3. Juxtamedullary Afferent Arterioles. Afferent arteriolar A1 receptors mediate constriction, whereas A2
receptors on afferent and efferent arterioles mediate
dilation (Murray and Churchill, 1985; Holz and Steinhausen,
1987; Givertz, 2009). Afferent arterioles perfused with
adenosine responded with persistent vasoconstriction
via A1 receptors on the smooth muscle (Hansen and
Schnermann, 2003; Hansen et al., 2007). The preglomerular vasorelaxant adenosine receptors were identified as A2A receptors (Carroll et al., 2006), whereas
dilation of efferent arterioles may be mediated by A2B
receptors (Al-Mashhadi et al., 2009). Vasodilation via
low-affinity A2 receptors and vasoconstriction via highaffinity A1 receptors and by a,b-meATP-sensitive P2
receptors (likely P2X1) has been demonstrated in rat
juxtamedullary afferent arterioles using a blood-perfused
juxtamedullary nephron preparation combined with
videomicroscopy to measure arteriolar diameter (Inscho
et al., 1991); the P2X receptors were later shown to be
present on the afferent, but not efferent, arterioles
(Inscho et al., 1992). Similarly, Weihprecht et al. (1992)
identified the P2 receptor causing vasoconstriction of
rabbit afferent arteries as a P2X receptor and also
showed a vasoconstrictor effect of adenosine via A1 receptors in the afferent arteriole.
ATP evokes a biphasic vasoconstriction of the preglomerular vasculature, and it was suggested that the
smooth muscle of juxtamedullary afferent arterioles
expresses both P2X1 and P2Y2 receptors (Inscho et al.,
1998, 1999). Both the initial and sustained phases of
ATP-mediated juxtamedullary afferent arteriolar vasoconstriction are dependent on the influx of extracellular Ca2+, and the sustained constriction is dependent
on Ca2+ entry via voltage-gated L-type calcium channels (Inscho et al., 1995). P2X1 receptor activation of
preglomerular microvascular smooth muscle cells increases [Ca2+]i via L-type Ca2+ channels (White et al.,
2001), but P2Y2 receptors mediating vasoconstriction
are also present (Inscho and Cook, 2002). P2X receptors on smooth muscle cells showed no difference in
distribution along the length of rabbit afferent arterioles (Gutiérrez et al., 1999). 20-Hydroxyeicosatetraenoic
acid, a metabolite of the arachidonic pathway, plays an
important role in the regulation of renal vascular and
tubular function, and 20-hydroxyeicosatetraenoic acid
has been shown to play a significant role in the renal
microvascular smooth muscle cell [Ca2+]i response to
P2X receptor activation (Zhao et al., 2004).
In keeping with sympathetic cotransmitter control of
afferent arterioles, ATP increases their reactivity to
low concentrations of NA (Hultström et al., 2007).
Up4A, a novel EDCF that acts via P2X1 receptors, is
a potent vasoconstrictor of rat juxtamedullary afferent
arterioles (Inscho et al., 2008). Intraglomerular ectonucleotidases regulate purine activities (Bakker et al.,
1993).
In the kidney, there is some independence of glomerular filtration rate and renal blood flow from arterial pressure between approximately 90 and 180 mm
Hg. This uncoupling occurs because of autoregulation
and ensures that there is a relative maintenance of
fluid and solute excretion in the face of fluctuations of
blood pressure. Autoregulation is brought about by
adjustments in the diameter of the afferent arteriole. It
involves a myogenic mechanism, common to many
arteries, in which the afferent arteriole contracts in
response to pressure and stretch and involves calcium
entry through voltage-dependent calcium channels. It
also involves the tubuloglomerular feedback mechanism in which the macula densa senses the sodium
chloride concentration of the filtrate and produces
Purinergic Signaling and Blood Vessels
a signal that causes afferent arteriolar constriction.
Tubuloglomerular feedback signals are coupled to autoregulatory preglomerular vasoconstriction through ATPmediated activation of P2X1 receptors (Inscho et al.,
2003). Evidence has been presented that autoregulation is impaired in P2X1 receptor knockout mice,
suggesting that ATP released from the macula densa
directly stimulates afferent arteriolar constriction via
P2X1 receptors (Inscho et al., 2004). Autoregulation and
P2X1 receptor-mediated afferent arteriolar responses
were impaired in a rat model of hypertension (Inscho
et al., 2011). However, seemingly conflicting evidence
has shown that the tubuloglomerular feedback response
is also abolished in A1 adenosine receptor knockout mice
(Brown et al., 2001; Sun et al., 2001).
ATP can stimulate secretion of renin from juxtaglomerular cells (Churchill and Ellis, 1993b), whereas
adenosine depresses renin secretion in sodium-restricted
rats (Osswald et al., 1978). A1 and A2 receptors mediate
inhibition and stimulation of renin secretion, respectively (Murray and Churchill, 1985). Mechanical
stimulation of a single juxtaglomerular cell initiated
propagation of an intracellular Ca2+ wave to up to
about 12 surrounding cells; this was prevented by
apyrase, which catalyzes the hydrolysis of ATP,
implicating ATP as the mediator responsible for the
propagation of Ca2+ signaling (Yao et al., 2003). These
authors also claimed that administration of ATP into
perfused rat kidney induced a rapid, potent, and
persistent inhibition of renin secretion with a transient
elevation of renal vascular resistance, perhaps after
breakdown to adenosine. An ATP-mediated intracellular Ca2+ wave has been demonstrated in renal juxtaglomerular endothelial cells, which may serve an important
feedback role during vasoconstriction (Bansal et al.,
2007). Bovine glomerular endothelial cells are equally
sensitive to mobilization of calcium by UTP and ATP
(Briner and Kern, 1994), suggesting that P2Y2 and/or
P2Y4 receptors may be involved.
There have been reviews about purinergic regulation
of renal blood flow (Inscho et al., 1994; Navar et al., 1996;
Inscho, 2001, 2009; Nishiyama et al., 2004; Jankowski,
2008; Schnermann and Briggs, 2008).
It has been proposed that adenosine mediates
hemodynamic changes in adult renal failure (Churchill
and Bidani, 1982; Smith et al., 2000). Cyclosporine has
become a standard component of the immunosuppressive regimen in both solid organ and bone marrow
transplantation as well as for the treatment of autoimmune diseases. However, a limiting factor in its use
has been the development of nephrotoxocity and hypertension in many patients. Hypertension is a feature of
chronic renal disease, and it has been claimed that this
is largely due to sympathetic overactivity triggered by
afferent signals emanating from the kidney and
resetting sympathetic tone by stimulation of hypothalamic centers (Orth et al., 2001). Both essential
141
hypertensive patients and patients with renal artery
stenosis show a dose-dependent vasodilation after adenosine infusion (Wierema et al., 1998, 2005). In raisedtone perfused kidneys from normal rats ATP elicited
constriction at low doses and vasodilatation at higher
doses; ATP-mediated vasoconstriction was increased in
hyperthyroid kidneys and severely attenuated in kidneys from hypothyroid rats, whereas the vasodilator
response in kidneys from hypothyroid rats was abolished (Vargas et al., 1996). A detailed review of purinergic signaling in renal ischemia can be found later in
this review.
Q. Hepatic Artery and Portal Vein
1. Hepatic Artery. Portally infused ATP leads to
transhepatic vasodilatation via P2Y receptors on the
endothelium, whereas ATP released from sympathetic
nerves leads to vasoconstriction of hepatic arteries via
P2X receptors on the muscle (Brizzolara and Burnstock,
1990, 1991; Phillips et al., 1998). Both endotheliumdependent and endothelium-independent vasodilation
of rabbit hepatic artery mediated by purines has been
described (Brizzolara and Burnstock, 1991). In the
rabbit perfused liver, both P2X vasoconstrictor and P2Y
vasodilator receptors (leading to release of NO) were
identified (Mathie et al., 1991b; Ralevic et al., 1991). In
the rat sinusoidal vascular bed, ATP impairs the flowlimited distribution of [3H]water (Fernandes et al.,
2003). ATP-MgCl2 restores depressed hepatocellular
function and hepatic blood flow after hemorrhage and
resuscitation (Wang et al., 1991). Adenosine-induced
dilation of the rabbit hepatic arterial bed is mediated
by A2 receptors (Mathie et al., 1991a).
2. Portal Vein. The first suggestion that ATP might
be a neurotransmitter in nonadrenergic vasodilator
nerves supplying the rabbit portal vein was published
by Che Su (Su and Sum, 1974; Su, 1975), and later ATP
was shown to be a cotransmitter with NA in sympathetic
vasoconstrictor nerves supplying this vein (Su, 1978a).
This was supported by subsequent experiments in the
rabbit, but not the guinea pig, portal vein (Burnstock,
et al., 1979). Brizzolara et al. (1993) showed that both
ATP and NO are inhibitory cotransmitters in NANC
nerves supplying the rabbit portal vein. Most of the ATP
released during transmural electrical stimulation of the
rabbit portal vein is from nerves (Levitt and Westfall,
1982). Nerve stimulation and ATP contracted the rat
portal vein at basal tone via P2X receptors, but caused
relaxation in veins with tone raised with ergotamine,
probably via P2Y receptors (Reilly et al., 1987). A
nonadrenergic contractile response of the guinea pig
portal vein to electrical field stimulation has been
described, which is mimicked by the response to UTP,
but not ATP (Ishizaki et al., 1997), perhaps indicating
an involvement of P2Y4 receptors on smooth muscle.
A1 receptors were identified as mediating inhibition
by adenosine of nerve stimulation-induced contractions
142
Burnstock and Ralevic
of the rabbit portal vein (Brown and Collis, 1983).
Inhibition of adrenergic neurotransmission by adenosine in the rat portal vein was also reported (Enero,
1981). However, evidence was presented by Kennedy
and Burnstock (1984) that the inhibitory prejunctional
actions of adenosine on the rat portal vein are mediated by A2 rather than A1 receptors. Experiments
carried out on electrical stimulation of the portal vein
in freely moving rats showed that overflow of NA is
under facilitatory control of its cotransmitter ATP
through prejunctional P2Y receptors (Smit et al.,
1998). ATP causes postjunctional potentiation of noradrenergic contractions in the portal vein of guinea pig
and rat (Kennedy and Burnstock, 1986).
There is evidence for two types of P2 receptor on the
longitudinal muscle of the rabbit portal vein: a P2
receptor mediating contractile responses to a,b-meATP
(P2X) and an endothelium-independent vasorelaxant
P2 receptor activated by ATP and 2-MeSATP (P2Y)
(Hughes and Vane, 1967; Burnstock et al., 1979;
Kennedy and Burnstock, 1985b). ATP activates cation
currents in the rabbit portal vein (Xiong et al., 1991;
Pacaud et al., 1994), consistent with P2X receptor
activation (Orre et al., 1996). The P2 receptor mediating contraction of the longitudinal muscle of the rat
portal vein is also the P2X receptor subtype (Reilly and
Burnstock, 1987), and P2X1 receptors have been identified on rat portal vein myocytes (Orre et al., 1996;
Mironneau et al., 2001). ATP, ADP, and UTP, but not
adenosine, introduced into the portal circulation of the
rat isolated perfused liver increased perfusion pressure
(probably via P2X, P2Y2, and/or P2Y 4 receptors),
whereas infusion of ATP, ADP, and adenosine, but not
UTP, transiently increased generation of NO (probably
via endothelial purine receptors) (Takemura et al., 1998).
Endothelium-independent relaxation of rat portal vein
smooth muscle by ATP is mediated, after breakdown
by ectonucleotidase, by adenosine activating via A2A
receptors (Guibert et al., 1998). The restoration of
hepatic blood flow with ATP-MgCl2 treatment after
hemorrhage in rats is due to increased portal vein
blood flow (Wang et al., 1992b).
R. Other Blood Vessels
From a study of the responses of canine lingual artery
to perivascular nerve stimulation, it was concluded that
neurogenic contractions were induced largely by ATP
acting via P2X receptors (Okamura et al., 1998).
P2Y1, P2Y2 (and/or P2Y4), and P2Y6 receptors were
claimed to mediate endothelium-dependent vasodilatation of human left internal mammary artery; no
evidence for the involvement of endothelial P2X4 receptors in vasodilation was found (Wihlborg et al., 2003).
P2Y12 receptor mRNA was shown to have a high expression among P2 receptors in human internal mammary vascular smooth muscle, and P2Y12 receptors
were claimed to mediate contraction of human internal
mammary artery and small veins (Wihlborg et al.,
2004).
Articular vessels supplying the rabbit knee joint
express smooth muscle P1 receptors, which mediate vasodilatation, and P2 receptors, which mediate vasoconstriction; an endothelium-dependent vasodilator
effect of ATP and ADP is also evident (Ferrell and
Khoshbaten, 1990; Matsuda et al., 2009).
Purinoceptors have been shown to be involved in the
regulation of local blood flow in the eye (Ziganshina
et al., 2012). ATP induced contraction, probably via
P2X1 receptors, in bovine ophthalmic and posterior
ciliary arteries and relaxation, probably via P1 receptors. Inhibition of bovine retinal microvascular pericyte
proliferation was mediated by adenosine (Jackson and
Carlson, 1992).
Two subtypes of P2 receptors exist on the pancreatic
vascular bed: in general P2X receptors mediate
vasoconstriction and P2Y receptors mediate vasodilation (Chapal and Loubatieres-Mariani, 1983; HillaireBuys et al., 1991). Adenosine-59-(b-thio)-diphosphate, a
P2Y1-selective agonist, caused endothelium-dependent
vasodilatation of the rat isolated perfused pancreas,
which was mediated partly by NO and PGI2 but also
through another mechanism that did not involve KATP,
SKCa, and BKCa channels (Saïag et al., 1996; HillaireBuys et al., 1998). P2X1, P2X2, P2Y1, and P2Y2 receptor
expression was shown using immunohistochemistry in
small blood vessels of the rat pancreas (Coutinho-Silva
et al., 2003). An endothelial vasocontractile P2Y14
receptor, sensitive to UDP-glucose and UDP, was described in porcine pancreatic arteries (Alsaqati et al.,
2013). The role of purine receptors in regulating endocrine and exocrine functions of the pancreas has been
reviewed (Novak, 2008).
S. Lymphatic Vessels
Transmural stimulation of bovine mesenteric lymphatics elicited a contraction followed by short- or longlasting relaxation; it was proposed that nonadrenergic
inhibitory nerves may contribute to the long-lasting
relaxation (Ohhashi and Roddie, 1981). Studies of
neuromuscular transmission in bovine mesenteric
lymphatics using the sucrose-gap technique reported
EJPs in response to nerve stimulation that, on repetitive stimulation, summed and facilitated to reach
threshold potential for firing of action potentials and
contraction (Allen and McHale, 1986), reminiscent of
EJPs mediated by ATP in response to sympathetic
nerve stimulation in the vas deferens and blood vessels
(see Burnstock and Holman, 1961; Burnstock, 1990b).
a,b-MeATP caused an intense, transient excitatory
effect on sheep isolated mesenteric lymphatics (Harty
et al., 1993). Hollywood and McHale (1994) presented
evidence that stimulation of nerves supplying the
sheep mesenteric artery produced excitation mediated
by release of ATP and NA. ATP increases lymphatic
Purinergic Signaling and Blood Vessels
smooth muscle [Ca2+]i and vasomotion via activation of
both P2X1 and P2Y2 receptors (Zhao and Van Helden,
2002).
In addition to direct excitation of lymphatic smooth
muscle, P2Y receptors on endothelial cells mediate
ATP-induced constriction via an endothelium-derived
excitatory factor, probably thromboxane A2 (Gao et al.,
1999). ATP-induced dilation and inhibition of pump
activity of lymph vessels via A1 receptors on smooth
muscle and on endothelium has been reported, probably acting via NO (Kousai et al., 2004). Shear stress
produces release of ATP from lymphatic endothelial
cells, which activates P2 receptors, thereby facilitating
NOS mRNA and protein expression (Kawai et al., 2010).
The endolymphatic sac epithelium of the mammalian inner ear absorbs endolymphatic fluid generated
from the stria vascularis in the cochlea to regulate
endolymph volume, and ATP has been shown to increase [Ca2+]i in these epithelial cells via P2Y receptors
(Wu and Mori, 1999).
IV. Long-Term Trophic Roles of Purines
and Pyrimidines
There are reviews describing the effect of purines
and pyrimidines on proliferation, differentiation, and
death of different cell types (Abbracchio, 1996; Abbracchio and Burnstock, 1998; Neary and Abbracchio, 2001;
Burnstock, 2002; Adair, 2004; Burnstock and Verkhratsky, 2010).
An important early article showed that intact innervation of the rabbit ear artery was necessary for
normal development and maintenance of the artery
wall, and trophic factors were implicated (Bevan and
Tsuru, 1981). Comparable findings were later obtained
with denervated pulmonary and mesenteric arteries
(Bevan, 1989). Impaired endothelial-mediated relaxation was observed after long-term denervation of the
auricular and central ear arteries (Mangiarua and
Bevan, 1986). Both endothelial and smooth muscle cell
migration was shown to take place in the repair of
injured vessel walls (Gotlieb, 1983). ATP and ADP
were shown to be mitogenic (Van Coevorden et al.,
1989) and ATP release from endothelial cells was
recognized (LeRoy et al., 1984; see Burnstock, 1999).
P1 and P2Y receptors mediate the trophic effects of
adenosine, ATP, ADP, UTP, and UDP on smooth
muscle and endothelial cells (Table 4).
A. Vascular Smooth Muscle
Vascular smooth muscle cell migration and proliferation are critical stages in the pathogenesis of
atherosclerosis, postangioplasty restenosis/neointimal
hyperplasia and chronic allograft rejection.
Extracellular ATP and ADP stimulate proliferation
of porcine aortic smooth muscle cells (Wang et al., 1992a).
ATP, released as a cotransmitter from sympathetic
143
nerves as well as from platelets, endothelial cells, and
damaged smooth muscle was proposed as a mediator of
vascular smooth muscle proliferation, which may play
a role in atherosclerosis and hypertension (Erlinge
et al., 1993). In addition, ADP released from platelets,
in synergy with peptide growth factors, leads to smooth
muscle proliferation at sites of vascular injury
(Crowley et al., 1994). ATP-induced modulation of cell
cycle-dependent gene mRNA levels, leading to rat
aortic smooth muscle cell proliferation, appeared to
be mediated by P2Y rather than P2X receptors, and it
was suggested that they may play a role in late postangioplasty restenosis (Malam-Souley et al., 1993), probably involving P2Y2 and/or P2Y4 receptors because
the effects were mimicked by UTP (Malam-Souley et al.,
1996). In a separate study, P2Y2 and/or P2Y4 receptors
sensitive to ATP and UTP, but not P2X1 receptors,
were similarly identified as mediators of proliferation
of rat aortic smooth muscle cells (Erlinge et al., 1995).
UDP acts as a growth factor for smooth muscle cells
cultured from rat aorta via activation of P2Y6 receptors
(Hou et al., 2002). Up4A stimulates DNA synthesis and
proliferation of human vascular smooth muscle cells
derived from the aorta; this is mediated by P2Y receptors involving the MAPK and P13K/Akt pathways
(Gui et al., 2011). Up4A is also a strong inductor of vascular smooth muscle cell migration via P2Y2 receptors
(Wiedon et al., 2012). UTP and UDP have been claimed
to induce rat aortic smooth muscle cell migration via
P2Y2 and P2Y6 receptors, respectively (Pillois et al.,
2002). Antiproliferative effects of UTP on cultured vascular smooth muscle cells derived from human internal
mammary artery and saphenous vein have been
claimed (White et al., 2000; Boarder et al., 2001). More
recently, P2X1 receptors were shown to mediate inhibition of proliferation of human coronary artery smooth
muscle cells via induction of the transcription factor
NR4A1 (Hinze et al., 2013).
Proliferation of vascular smooth muscle has consistently been shown to be accompanied by an increased
expression of P2Y receptors. The differentiated contractile phenotype of vascular smooth muscle expresses
predominantly P2X1 receptors, whereas in the dedifferentiated synthetic phenotype, P2X1 receptors are
downregulated and the mitogenic P2Y1 and P2Y2 transcripts upregulated (Erlinge et al., 1998). In a study of
human umbilical vein, it was claimed that shear stress
led to decreased expression of P2X1 receptors on smooth
muscle (leading to reduced tone) and increased expression of P2Y2 and P2Y6 receptors (which stimulate migration and growth of muscle cells), a similar phenotypic
shift as seen from cultured contractile to synthetic
smooth muscle cells (Wang et al., 2003a). Upregulation
of P2Y2 receptors and the mitogenic actions of ATP and
UTP on coronary artery smooth muscle cells have been
demonstrated in both in vitro organ cultures and in vivo
stented coronary arteries (Shen et al., 2004). Cytokines
144
Burnstock and Ralevic
induce upregulation of P2Y2 receptors on vascular
smooth muscle cells, resulting in increased mitogenic
responses to UTP and ATP (Hou et al., 2000). Arrestindependent regulation of P2Y2 receptor-stimulated MAPK
signaling is essential for migration of aortic smooth muscle cells, a key event in vascular remodeling (Morris
et al., 2012).
The mechanisms by which nucleotides promote
mitogenesis have been investigated. Low ATP concentrations stimulate expression of genes for the contractile vascular smooth muscle phenotype, whereas high
concentrations of ATP cause a phenotypic shift from
the contractile to the synthetic phenotype; this shift is
dependent on a transient activation of PKA, which
inhibits activation of a serum response factor (Hogarth
et al., 2004). ATP promotes vascular smooth muscle
cell DNA synthesis and cell proliferation during
embryonic and postnatal development after injury
and in atherosclerosis through the activation of
ERK1/2 involving both PKC-d and Ca2+/calmodulindependent protein kinase II-d2 (Ginnan et al., 2004).
ATP-stimulated coronary artery smooth muscle proliferation requires second messenger signals of both
the ERK and phosphatidylinositol-3-kinase pathways
(Wilden et al., 1998). Phosphorylation of b-catenin,
a protein that controls cell-cell adhesion and cell proliferation by PKA, promotes ATP-induced proliferation
of vascular smooth muscle cells (Taurin et al., 2008).
ATP stimulates prostaglandin E2/cyclin D1-dependent
proliferation of vascular smooth muscle via STAT3
activation and involves PKC-dependent NADPH oxidase/
ROS generation (Lee et al., 2013). Tyrphostin, a specific
inhibitor of tyrosine kinases, inhibited ATP-induced
DNA synthesis, cell proliferation, and fos-protein
expression, but not ATP-induced Ca2+ influx or vasoconstriction, in rat aortic smooth muscle cells (Erlinge
et al., 1996). The expression of osteopontin, a chemokinetic agent for several cell types, is involved in vessel
remodeling and is stimulated by UTP (Renault et al.,
2005).
Overexpression of E-NTPDase 1/CD39 decreases
vascular smooth muscle cell proliferation and prevents
neointima formation after angioplasty, consistent with
an involvement of nucleotides in these processes
(Koziak et al., 2008). E-NTPDase 1/CD39 is expressed
on mouse carotid artery smooth muscle cells and is
required for neointimal formation (Behdad et al., 2009).
These authors showed further that E-NTPDase 1/CD39
deletion impairs smooth muscle cell migration in vitro
and inhibits neointimal formation in a murine model of
injured carotid arteries.
Vascular calcification is associated with atherosclerosis, type 2 diabetes, end-stage renal disease, and aging.
Extracellular PPi is a critical inhibitor of calcification.
The PPi-generating proteins include ectophosphodiesterase/
pyrophosphatase, which catalyzes the hydrolysis of
released ATP to produce PPi. Addition of ATP rescued
cAMP- and phosphate-treated vascular smooth muscle
cell cultures from progression to the calcified state
(Prosdocimo et al., 2010).
Reviews concerned with the trophic effects of ATP on
vascular smooth muscle and endothelial cells are
available (Erlinge, 1998; Burnstock, 2002).
A1 receptors mediate the mitogenic effect of adenosine on porcine coronary artery smooth muscle cells;
8-cyclopentyl-1,3-dipropyl-xanthine, a selective antagonist of the A1 receptor, prevented the proliferation of
smooth muscle (Kang et al., 2009). Evidence for adenosine stimulation of pig coronary artery smooth muscle
cell proliferation via A1 receptors has similarly been
presented (Shen et al., 2005). Adenosine, acting via
both A1 and A2 receptors, stimulates DNA synthesis in
rat cultured arterial smooth muscle cells (Jonzon et al.,
1985). However, adenosine, via A2B receptors, has been
reported to inhibit growth of rat and human aortic
smooth muscle cells (Dubey et al., 1996, 1998; Jackson
et al., 2011). Strong effects of adenosine on gene
induction in human coronary artery vascular smooth
muscle cells via A2B receptors have been described
associated with the antiproliferative effects of adenosine
TABLE 4
Purine receptors involved in long-term tropic signaling
Smooth Muscle
P2X
Proliferation/
mitogenesis
Migration
P2Y
P2Y2
P2Y2
P2Y6
P2Y2
P2Y6
and/or P2Y4 (+)
and/or P2Y4 (2)a
(+)
(+) (P2Y4) (+)
(+)
Endothelial Cells
P1
P2X
A1 (+)
A2A (2)b
A2B (2)c
Angiogenesis
Apoptosis
P2Y
P1
P2Y1 (+)
P2Y2 and/or P2Y4 (+)
P2Y13 (+)
P2Y1 (+)
P2Y2 and/or P2Y4 (+)
A2A (+)
A2B (+)
P2Y1 (+)
P2Y2 and/or P2Y4 (+)
A2B (+)
A2A (+)
A2B (+)
A3 (+)d
A2A (+)
A2B (+)
P2X7 (+)
+, Stimulation; 2, inhibition.
a
Human internal mammary artery and saphenous vein (White et al., 2000; Boarder et al., 2001).
b
Pulmonary artery (hypertension and smooth muscle proliferation in A2A receptor knockouts) (Xu et al., 2011).
c
Human and rat aortic smooth muscle cells (Dubey et al., 1996, 1998).
d
Human endothelial progenitor cells (Fernandez et al., 2012).
Purinergic Signaling and Blood Vessels
on vascular smooth muscle cells (Mayer et al., 2011).
A2B receptor agonists have been shown to inhibit
neointimal lesion development after arterial injury in
apolipoprotein E-deficient mice, and it was suggested
that A2B agonism may be a therapeutic approach in the
prevention of restenosis (Bot et al., 2012). Adenosineinduced apoptosis of human arterial smooth muscle
cells has also been shown to involve A2B receptors
(Peyot et al., 2000). A3 receptor activation induced
proliferation of primary human coronary smooth
muscle cells, involving the induction of early growth
response genes (Hinze et al., 2012). The activity and
expression of ecto 59-nucleotidase/CD73 are increased
by thyroid hormones, which would be expected to
result in higher extracellular levels of adenosine and
consequently influence vascular smooth muscle cell
proliferation (Tamajusuku et al., 2006). Adenosine has
been claimed to regulate human vascular smooth muscle cell proliferation and migration, in part by affecting
the expression of hyaluronic acid synthase (Grandoch
et al., 2011).
B. Vascular Endothelial Cells
It was recognized early that nucleotides can induce
endothelial cell proliferation and migration (McAuslan
et al., 1983; Van Coevorden et al., 1989). ADP promotes
human endothelial cell migration by activating P2Y1
receptor-mediated MAPK pathways, perhaps contributing to re-endothelialization and angiogenesis after
vascular injury (Shen and DiCorleto, 2008). Evidence
has been presented that stimulation of human endothelial cells via P2Y1 receptors activates VEGF-2 to
stimulate angiogenesis (Rumjahn et al., 2009). It has
been claimed that proliferation of endothelial cells is
induced by a VEGF-A 165-ATP complex (Gast et al.,
2011). ATP causes proliferation of bovine cultured
corneal endothelial cells via P2 receptors (Cha et al.,
2000). P2Y1 and P2Y13 receptors mediate Ca2+ signaling and proliferation of pulmonary artery vasa vasorum endothelial cells and may represent targets for
treatment of pathologic vascular remodeling involving
vasa vasorum expansion (Lyubchenko et al., 2011).
Small conductance Ca2+-activated K+ channels function to enhance cell proliferation by ATP on brain
endothelial cells (Yamazaki et al., 2006). UTP, as well
as ATP, has mitogenic and angiogenic actions on vascular endothelial cells, implicating mediation by P2Y2
and possibly P2Y4 receptors (Satterwhite et al., 1999).
P2Y2 and possibly P2Y4 receptors mediate the trophic
actions of UTP and ATP in HUVECs, influencing
cytoskeletal changes, cellular adhesion, and motility
(Kaczmarek et al., 2005). P2Y4 mRNA was detected in
primary endothelial cells isolated from mouse heart
(but not lung), and studies of P2Y4 knockout mice led to
the conclusion that the P2Y4 receptor is an important
regulator of angiogenesis and inflammation (Horckmans
et al., 2008). It has been suggested that ATP, via P2Y11
145
receptors, impairs endothelial cells proliferation by
inducing cell cycle arrest and sensitizing the cells to
cisplatin-induced death (Xiao et al., 2011). There is
evidence that stimulation of P2X7 receptors enhances
apoptosis of endothelial cells mediated by lipooligosaccharide, which causes release of ATP (Sylte
et al., 2005).
Angiogenic expansion of the vasa vasorum contributes to the progression of systemic and pulmonary
vascular diseases. Vasa vasorum endothelial cells were
isolated from the pulmonary artery adventitia, and
ATP release during hypoxia was shown to have mitogenic actions (Gerasimovskaya et al., 2005). ATP was
shown to dramatically increase DNA synthesis, migration, and tube formation in vasa vasorum endothelial
cells (Gerasimovskaya et al., 2008). Vasa vasorum
endothelial cells are a potent source of extracellular
ATP in the pulmonary artery wall, and PI3K and Rho/
ROCK pathways in response to ATP are the critical
signaling components of the autocrine/paracrine signaling loop linking ATP release and ATP-induced
angiogenic responses (Woodward et al., 2009). P2Y
receptor-mediated stimulation of brain capillary endothelial cells enhanced cell proliferation by apaminsensitive small-conductance Ca2+-activated K+ channels in the majority of cells but also triggered cell death
in a subpopulation (Yamazaki et al., 2011). Thymosin
b-4 (Tb4) is a peptide released by platelets to improve
wound healing. It has been shown recently that Tb4
increases cell surface ATP levels via ATP synthase
and that P2X4 receptors are required for Tb4-induced
HUVEC migration (Freeman et al., 2011).
Enzymatic regulation of extracellular levels of nucleotides influences endothelial cell proliferation and
differentiation and angiogenesis. Pigment epitheliumderived factor (PEDF) is a potent blocker of angiogenesis in vivo and of endothelial cell migration. Notari
et al. (2010) suggested that PEDF-mediated inhibition
of ATP synthase may form part of the biochemical
mechanisms by which PEDF exerts its antiangiogenic
activity. Ecto-F1F0-ATP synthase/F1-ATPase, an enzymatic complex responsible for ATP synthesis in mitochondria, is also expressed on endothelial cells, where
it binds angiostatin, regulates surface ATP levels, and
inhibits endothelial cell proliferation and differentiation (Burwick et al., 2005; Champagne et al., 2006).
Stimulation of cell surface F1-ATPase activity by
apolipoprotein A-1 inhibits endothelial cell apoptosis
and promotes proliferation (Radojkovic et al., 2009).
Deletion of E-NTPDase 1/CD39, the principal ectonucleotidase expressed by endothelial cells, resulted in
inhibition of angiogenesis, causing decreased growth of
implanted tumors and inhibiting development of pulmonary metastases; abnormalities in endothelial cell
adhesion and integrin dysfunction were observed, involving decreased activation of focal adhesion kinase
and extracellular signaling-regulated kinase-1 and -2
146
Burnstock and Ralevic
in endothelial cells (Jackson et al., 2007). It was suggested that the adhesion defect occurred through P2
receptor desensitization because it was corrected by
apyrase treatment of the E-NTPDase/CD39 knockout
mice (Jackson et al., 2007). More recently, it was shown
that vascular E-NTPDase/CD39 expressed by liver
sinusoidal endothelial cells promotes tumor cell growth
by scavenging extracellular ATP (Feng et al., 2011).
It was suggested early that adenosine increased
capillary density; dipyridamole, which inhibits uptake
of adenosine, making more extracellular adenosine
available, increases capillary proliferation (Wright et al.,
1981). Long-term vasodilation, perhaps via the action
of adenosine (after breakdown of released ATP) stimulated capillary growth in rabbit heart and skeletal
muscle (Ziada et al., 1984). Hypoxia-induced angiogenesis in chick chorioallentoic membranes is mediated by
adenosine (Dusseau and Hutchins, 1988). Adenosine
and hypoxia stimulated proliferation and migration of
bovine aortic and coronary venular endothelial cells
(Meininger et al., 1988; Ziche et al., 1992) and HUVECs
(Ethier et al., 1993) via A2 receptors (Sexl et al., 1995;
Ethier and Dobson, 1997). In HUVECs and pulmonary
endothelial cells, proliferation involved A2A receptors
(Sexl et al., 1995; Ahmad et al., 2013). Adenosine stimulates canine retinal microvascular endothelial cell
migration and tube formation (Lutty et al., 1998) and
proliferation and migration of human retinal endothelial cells (Grant et al., 1999) via A2B receptors (Grant
et al., 2001). Adenosine increases the migration of human
endothelial progenitor cells via A2B receptor activation
(Rolland-Turner et al., 2013). A2B receptors mediate
proliferation of porcine and rat arterial endothelial
cells (Dubey et al., 2002). A2B receptors in human skin
microvascular endothelial cells modulate expression of
angiogenic factors (Feoktistov et al., 2002). Adenosine,
via A2A receptors, promotes wound healing and mediates angiogenesis in mice in response to tissue injury
(Montesinos et al., 2002).
Adenosine cooperates with hypoxia to stimulate
VEGF, and it was suggested that adenosine receptors
may present a potential therapeutic target for regulation of angiogenesis (Ryzhov et al., 2007). Macrophages
play a key role in induction of angiogenesis, and there
is synergistic upregulation of VEGF expression in
macrophages by A2A receptor agonists and endotoxin
(Ramanathan et al., 2007). Adenosine, acting via A2A
receptors, downregulates the production by human
macrophages of a soluble form of the receptor for VEGF
(sFlt-1), a potent antiangiogenic factor that acts by
trapping circulating VEGF (thereby preventing its
binding to VEGF receptors) and upregulates the
membrane form (mFlt-1), identifying a mechanism
whereby adenosine may cause angiogenesis (Léonard
et al., 2011). Adenosine A2A receptors were shown to
be a target of HIF-2a in pulmonary endothelial cells
and were implicated in angiogenesis, as assessed by
increases in cell proliferation, cell migration, and tube
formation (Ahmad et al., 2009). It has been claimed
that adenosine is an endogenous inhibitor of neutrophilmediated injury to endothelial cells (Cronstein et al.,
1986). A1 receptor blockade abolishes ischemic preconditioning observed in humans during coronary angioplasty produced by repeated coronary balloon inflation
(Tomai et al., 1996).
Figure 8 summarizes the P1 and P2 receptor subtypes on both smooth muscle and endothelial cells that
mediate proliferation.
V. Vascular Diseases
Vascular remodeling plays a pivotal role in the progression of conditions associated with ischemic hypoxia
and inflammation in diseases such as hypertension,
atherosclerosis, restenosis, vascular insufficiency, neoplasia, and transplant rejection. Reviews about the
involvement of purinergic signaling in cardiovascular
diseases are available (Ralevic and Burnstock, 2003;
Erlinge and Burnstock, 2008; Ralevic, 2009; Burnstock
and Verkhratsky, 2012; Schuchardt et al., 2012; Headrick
et al., 2013). The relevance of ectonucleotidases for the
treatment of cardiovascular disorders has also been
reviewed (Mathieu, 2012). A number of cardiovascular
purine receptors are now targeted for clinical use. P2Y12
receptors mediate platelet aggregation, and clopidogrel
and prasugrel, P2Y12 antagonists, have been very
successful clinically against thrombosis and stroke
(Hollopeter et al., 2001; Baker and White, 2009). Bolus
injection of adenosine (Adenocard; Astellas Pharma
US, Inc., Northbrook, IL) is used clinically to slow
conduction time through the A-V node, interrupt the
reentry pathways through the A-V node, and restore
normal sinus rhythm in patients with paroxysmal
supraventricular tachycardia. A 1 receptor agonists
were clinical candidates to treat paroxysmal supraventricular tachycardia (Rankin et al., 1992) and afford
protection in ischemia-reperfusion injury (Mizumura
et al., 1996). P2 receptors have been implicated in migraine and vascular pain (Burnstock, 1989b), diabetic
microvascular disease (Nilsson et al., 2006), angiogenesis, and vascular remodeling (see Erlinge and Burnstock, 2008). Detailed analysis of the roles of purinergic
signaling in hypertension, atherosclerosis, and diabetes follows and is summarized in Table 5.
A. Hypertension
Increased sympathetic nerve activity occurs in
hypertension, and there is associated hyperplasia and
hypertrophy of arterial walls, probably involving brain
stem hypoperfusion in driving increased sympathetic
activity (see Cates et al., 2012). Guanethidine was used
in early times for the treatment of hypertension (Bauer
et al., 1961), in retrospect inhibiting the release of both
NA and ATP cotransmitters from sympathetic nerves.
Purinergic Signaling and Blood Vessels
Hypertrophy of cerebral vessels occurs in spontaneously hypertensive rats (SHR), and it was suggested
that sympathetic nerves may be involved in this
trophic effect (Hart et al., 1980). Inhibitory prejunctional purinergic modulation of vascular sympathetic
neurotransmission in SHR is diminished via both
adrenoceptors and A1 receptors (Kamikawa et al.,
1980, 1983; Jackson, 1987; Illes et al., 1989; Yu et al.,
1997; Park et al., 2010a). There is also impaired
function of prejunctional A1 receptors on perivascular
sympathetic nerves in deoxycorticosterone acetate
(DOCA)-salt hypertensive rats (Sangsiri et al., 2013).
The vasoconstrictor response of tail arteries of SHR
to sympathetic nerve stimulation was inhibited by
desensitization of P2X receptors with a,b-meATP,
although it was little affected in Wistar-Kyoto (WKY)
normotensive rats (Vidal et al., 1986; Bulloch and
McGrath, 1992; Brock and Van Helden, 1995). It was
concluded that ATP plays a more important role in
sympathetic vasoconstriction in SHR compared with
normotensive rats (see also Goonetilleke et al., 2013),
although this has been contested (Dalziel et al., 1989).
147
Pressor responses to renal nerve stimulation at 1 Hz in
SHR kidneys was claimed to be due entirely to the
release of ATP from sympathetic nerves (Rump et al.,
1990). EJPs are enhanced in the smooth muscle of
mesenteric arteries in SHR (Brock and Van Helden,
1995). In contrast, sympathetic nerve-stimulated release of ATP appeared to be unaltered or impaired in
rat mesenteric arteries in DOCA-salt hypertension,
although release of NA was increased (Luo et al., 2004;
Demel and Galligan, 2006, 2008). However, P2X1 receptor agonist-induced afferent arteriolar vasoconstriction is impaired in DOCA-salt hypertensive rats (Guan
et al., 2012). The contribution of ATP to excitatory sympathetic neurovascular transmission increased when
the pressure of rat small mesenteric arteries was raised
from 30 to 90 mmHg, which is similar to the pressure
in these arteries in vivo (Rummery et al., 2007). Sympathetic nerve-mediated vasoconstriction was augmented
during diet-induced obesity because of an increase in
sympathetic nerve density and release of ATP (Haddock
and Hill, 2011). NPY postjunctional augmentation of
ATP vasocontractions after release from sympathetic
Fig. 8. Schematic diagram of long-term (trophic) actions of purines released from nerves, platelets, and endothelial cells (which also release UTP)
acting on P2 receptors to stimulate or inhibit cell proliferation. ATP released as a cotransmitter from sympathetic nerves and sensory-motor nerves
(during axon reflex activity) stimulates smooth muscle cell proliferation via P2Y2 and/or P2Y4 receptors via a mitogen-activated protein kinase (MAPK)
cascade, whereas adenosine resulting from enzymatic breakdown of ATP acts on P1 (A2) receptors to inhibit cell proliferation (via elevation of cAMP).
ATP and UTP released from endothelial cells stimulate endothelial and smooth muscle cell proliferation via P2Y1, P2Y2, and P2Y4 receptors.
Adenosine resulting from ATP breakdown acts on P1 (A2) receptors to stimulate endothelial cell proliferation and regulate the release of plateletderived growth factor (PDGF) from platelets. (Reproduced from Burnstock, 2002, with permission from Lippincott, Williams and Wilkins).
148
Burnstock and Ralevic
perivascular nerves is lost in kidneys of adult SHR,
possibly as an adaptive mechanism (Vonend et al.,
2005a).
Sympathetic vasoconstriction was not mediated by
a-adrenoceptors in forearm arteries of patients with
essential hypertension (Taddei et al., 1989). Autonomic
dysreflexia, a potentially life-threatening episodic hypertension that often develops after spinal cord lesion,
is induced by increased sympathetic activity, and it
seems likely that ATP released as a cotransmitter from
sympathetic nerves is involved as well as NA (Groothuis
et al., 2010).
Both increases and decreases in vasocontractile responses to exogenous P2 receptor agonists in hypertension have been reported. The mesenteric vascular bed
of SHR shows potentiated responses to exogenous ATP
and NA (Naito et al., 1998). Increased responsiveness
of the vasculature of rat isolated perfused kidneys to
a,b-meATP in SHR has also been reported (Fernandez
et al., 2000), and ATP-induced vasoconstriction is significantly potentiated in SHR aorta (Yang et al., 2004).
In contrast, P2X1 receptor-mediated vasoconstriction of
afferent arterioles in the rat kidney is attenuated in
Ang-II-dependent hypertension (Inscho, 2009). Immunosuppression preserves renal autoregulatory function
and microvascular P2X1 receptor reactivity in Ang-IIhypertensive rats (Guan et al., 2013). The sensitivity of
contractile responses to a,b-meATP, likely involving
P2X1 receptors, was also significantly reduced in isolated subcutaneous veins, but not arteries, from
hypertensive patients (Lind et al., 1997). Treatment of
cultured vascular smooth muscle cells with a,b-meATP
had little effect on nerve growth factor (NGF) secretion by WKY rat smooth muscle but increased NGFsecretion by SHR smooth muscle (Spitsbergen et al.,
1995). Abnormalities in 59-nucleotidase activity have
been reported in SHR (Hadjiisky et al., 1983). Elevated
ecto-59-nucleotidase-mediated increase in renal adenosine signaling via A2B receptors contributes to chronic
hypertension (Zhang et al., 2013b). Exercise training in
patients with essential hypertension alters the balance
between vasodilating and vasoconstricting compounds,
including a reduction in exercise-induced increase in
ATP (Hansen et al., 2011). Diadenosine polyphosphates,
Ap4A, Ap5A, and Ap6A, are potent vasoconstrictors
that act via P2X1 and P2Y2 receptors (Schluter et al.,
1994). Ap5A and Ap6A are found in higher levels in
platelets from patients with hypertension and could
contribute to their increased peripheral vascular resistance (Hollah et al., 2001). The concentration of Up4A,
a dinucleotide claimed to be an endothelium-dependent
vasoconstrictor, is increased in plasma of juvenile hypertensives and may contribute to the early development
of primary hypertension (Jankowski et al., 2007).
Up4A-induced contractions, mediated by P2X1, P2Y2,
or P2Y4 receptors, were increased in renal, basilar, and
femoral, but not in pulmonary arteries from DOCA-salt
hypertensive rats (Matsumoto et al., 2011, 2012). The
authors attributed this to enhanced P2Y signaling in
the renal artery, because contractions mediated by
P2Y2, P2Y2/4, and P2Y6 receptor agonists were also
enhanced; there was no change in renal artery protein
expression of P2Y2, P2Y4, and P2Y6 receptors in DOCAsalt hypertension, but ERK activation stimulated by
TABLE 5
Changes in expression and responses of purine receptors in different vascular pathologies
Smooth Muscle
P1
Hypertension
Endothelial Cells
P2X
P2Y
P1
P2X1 ↑contraction
P2X1 ↓contractiona
P2Y ↑contraction
A1 ↓affinity (CNS)
A2A knockout
detrimentalb
P2X7 ↑protein
Heart failure
Diabetes
Varicose disease
Inflammation
P1↓ relaxationg
P2X ↓contraction
P2X6 ↑proteinf
P2X4
Overexpression in
heart beneficiale
P2X1 ↓protein
P2Y1 ↑protein
P2Y2 ↑protein
P2Y
P2Y2 ↑Ca2+ response
P2Y1 knockout
protectivec
P2Y2 ↑mRNA
Atherosclerosis
P2X
P2YATP ↑relaxation
P2YATP ↓relaxation
P2Y6 mRNA↑d
P1↓relaxationg
P2Y2 and/or P2Y4 ↓relaxation
P2Y6 ↑protein
CNS, central nervous system.
a
Afferent arterioles of rat kidney (Inscho, 2009) and human subcutaneous veins (Lind et al., 1997).
b
A2A receptor knockout led to pulmonary artery hypertension and smooth muscle proliferation in mice (Xu et al., 2011).
c
P2Y1/apolipoprotein E double-knockout mice had reduced atherosclerotic lesions (Hechler et al., 2008).
d
Diet-induced (apolipoprotein E-deficient mice) atherosclerosis (Guns et al., 2010).
e
Transgenic A1 receptor overexpression increased myocardial resistance to ischemia (Matherne et al., 1997) and genetic deletion of A1 receptors limits myocardial ischemic
tolerance (Reichelt et al., 2005).
f
Human myocardium in chronic heart failure (Banfi et al., 2005).
g
Reduced adenosine-mediated vasodilatation involving smooth muscle and/or endothelium.
Purinergic Signaling and Blood Vessels
Up4A was enhanced (Matsumoto et al., 2011). P2Y2
receptor gene haplotypes are associated with essential
hypertension in Japanese men (Wang et al., 2010b).
ADP produces endothelium-mediated vasodilation
(probably via P2Y1 receptors) and decreases the increased vasoconstrictor nerve-mediated stimuli in renovascular hypertension in rats; it was suggested that
this may be significant when ADP (probably after
degradation of ATP) is released from platelets and
erythrocytes (Almeida et al., 1992). Red blood cell
concentrations of ATP and GTP are higher in SHR
than WKY rats (Yeung et al., 2008). However, there is
impaired release of ATP from red blood cells of humans
with primary pulmonary hypertension (Sprague et al.,
2001, 2003). Endothelium-dependent relaxation to
ACh, but not to ATP, was augmented in estrogentreated SHRs (Williams et al., 1988). The Ca2+ responses
of human hand vein endothelial cells to ATP were
significantly larger in pregnant women than in those
from nonpregnant and preeclamptic women (Mahdy
et al., 1998). All-cis-5,8,11,14,17-icosapentaenoate, a major
active component of fish oil, increases the release of
ATP from endothelial cells, leading to attenuation of the
blood pressure rise seen with advancing age (Hashimoto
et al., 1998a). In the aorta of SHR, endothelium-dependent
contractions elicited by ATP involve the release of thromboxane A2 and PGI2 and possibly also prostaglandin H2
(Gluais et al., 2007). There is enhanced production of
EDCF in SHR and old WKY rats, which would counteract the action of EDRF, thus reducing the vasodilator
action of adenine nucleotides (Mombouli and Vanhoutte,
1993).
It was proposed that infusion of ATP-MgCl2 may be
clinically useful in the treatment of children with
pulmonary hypertension (Fineman et al., 1990; Brook
et al., 1994; Nalos et al., 2003). Endothelium-dependent
relaxation to ATP has been demonstrated in human
pulmonary arteries (Greenberg et al., 1987). On the
other hand, ATP is a mitogen for pulmonary artery
smooth muscle cells, which may be relevant for the
pathophysiological basis of pulmonary hypertension
(Zhang et al., 2004). ATP and UTP stimulate vascular
smooth muscle cell proliferation in SHR via P2Y2 and/
or P2Y6 receptors (Chang et al., 1995; Harper et al.,
1998). Moreover, intrapulmonary arteries respond by
vasoconstricting to ATP in broiler chickens susceptible
to idiopathic pulmonary arterial hypertension (Kluess
et al., 2012). Again, the balance between endothelial
versus smooth muscle stimulation by ATP may regulate blood pressure in different directions, and we are
far from a full understanding of the role of the purinergic
system in pulmonary hypertension.
Data have been presented that indicate the potential
beneficial effects of clopidogrel by improving hypertensionrelated vascular functional changes (Giachini et al.,
2010). It was suggested that the effects were not due to
the direct actions of clopidogrel on the vasculature, but
149
rather that activated platelets contribute to endothelial dysfunction, perhaps via impaired NO bioavailability. Endothelial dysfunction can potentially affect
purinergic signaling involving both P2 and P1 receptors (see below) as well as having broader prohypertensive effects.
In the kidney of transgenic hypertensive rats, the
glomeruli showed an abundance of P2X7 receptor immunostaining (in podocytes, endothelium, and mesangial cells), whereas in kidneys from normal rats there
was only low level P2X7 receptor immunostaining
(Vonend et al., 2004). In P2X7 receptor knockout mice,
hypertension and renal injury were attenuated in DOCAsalt hypertension, suggesting that the P2X7 receptor
plays a key role in the development of hypertension via
increased inflammation (Ji et al., 2012). Common
genetic variations in a region of the P2X7 and P2X4
receptor genes had a small, but significant, effect on
blood pressure in humans, and it was suggested that
drugs affecting P2X receptor signaling may have
promise as clinical antihypertensive agents (PalominoDoza et al., 2008).
Plasma adenosine concentrations are elevated in
conscious SHR (Yamada et al., 1992) and in Dahl saltsensitive rats (Yamada et al., 1995). Adenosine has been
claimed to activate the vascular renin-angiotensin
system in hypertensive subjects (Taddei et al., 1992).
Adenosine, after breakdown of ATP released from
sympathetic nerves, was claimed to have trophic
effects on both vascular smooth muscle and endothelial
cells (Osswald and Azevedo, 1991). A1 receptor antagonism was shown to reduce salt-induced hypertension
and was associated with an attenuation of renal injury
and a reduction of plasma renin activity and aldosterone concentration (Uehara et al., 1995). In rats with
hypertension due to 7 days of treatment with the P1
receptor antagonist 1-3-dipropyl-8-sulfophenylxanthine,
there was an increase in sensory-motor vasodilation of
the mesenteric arterial bed (Ralevic et al., 1996), perhaps as a compensatory mechanism. A2A receptor knockout mice had increased proliferation of endothelial cells
and increased smooth muscle hypertrophy and collagen deposition in the pulmonary arteries and increased
wall area thickness and smooth muscle actin immunoreactivity in the pulmonary resistance vessels, suggesting that adenosine, acting at A2A receptors, is an
important regulatory mechanism to protect against
development of pulmonary arterial hypertension (Xu
et al., 2011). Increased ATP hydrolysis by ectonucleotidases resulting in an accumulation of adenosine in
the kidney of hypertensive animals has been reported
(Fürstenau et al., 2010).
A2 receptor agonists produce vasodilation and hypotension in conscious SHR (Webb et al., 1990; Yagil and
Miyamoto, 1995), identified later as A2A receptors
(Leal et al., 2012). A2 receptors mediate vasorelaxation
in part via the endothelium and release of NO, and
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Burnstock and Ralevic
endothelial dysfunction may cause the attenuation of
adenosine receptor-mediated responses seen in aortae
of SHR (Fahim et al., 2001; Nejime et al., 2009). However,
NO plays, at most, a minor part in adenosine-induced
vasodilation in human hypertensive kidney (Wierema
et al., 2005). A2A receptor activation is required for
adenosine-induced mesenteric relaxation, and a decreased density of A2A receptors may contribute to the
decreased mesenteric relaxation in portal hypertensive
rabbit (de Brito et al., 2002). Hypertension is also
associated with chronic kidney disease, and elevated
levels of adenosine, acting on A2B receptors, have been
claimed to mediate this effect (Zhang et al., 2011). It
has also been claimed that a single oral dose of AMP
improved hypertension and hyperglycemia in strokeprone spontaneously hypertensive rats (Ardiansyah
et al., 2011). A1 receptor knockout mice exhibit
a decreased blood pressure response to low-dose AngII infusion (Lee et al., 2012). The authors suggest that
this is due to the action of A1 receptors in the proximal
tubule, which allows excess Na+ reabsorption and ultimately Na+ retention that contributes to hypertension.
Elevated maternal blood pressure occurs in preeclampsia. High adenosine levels were found in the
fetal-placental circulation in preeclamptic pregnancies
(Escudero and Sobrevia, 2009), and A2A receptor-NO
signaling was implicated (Escudero et al., 2013). An
increase in maternal plasma adenosine concentration
has been reported in preeclampsia compared with
normal pregnancy (Yoneyama et al., 2001). Increased
maternal-fetal plasma adenosine deaminase and xanthine oxidase activity in preeclampsia may be related
to the pathogenesis of preeclampsia (Karabulut et al.,
2005). Fetal endothelial cell proliferation and migration are reduced in preeclampsia and appear to be
related to lower A2A receptor expression in placental
endothelium and reduced A2A receptor-mediated responses (Escudero et al., 2008). Patients with preeclampsia with chronic uteroplacental ischemia have high
fetal plasma concentrations of adenosine (Espinoza
et al., 2011).
B. Atherosclerosis and Coronary Artery Disease
ATP signaling is involved in atherosclerosis (Burnstock,
2002, 2008b; Di Virgilio and Solini, 2002; Plank et al.,
2006, 2007; Seye et al., 2006; Guns et al., 2010; Zerr
et al., 2011). Adenosine and ATP promote endothelial
and smooth muscle cell proliferation and increase expression of VEGF and growth of new vessels (Burnstock,
2002). Hypoxia is an important stimulus to vascular
growth, and it is believed that ATP, which is released
from endothelial cells during hypoxia, and its breakdown product adenosine have important roles as mediators of blood vessel growth.
An early study reported that adenosine produces an
increase in cAMP and decrease in DNA synthesis in
cultured arterial smooth muscle cells and suggested
that this might result in the regulation of cell proliferation through actions at adenosine A1 and A2
receptors (Jonzon et al., 1985). The authors speculated
that adenosine could be one of several regulatory
factors in the development of atherosclerosis and might
also regulate the release of a smooth muscle mitogen,
platelet-derived growth factor. It was later shown that
A2B receptors may mediate inhibition of the growth of
human aortic smooth muscle cells (Dubey et al., 1999).
There is now evidence that adenosine also regulates
endothelial cell proliferation in angiogenesis (Adair,
2005). Endothelial cell proliferation is mediated by
adenosine A2A and A2B receptors, and some of the
mitogenic effects are mediated via modulation of VEGF
signaling. Inactivation of A2A receptors protects apolipoprotein E-deficient mice from atherosclerosis (Wang
et al., 2009a). Adenosine modulates HIF-1a, VEGF, IL-8,
and foam cell formation in a human model of hypoxic
foam cells (Gessi et al., 2010). The authors claim that
A2B and A3 antagonists may be able to block steps in
the atherosclerotic plaque development. However, A3
receptor deficiency does not influence atherosclerosis
(Jones et al., 2004). A recent review focuses on the
influence of adenosine and A2A receptors in particular
as a regulatory mechanism to control the formation of
foam cells under conditions of lipid loading (Reiss and
Cronstein, 2012). It has been shown that ecto-59nucleotidase/CD73-derived adenosine acts as an endogenous modulator protecting against vascular
inflammation and monocyte recruitment, thus limiting
the progression of atherosclerosis. Deletion of ecto-59nucleotidase/CD73 in mice, which leads to a reduction
of adenosine, promotes atherogenesis, most likely by
de-inhibition of resident macrophages and T cells
(Buchheiser et al., 2011), but did not alter angiogenesis
(Böring et al., 2013). ETA receptor antagonism restores
the myocardial perfusion response to adenosine in
experimental hypercholesterolemia (Bonetti et al., 2003).
Hypercholesterolemia abolishes voltage-dependent K+
channel contribution to adenosine-mediated relaxation
in porcine coronary arterioles (Heaps et al., 2005).
Recent articles discuss the role of adenosine, acting via
A2B receptors, in the development of atherosclerosis
and the risk factors associated with this pathology
(Koupenova et al., 2012a, 2012b).
ATP and ADP have been shown to stimulate endothelial cell migration as well as proliferation (McAuslan
et al., 1983; Van Coevorden et al., 1989), probably via
P2Y receptors. ATP and ADP stimulate DNA synthesis
and cell proliferation of porcine aortic smooth muscle
cells via activation of P2Y receptors (Wang et al.,
1992a). UTP also has powerful mitogenic actions on
vascular smooth muscle and, because the mitogenic
effects of UTP and ATP were approximately equipotent
(Erlinge et al., 1995; Malam-Souley et al., 1996), this
suggests an involvement of P2Y2 and/or P2Y4 receptors
in chronic inflammation and atherosclerosis (Seye and
Purinergic Signaling and Blood Vessels
Weisman, 2010). ATP-induced cyclooxygenase-2 expression is via p42/p44, MAPK, p38, and nuclear factor
(NF)-kB in vascular smooth muscle cells, and nucleotides may promote atherosclerosis via these mechanisms (Wang and Yang, 2006). A novel role for P2Y2
receptors in the development of atherosclerosis has
been suggested, whereby UTP induces vascular cell
adhesion molecule-1 expression in coronary artery
endothelial cells, leading to the recruitment of monocytes associated with the development of atherosclerosis (Seye et al., 2002, 2003; see also Otte et al., 2009).
There was upregulation of vascular smooth muscle
P2Y2 receptor mRNA by MAPK-dependent growth
factor, which may be important in atherosclerosis and
neointima formation after balloon angioplasty (Hou
et al., 1999). Intimal hyperplasia in collared rabbit
carotid artery is mediated by upregulation of P2Y2
receptors (Seye et al., 2002) and may be a useful indicator of the early stages of atherosclerosis (Elmaleh
et al., 1998). An important role of P2 receptors in
homocysteine-induced atherosclerosis has been shown
(Sharma et al., 2007). ATP and UTP are chemotactic
for dendritic cells via the P2Y2 receptor and can attract
inflammatory cells to the atherosclerotic plaque (Idzko
et al., 2002). Up4A has been reported to be a potent
mediator of pro-inflammatory responses in the atherosclerotic vascular wall involving Nox1-dependent ROS
activation via P2Y2 receptors (Schuchardt et al., 2011).
A major contribution of endothelial P2Y1 receptors in
the regulation of TNFa-induced vascular inflammation
has been claimed (Zerr et al., 2011). Reduced atherosclerotic lesions were found in P2Y1/apolipoprotein E
double-knockout mice, and it was concluded that P2Y1
receptors contribute to atherosclerosis, possibly through
their role in nonhemotopoietic-derived cells (Hechler
et al., 2008). Cytokines and chemokines play roles in
the initiation and progression of atherosclerosis, where
they promote recruitment and migration of inflammatory cells into the atherosclerotic lesion. Among the
chemokines is the C-C motif ligand 2 (CCL2), and it has
been shown that extracellular nucleotides can induce
CCL2 expression in human aortic smooth muscle cells,
probably via P2Y1 and/or P2Y11 receptors (Kim et al.,
2011). In diet-induced (apolipoprotein E-deficient mice)
atherosclerosis, there was increased expression of P2Y6
receptor mRNA in the atherosclerotic regions, and the
P2 receptor antagonists suramin and PPADS both
reduced plaque size (Guns et al., 2010). Apolipoprotein
A-I is the main protein constituent of high-density
lipoprotein. It was claimed recently that P2Y12 receptors mediate the formation of atherosclerotic lesions in
apolipoprotein E-deficient mice (Cavelier et al., 2012;
Li et al., 2012a). The vasodilatory responses to ATP,
but not adenosine, are impaired in young apolipoprotein E-deficient mice that might represent the critical
initiating event in pathologic vascular remodeling and
atherogenesis (Mercier et al., 2012).
151
Atherosclerotic damage results in the disappearance
of endothelium-dependent responses to ATP (Burnstock,
2006). Impairment of ATP endothelium-mediated
relaxations occurred in the aorta of atherosclerotic
rabbits (Ragazzi et al., 1989). This was also the case in
Watanabe heritable hyperlipidemic rabbits, except in
12- to 14-month-old rabbits, when ATP-mediated relaxations were increased, suggesting that compensatory
responses evolve during atherogenesis to maintain
vasodilator functions (Chinellato et al., 1991). Nucleotide
receptor activity (via unknown receptors) is preserved for
longer than that of other endothelial receptors, including
P2Y receptors in Watanabe heritable hyperlipidemic
rabbits (Ragazzi et al., 1993; Chinellato and Ragazzi,
1995). Low-density lipoprotein causes attenuation of NOmediated endothelial responses in coronary arteries induced by adenosine receptor activation (Abebe and
Mustafa, 1997).
Vascular injury represents a critical initiating event
in the pathogenesis of various vascular diseases. Large
amounts of ATP are released from injured cells and,
as described above, ATP and adenosine have potent
actions on smooth muscle and endothelial cell growth,
migration, proliferation, and death. Vascular endothelial cells are continuously exposed to variations in
blood flow, which plays an important role in vessel
growth or regression and in the local development of
atherosclerosis. The shear stress leads to a substantial
release of ATP and UTP from endothelial cells
(Burnstock, 1999), and these purines might mediate
alterations in the balance between proliferation and
apoptosis. Apoptotic cell death is recognized to occur
in a number of vascular diseases, including atherosclerosis, restenosis, and hypertension (Thomas et al.,
1976; Mallat and Tedgui, 2000). ATP release from
endothelium and smooth muscle may occur across
connexin hemichannels, and connexin hemichannel
formation has been shown to be regulated by ATP
(Jiang et al., 2005; Lurtz and Louis, 2007). The pattern
of vascular connexins is altered during atherosclerotic
plaque formation and in restenosis, affecting gapjunctional communication between smooth muscle
cells, and genetically modified connexin expression
alters the course of atherosclerosis and restenosis
(Chadjichristos et al., 2006). Connexins have been
claimed to participate in the initiation and progression
of atherosclerosis (Morel et al., 2009).
ATP release from endothelial cells in the rat caudal
artery is impaired in atherosclerosis (Shinozuka et al.,
1994). A high-cholesterol diet decreased the spontaneous and NA-evoked release of ATP from caudal artery
of aged rats, leading to an increase in blood pressure,
and it was suggested that the main source of ATP was
the endothelial cells, with a lesser contribution of
smooth muscle (Hashimoto et al., 1998b). On the other
hand, ATP release from endothelial cells by shear
stress is enhanced in inflammatory states (Bodin and
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Burnstock and Ralevic
Burnstock, 1998), and this might represent a protective
mechanism by inhibiting natural killer (NK) cell
recruitment and consequently NK cell-mediated plaque formation, a mechanism suggested to involve
P2Y11 receptors (Gorini et al., 2010). NK cells represent the main source of interferon-g that contributes to
atherosclerotic plaque progression; fractalkine expressed by endothelial cells mediates NK recruitment, and
its killing of endothelial cells and high fractalkine
mRNA is found in advanced atherosclerotic lesions in
human arteries. ATP releases histamine from mast
cells and releases inflammatory cytokines such as IL-1
from immune cells via P2X7 receptors.
Saphenous vein, internal mammary, and radial
arteries have been used as grafts for coronary bypass
surgery; the level of endothelial P2Y2 receptors is
comparable in all three vessels, but endothelial P2X4
receptors vary from high in saphenous vein to
significantly lower in the other two vessels. It has
been suggested that P2X 4 receptors play a more
significant role in intense proliferation in atherosclerosis and restenosis than P2Y2 receptors, as reflected
by the susceptibility of saphenous vein grafts to
atherosclerosis compared with internal mammary
arteries (Ray et al., 2002). In another study, P2X1
and P2Y6 receptors mediated more prominent contractions in the saphenous vein compared with the internal
mammary artery; it has been suggested that selective
antagonists to these receptors may prevent vasospasm
and restenosis in the saphenous vein during and after
revascularization surgery (Borna et al., 2003).
Atherosclerosis is an inflammatory disease induced
by hypercholesteremia, and an increase in E-NTPDase
1/CD39 (apyrase) and subsequent ATP and ADP hydrolysis has been shown in platelets of hypercholesteremic
patients (Duarte et al., 2007). The authors suggest that
this might be beneficial in reducing thrombus formation, but may also contribute to future fatal events
such as unstable angina and myocardial infarction.
Newly developing vascular endothelia express very
high levels of the ectonucleotidase E-NTPDase1/CD39
also seen under hypoxic conditions (Eltzschig et al.,
2003). Angiogenesis requires the dynamic interaction
of endothelial cell proliferation and differentiation with
orchestrated interactions between extracellular matrix
and surrounding cells (such as vascular smooth muscle
and/or pericytes). Such interactions could be coordinated by interplay between nucleotide release, P2
receptor modulation, and altered NTPDase expression
(Goepfert et al., 2001). Although the relationship between atherosclerosis and aneurysm growth and rupture is still not clear, atherosclerotic plaques have been
found in the aneurysmal wall; using a numerical model
of ATP transport in aneurysms found at arterial bends,
a low concentration of ATP was indicated at the proximal side of the aneurysmal site, which may be significant
in pathologic changes in the growth and rupture of
aneurysms (Imai et al., 2010). Reduction of ectoNTPDase1 and 2 (but not ecto-59-nucleotidase) was shown
in atherosclerotic blood vessels of patients with abdominal aortic aneurysm, and it was suggested that this
may be responsible for the development of atheroscleroticlike diseases (Lecka et al., 2010). A recent review
considers the therapeutic potential of NTPDases to
prevent intimal hyperplasia (Kaczmarek and Koziak,
2011).
Atherosclerosis of coronary vessels is often known as
coronary artery disease. Administration of ATP into
the left coronary artery has been used to treat patients
with coronary artery disease in preference to papaverine (Sonoda et al., 1998). ATP acts on endothelial P2Y
receptors to cause release of NO and subsequent
vasodilation. Intravenous infusion of ATP has also
been used for detecting coronary artery disease in
patients unable to perform conventional exercise stress
testing adequately (He et al., 2002). Platelet adhesion
and aggregation is a key step in the development of
inflammation, thrombosis, and atherosclerosis. Thus
platelet aggregation inhibitors, such as clopidogrel, an
antagonist of ADP-sensitive P2Y12 receptors, have
been used to prevent and treat coronary artery disease
(Zeidner et al., 2008). It has been suggested that ADPmediated migration of host smooth muscle-like cells
and CD45+ leukocytes, via P2Y12 receptors, may play
a role in the development of transplant arteriosclerosis, partly by monocyte chemoattractant protein-1
(Harada et al., 2011). Prasugrel, a P2Y12 receptor
antagonist, has been used for the treatment of acute
coronary syndrome (Jauregui et al., 2009). Clinical
trials with clopidogrel and ticlopidine (P2Y12 receptor
antagonists) in patients with atherosclerotic disease
have shown significant benefit compared with aspirin.
Intravenous adenosine in cardiovascular magnetic resonance imaging is safe and well tolerated even in patients with severe coronary artery disease (Karamitsos
et al., 2009).
In conclusion, adenosine, ATP, ADP, and UTP
stimulate several inflammatory responses known to be
important for atherosclerosis development (Wang
et al., 2009a; Gessi et al., 2010; Erlinge, 2011). The
long-term (trophic) roles of purinergic signaling in
vascular smooth muscle and endothelial cell proliferation and death, which have been implicated in atherosclerosis and restenosis, suggest that therapeutic
strategies in relation to these events should be explored (Di Virgilio and Solini, 2002; Ralevic and
Burnstock, 2003; Seye et al., 2006; Burnstock, 2008b;
Erlinge and Burnstock, 2008; Ralevic, 2009).
C. Ischemia
Ischemia leads to injury of most organs in the body
(see Linden, 2006). Purines and pyrimidine nucleotides, released at the site of cell damage, generally
contribute to injury, but protective effects have also
Purinergic Signaling and Blood Vessels
been described. Adenosine, released during ischemia,
is generally protective (see Grenz et al., 2012b).
1. Heart. An influential article by Berne (1963)
suggested that adenosine was the physiologic regulator
of blood flow during reactive hyperemia after hypoxia,
and early articles supported this hypothesis (Scott
et al., 1979; Belardinelli et al., 1981). However,
evidence was later presented that questioned the
hypothesis. For example, although theophylline, an
adenosine receptor antagonist, blocked coronary vasodilation by perfused adenosine, it did not block reactive
hyperemia (Rehncrona et al., 1978; Heistad et al.,
1981; Pinard et al., 1989). It was also noted that
although reactive hyperemia occurred after about 10
seconds, adenosine did not appear in the perfusate
until about 90 seconds. In a counterhypothesis, Burnstock (1993b) proposed that the initial phase of
vasodilation after hypoxia was due to ATP released
from endothelial cells to cause vasodilation via NO,
whereas adenosine (after breakdown of ATP) contributed only to the later stages of reactive hyperemia by
acting on P1 receptors on the smooth muscle. The delay
in appearance of adenosine in the perfusate was
explained by the fact that ADP (after rapid breakdown
of ATP) inhibits 59-nucleotidase, the enzyme that
mediates breakdown of AMP to adenosine.
Endogenous adenosine is an important mediator of
ischemic preconditioning and postconditioning (see
Riksen et al., 2009). The cardioprotective effect of
ischemic preconditioning is dependent on activation
of adenosine A1 receptors in the first few minutes of
reperfusion (Solenkova et al., 2006). In contrast, the
infarct size-limiting effect of myocardial ischemic
postconditioning is mediated by the activation of
adenosine A2A receptors at the time of reperfusion
(Morrison et al., 2007). Transgenic A1 receptor overexpression increased myocardial resistance to ischemia
(Matherne et al., 1997). Conversely, genetic deletion of
A1 receptors limits myocardial ischemic tolerance
(Reichelt et al., 2005). In male patients with stable
angina, capadenoson, an oral A1 receptor agonist,
lowers exercise heart rate, which is associated with
prolongation of time to ischemia (Tendera et al., 2012).
In situ ischemic preconditioning conferred cardioprotection in A1, A2A, and A3, but not A2B knockout mice or
in wild-type mice after inhibition of the A2B receptors,
and it was suggested that 59-nucleotidase and A2B
agonists might be considered as therapy for myocardial
ischemia (Eckle et al., 2007; see also Aherne et al.,
2011). Activation of A3 receptors protects against
myocardial ischemia-reperfusion injury in mice, an
effect that disappears in A3 knockout mice (Harrison
et al., 2002; Ge et al., 2006; Wan et al., 2011). CD73derived adenosine promoted cardiac remodeling and
recovery of ventricular performance after ischemiareperfusion, most likely by acting on T cells (Bönner
et al., 2012).
153
Activation of adenosine receptors with exogenous
ligands mimics the cardioprotective effect of preconditioning. Intracoronary adenosine protects against
reperfusion injury after coronary occlusion (Olafsson
et al., 1987; Babbitt et al., 1989; Ledingham et al.,
1990; Thornton et al., 1992), an action mediated by A1
receptors (Liu et al., 1991). Activation of A1 and A2A receptors has been shown to reduce ischemia-reperfusion
injury in the heart (Schlack et al., 1993; Lozza et al.,
1997). Brief intravenous infusion of ATL-146e, a selective adenosine A2A receptor agonist (added 30 minutes
before reperfusion), reduced myocardial infarct size at
48 hours after reperfusion after a period of ischemia
(Patel et al., 2009). Selective A3 receptor activation is
cardioprotective in wild-type hearts and hearts overexpressing A1 receptors. A more recent article (Xi et al.,
2009) claimed that A2A and A2B receptors work in
concert to induce strong protection against reperfusion
injury in rat hearts, and cooperative activation of A1
and A2A receptors to produce cardioprotection in ischemiareperfused mouse heart has also been reported (Urmaliya
et al., 2010). Evidence that activation of both A1 and A2
receptors during hypoxia can attenuate myocardial
injury was claimed (Stambaugh et al., 1997; Tracey
et al., 1997; Liang and Jacobson, 1998). Endogenous
adenosine makes a significant contribution to A1 agonistmediated prevention of necrosis in a cardiac cell model
of ischemia by cooperative interactions with both A2A
and A2B receptors, but does not play a role in A3 agonistmediated protection (Urmaliya et al., 2009; Methner
et al., 2010). It was reported that A1 and A3 receptor
agonists reduce hypoxic injury through the involvement of p38 MAPK (Leshem-Lev et al., 2010). Adenosine
stimulates the recruitment of endothelial progenitor
cells to the ischemic heart to enhance revascularization
(Goretti et al., 2012).
A reduced sensitivity to adenosine has been found
in the ischemic or hypoxic heart (Zucchi et al., 1989;
Vanhaecke et al., 1990). A2 receptor binding in the
heart is modified by ischemia (Zucchi et al., 1992), and
ischemia-reperfusion selectively attenuated coronary
vasodilatation mediated by A2, but not A1 receptor
agonists (Cox et al., 1994). Attenuation of responsiveness would tend to counteract the cardioprotective effects
of adenosine, but the importance of this is not yet clear.
The mechanism underlying cardioprotection by
adenosine is not fully understood. Adenosine activation
of the reperfusion injury salvage kinase pathway,
involving phosphorylation of Akt and/or ERK1/2, which
leads to inhibition of mitochondrial permeability transition pore formation (Hausenloy et al., 2005; Hausenloy
and Yellon, 2006; Murphy and Steenbergen, 2008) may
be involved. One study concluded that cardioprotection
by adenosine is dependent on NO and is mediated principally by activation of a neurogenic pathway (Manintveld
et al., 2005). It was suggested that ischemic stressinduced preconditioning is dependent on the concomitant
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Burnstock and Ralevic
stimulation of both adenosine and NA receptors, and it
was claimed that P1 receptor-mediated cardioprotection occurs only if a1-adrenoceptor activation is intact
(Winter et al., 1997). The infarct-sparing effect of A2A
receptor activation has been suggested to be primarily
due to inhibition of CD4+ T-cell accumulation and
activation in the reperfused heart (Yang et al., 2006).
Another report claims that adenosine triggers the
nuclear translocation of PKC« in cardiomyoblasts (Xu
et al., 2009).
It was claimed early that reflex responses mediated
by cardiac sympathetic afferent nerves during myocardial ischemia were caused by adenosine released from
the ischemic myocardium mediated by A1 receptors,
but more recently it was suggested that ATP activates
sympathetic afferents (Fu and Longhurst, 2010). There
is decreased adenosine protection in reperfusion injury
in aging rats (Gao et al., 2000). Reduced A3 receptor
transcription may contribute to improved ischemia
tolerance in aged hearts (Ashton et al., 2003). Low-dose
adenosine infusion reduced the ischemic burden and
improved left ventricular regional systolic function in
the ischemic walls of patients with exercise-induced
myocardial ischemia (Sadigh et al., 2009). Reviews
concerned with the role of adenosine in preconditioning
and ischemia-reperfusion injury are available (Sollevi,
1986; de Jong et al., 2000; Ganote and Armstrong,
2000; Sommerschild and Kirkeboen, 2000; Lasley
et al., 2001; Przyklenk and Whittaker, 2005; Cohen
and Downey, 2008; Drew and Kingwell, 2008; Laubach
et al., 2011).
Although the early focus was on the role of adenosine
in ischemic and reperfusion injury, there is increasing
interest in the role of ATP in this condition. Indeed,
extracellular ATP and adenosine appear to play complementary, protective roles in ischemic preconditioning through P2Y and P1 receptors, respectively (Ninomiya
et al., 2002). A possible role for nucleotides in cardiac
ischemia was first raised in 1948, with the emphasis on
degradation of nucleotide, which appears to take place
within the muscle cells during ischemia (Stoner et al.,
1948). Following this way of thinking, local infusion of
ATP was used to delay successfully the onset of
irreversible ischemic injury and the role of high energy
phosphate in preservation of ischemic myocardium
recommended (Kaul et al., 1977). Delayed resynthesis
of ATP after its depletion during myocardial ischemia
was proposed (Reimer et al., 1981), and ATP-MgCl2
was used for the treatment of ischemia (see Chaudry,
1983; McDonagh et al., 1984; Kopf et al., 1987). ATPloaded liposomes have been recommended for the treatment of myocardial ischemia (Hartner et al., 2009).
Others have shown that ischemia is accompanied by an
increased release of ATP from cardiac myocytes and
sympathetic nerves (Lai and Nishi, 2000; Sesti et al.,
2003; Clarke et al., 2009). It has been suggested that
release of ATP from cardiomyocytes is strictly regulated
during ischemia by a negative feedback mechanism
consisting of maxi-anion channel-derived ATP-induced
suppression of ATP release via hemichannels in
cardiomyocytes (Kunugi et al., 2011). In a recent article
(Cosentino et al., 2012), it was shown that ischemic/
hypoxic stress induced rapid ATP release from cultured cardiomyocytes and that distinct P2 receptors
regulated cardiomyocyte death, perhaps via P2X7 and
P2Y2 receptors. It has been claimed that P2X7 receptormediated inhibition in stellate ganglia prevents increased
sympathoexcitatory reflex via sensory-sympathetic
coupling induced by myocardial ischemic injury (Tu
et al., 2013). Ischemia-induced accumulation of ATP in
the extracellular space was suggested to trigger enhancement of [Cl2]i in ventricular muscle during
ischemic conditions (Lai and Nishi, 2000). Release of
ATP from cardiac myocytes in response to ischemia is
likely to be via connexin hemichannels (Clarke et al.,
2009). In another study, it was suggested that ATP
release from cardiac myocytes via pannexin-1 channels
during early ischemia may be an early paracrine event
leading to profibrotic responses to ischemic cardiac
injury (Dolmatova et al., 2012). Tissue transglutaminase
2 protects cardiomyocytes against ischemia-reperfusion
injury by regulating ATP synthesis (Szondy et al.,
2006). Pannexin 1/P2X7 receptor channels mediate
release of cardioprotectants induced by ischemic preand postconditioning (Vessey et al., 2010). There is
upregulation of P2X7 receptors in rat superior cervical
ganglia after myocardial ischemic injury (Kong et al.,
2013). It has been claimed that ATP postconditioning
provides a powerful protective effect in a rat model of
ischemia-reperfusion due partly to antioxidation and
partly to inhibition of inflammation (Yao and Liu, 2010).
Extracellular ATP protects against reperfusioninduced failure of the endothelial barrier in rat hearts
(Gündüz et al., 2006). Extracellular ATP also protects
human cultured myocardial endothelial cells from
apoptotic cell death during hypoxia by activating
P2Y2 receptor-mediated MEK/ERK- and P13K/Aktsignaling (Urban et al., 2009). UTP, released during
cardiac ischemia, was claimed to act via P2Y2 (and/or
P2Y4) receptors to play a substantial role in mediating
cardioprotection from hypoxic damage (Yitzhaki et al.,
2005; Erlinge et al., 2005; Wee et al., 2007). It has been
suggested that the P2Y4 receptor could be a therapeutic
target to regulate cardiac remodeling and postischemic
revascularization (Horckmans et al., 2012). It has been
suggested that P2Y6 and P2Y11 receptors are involved
in pyridoxal-59-phosphate-induced cardiac preconditioning in rat hearts (Millart et al., 2009). ADP acting
on endothelial P2Y1 receptors plays a major role in coronary flow during postischemic hyperemia (Olivecrona
et al., 2004). ADP, acting via P2Y1 receptors, mediates
release of tissue plasminogen activator during ischemia and postischemic hyperemia; tissue plasminogen
activator is involved in maintaining the endothelial
Purinergic Signaling and Blood Vessels
wall of blood vessels free of thrombi formation, and it
was suggested that this action of ADP may counteract some of the platelet activating effects of ADP
(Olivecrona et al., 2007). AZD6140, a reversible oral P2Y12
receptor antagonist, inhibits adenosine uptake into
erythrocytes and enhances coronary blood flow after
local ischemia or intracoronary adenosine infusion
(Björkman et al., 2007). After ischemia-reperfusion injury,
the coronary vasodilator effect of Ap4A is impaired,
probably due to reduced responsiveness of P2Y receptors to Ap4A (García-Villalón et al., 2011). Extracellular
tri- and diphosphates were claimed to be responsible
for cardioprotection against hypoxic damage, probably
by preventing free radical formation (Golan et al.,
2011). Ap3A, a vasoactive mediator stored in platelet
granules, induces coronary vasodilation, which is attenuated by ischemia-reperfusion due to the functional
impairment of P2Y receptors (Garcia-Villalón et al.,
2012).
Extracellular ATP augments cardiac contractility by
elevating intracellular calcium in cardiac myocytes.
Impairment of extracellular ATP-induced Ca2+ mobilization in rat hearts after ischemia and reperfusion has
been described (Saini et al., 2005). In a rat model of
ischemic congestive heart failure, there was selective
downregulation of the P2X receptor-mediated pressor
effects, whereas the hypotensive effects mediated by
endothelial P2Y receptors were unaffected (Zhao et al.,
2000). Cardiac-specific overexpression of human P2X4
receptors confers a beneficial effect in the left anterior
descending artery ligation model of ischemic cardiomyopathy (Sonin et al., 2007). Transgenic overexpression of P2X4 receptors in mouse heart led to an
enhanced cardiac contractile performance after ischemic infarction and increased survival at 1 and 2 months
after infarction; the actions suggest that enhanced
contractile function via P2X4 receptors of the noninfarcted areas was likely to be a rescuing mechanism
(Sonin et al., 2008). A recent review discusses P2X4
receptors as targets for cardiac ischemia (Yang and
Liang, 2012). There was selective upregulation of P2X6
receptors in the myocardium of patients undergoing
heart transplantation because of chronic heart failure
(Banfi et al., 2005).
P2X3 receptors have been identified on afferent
terminals in the heart activated by ATP, perhaps
associated with angina pectoris (Zhang et al., 2008).
P2X3 receptors were upregulated in rat stellate ganglia
after myocardial ischemic injury and may underlie
ischemic pain (Shao et al., 2007; Wang et al., 2008,
2009d). Myocardial ischemic injury induced an increase in expression of P2X3 receptors in superior
cervical and dorsal root ganglion neurons, which led to
aggravated sympathoexcitatory reflexes (Li et al.,
2011a). The authors also claimed that oxymatrine,
a Chinese herbal remedy for ulcers and tumors, may
decrease the expression of P2X3 receptors and depress
155
the aggravated sympathoexcitatory reflex induced by
ischemic injury. Mesenchymal stem cell-derived exosomes increase ATP levels and decrease oxidative stress
to enhance myocardial viability and prevent adverse
remodeling after myocardial ischemia-reperfusion injury (Arslan et al., 2013).
A protective role of E-NTPDase 1/CD39 in ischemiareperfusion injury has been shown. Targeted deletion
of E-NTPDase 1/CD39 led to heightened levels of
myocardial ischemia-reperfusion injury, which was
corrected by infusion of AMP or apyrase (which
degrades nucleotides) (Köhler et al., 2007). More
recently, transgenic expression of human E-NTPDase
1/CD39 in pigs was shown to protect against myocardial ischemia-reperfusion injury (Wheeler et al., 2012).
Interestingly, robust and selective induction of
E-NTPDase 1/CD39 was shown after preconditioning in
mouse heart (Köhler et al., 2007). Similarly, ischemic
preconditioning increases 59-nucleotidase activity and
adenosine release during myocardial ischemia and
reperfusion in dogs (Kitakaze et al., 1993). Ectonucleotidase on sympathetic nerve endings attenuates ATP
and NA exocytosis in myocardial ischemia (by reducing
ATP levels and consequently the prejunctional facilitatory effects of ATP) (Sesti et al., 2003). Conversely,
overexpression of E-NTPDase 1/CD39 resulted in
enhanced removal of exogenous ATP (Corti et al., 2011)
and protection against murine myocardial ischemic
injury (Cai et al., 2011). Because ATP availability
greatly increases in myocardial ischemia, it has been
suggested that recombinant E-NTPDase 1/CD39 may
offer a novel therapeutic approach to the damage
caused by ischemia by reducing sympathetic activity
(Corti et al., 2011). E-NTPDase 1/CD39 deletion led to
an attenuation of the activity of sympathetic pre- and
postsynaptic P2X receptors (attributed to P2X receptor
desensitization) perhaps because of prolonged exposure to ATP that accompanies E-NTPDase 1/CD39
deletion, and it was suggested that E-NTPDase 1/CD39
can potentially prevent the transition from myocardial
ischemia to infarction (Schaefer et al., 2007).
2. Brain and Spinal Cord. The hypothesis of Berne
(1963) that adenosine is the physiologic regulator of
reactive hyperemia was supported for the cerebral
circulation by some authors (e.g., Winn et al., 1980;
Emerson and Raymond, 1981; Kung et al., 2007) but
not by others when the increase in blood flow that
occurred in hypoxia was shown not to be clearly related
to changes in adenosine concentration (Rehncrona
et al., 1978; Heistad et al., 1981; Pinard et al., 1989).
ATP, as well as adenosine, was measured in the
perfusate of rat cerebral cortex during hypoxia (Phillis
et al., 1993). Real-time measurements showed release
of purines during ischemia in hippocampal slices and
suggested that ATP and adenosine release during
ischemia are, to a large extent, independent processes
(Frenguelli et al., 2007). The roles of adenosine and
156
Burnstock and Ralevic
adenine nucleotides as regulators of cerebral blood flow
in hypertension, hypoxia/ischemia, and hypercapnia/
acidosis have been reviewed (Burnstock, 1982; Phillis,
2004; Dale and Frenguelli, 2009; Thauerer et al., 2012).
Extracellular nucleotides modulate BBB responses to
ischemic events, and NTPDase activity was shown to
significantly increase after ischemia/hypoxia in vitro
(Ceruti et al., 2011a).
The GPR17 (P2Y-like) receptor appears on microglia/
macrophages after ischemia; it may play a role in both
inducing neuronal death in ischemia and in orchestrating the local repair responses (Lecca et al., 2008;
Zhao et al., 2012). Cortical spreading depression releases
ATP into the extracellular space, and the subsequent
activation of P2Y receptors makes a major contribution
to the induction of ischemic tolerance in the brain
(Schock et al., 2007). Endothelial P2Y2 receptormediated dilations of rat middle cerebral artery to
UTP were potentiated after ischemia-reperfusion,
whereas P2Y1 receptor-mediated dilation was attenuated after ischemia-reperfusion (Marrelli et al., 1999).
Astrocyte P2Y1 receptors were involved in the regulation of cytokine/chemokine transcription and brain
damage in a rat model of cerebral ischemia (Kuboyama
et al., 2011). A role for P2Y12 receptors in ischemia in
terms of microglial mediated neurotoxicity has been
proposed, suggesting an additional benefit of clopidogrel (Webster et al., 2010).
Increased extracellular glutamate levels and subsequent excitotoxicity can lead to neuronal death.
Activation of P2X receptors and consequent Ca2+ influx
might contribute to the ischemia-induced facilitation of
glutamate release (Zhang et al., 2006). Purinergic
facilitation, via P2X and A2A receptors, of glutamate
release in ischemic hippocampus was shown (Sperlágh
et al., 2007). Delayed P2X4 receptor expression in
microglia after hypoxia-ischemia in postnatal (P3) rat
brain has been reported, and it was suggested that this
may play a role in neuroinflammation and injury
progression (Wixey et al., 2009). Young age and low
temperature, but not female sex, delay ATP loss and
glutamate release and protect Purkinje cells during
simulated ischemia in cerebellar slices (Mohr et al.,
2010). Mild hypothermia has been considered as a
neuroprotective strategy for the management of ischemic brain injury. However, it was reported recently
that ATP induction of mild hypertension in rats has a
strikingly detrimental impact on focal cerebral ischemia (Zhang et al., 2013a). P2 receptor stimulation
plays a deleterious role during severe ischemic conditions in rat hippocampal slices (Coppi et al., 2007).
ATP and a,b-meATP, likely via P2X receptors, have
been shown to accelerate recovery from hypoxic/
hyperglycemic perturbations of guinea pig hippocampal neurotransmission (Aihara et al., 2002). Neuroprotective effects of the P2 receptor antagonist PPADS
on focal cerebral ischemia-induced injury in rats have
been reported (Lämmer et al., 2006). Reactive blue 2,
a P2 receptor antagonist, partially protected against
neurologic impairment after cerebral focal ischemia in
rats (Melani et al., 2006). P2X1 and P2X2 receptor
knockout mice were significantly protected in a model
of ischemic stroke (Bargiotas et al., 2011).
Recent experiments showed that P2X7 receptors
mediate ischemic damage in oligodendrocytes (Domercq
et al., 2010) and blockade of P2X7 receptors attenuates
postischemic injury (Matute, 2011; Arbeloa et al.,
2012). P2X7 receptors may be involved in hypoxicischemic injury of radial glia clone L2.3 cells (Zeng
et al., 2012). There is upregulation of P2X7 receptors
after ischemia in the cerebral cortex of rats (Franke
et al., 2004). Supersensitivity of P2X7 receptors in
cerebrocortical cell cultures after in vitro ischemia has
also been reported (Wirkner et al., 2005). P2X7 receptor
expression on microglia was increased by both ischemia and reactive blue 2 in rats; hence, the protection
against ischemic neurologic impairment by reactive
blue 2 was suggested to be mediated through increased
expression of P2X7 receptors (Melani et al., 2006).
Downregulation of P2X7 receptor expression in rat
oligodendrocyte precursor cells occurs after hypoxic
ischemia (Wang et al., 2009b). There is a recent review
that discusses the role of P2X7 receptors in cerebral
ischemia (Bai and Li, 2013). Endothelial cells at the
BBB were shown to be extremely susceptible to cell
death in ischemic conditions, whereas the other BBB
cells, astrocytes, and pericytes, were more resistant
(Kittel et al., 2010).
Early articles showed release of adenosine from
ischemic brain (Berne et al., 1974; Winn et al., 1979;
Phillis et al., 1987; see Chu et al., 2013), and adenosine
was shown to have a protective effect against ischemic
injury (Hagberg et al., 1987; Dux et al., 1990; Boissard
et al., 1992; Miller and Hsu, 1992; Rudolphi et al.,
1992; Schubert and Kreutzberg, 1993). An involvement
of adenosine in cerebral blood flow regulation in hypercapnia has also been reported (Phillis and Delong,
1987; Phillis et al., 2004). During the postischemic
period, adenosine is elevated in the cerebrospinal fluid
and could affect reperfusion (Meno et al., 1991).
Prevention of spinal cord injury was achieved with
regular infusion with adenosine (Herold et al., 1994;
Reece et al., 2008). In the early stages of hypoxia, adenosine is likely to be released per se from rat striatum
rather than being derived from released ATP (Melani
et al., 2012); furthermore, repeated hypoxia results in
reduced production of extracellular adenosine, and this
may underlie the increased vulnerability of the
mammalian brain to repetitive or secondary hypoxia/
ischemia (Pearson et al., 2003). Endogenous adenosine,
acting via A1 receptors, inhibits striatal GABAergic
transmission during in vitro ischemia (Centonze et al.,
2001). Inosine, as well as adenosine, reduced astroglial
injury in ischemia, and it was suggested that adenosine
Purinergic Signaling and Blood Vessels
was acting after breakdown to inosine (Haun et al.,
1996). The diadenosine polyphosphate Ap4A protects
against injury induced by ischemia in rat brain through
actions at P1 adenosine receptors (Wang et al., 2003b).
Hypoxia can induce upregulation of CD73 expression
in brain microvessel endothelial cells (Li et al., 2006),
which would be expected to lead to increased formation
of adenosine extracellularly. Transgenic overexpression of adenosine kinase, which removes adenosine
through phosphorylation to AMP, renders the brain
more susceptible to injury from ischemia, perhaps by
reducing the extracellular levels of adenosine (Pignataro
et al., 2007). Downregulation of hippocampal adenosine kinase after focal ischemia appears to be an endogenous neuroprotective mechanism (Pignataro et al.,
2008).
There is a general consensus that agonist stimulation of A1 receptors reduces brain damage after
experimentally induced ischemia. Hence, it has been
suggested that A1 agonists may be used clinically in
the treatment of ischemic brain disorders (Bischofberger
et al., 1997). A1 receptor agonists have been claimed to
play a pivotal role in protection from hypoxic insults
(Sebastião et al., 2001). A1 receptor activation decreases
cytotoxic amino acid release from both neurons and
glial cells (Schubert et al., 1994; Von Lubitz et al.,
1996; Pearson et al., 2006). A1 receptor agonists were
particularly effective against cerebral ischemia (Von
Lubitz et al., 1994, 1999; Chen et al., 2006) and
cerebral ischemia preconditioning (Heurteaux et al.,
1995). However, deletion of A1 receptors was reported
not to alter neuronal damage after ischemia in vivo or
in vitro (Olsson et al., 2004). Short cerebral ischemic
preconditioning upregulates A1 and A2B receptors in
the hippocampal CA1 region of rats (Zhou et al., 2004).
An increase in A1 receptor gene expression in cerebral
ischemia in rats has been reported (Lai et al., 2005).
The A1 receptor enhancer PD 81,723 failed to protect
against ischemia-reperfusion evoked cerebral injury
(Cao and Phillis, 1995) but provided significant neuroprotection against hypoxic-ischemic injury in newborn
rats (Halle et al., 1997). A1 receptors might contribute
to the enhancement of inhibiting synaptic transmission
in CA1 pyramidal neurons after forebrain ischemia,
leading to delay in the process of neuronal cell death
(Liang et al., 2009). In vitro ischemic preconditioning
allows CA1 hippocampal neurons to become resistant
to prolonged exposure to ischemia; adenosine, by stimulating A1 receptors, plays a crucial role, A2A receptors
are not involved, whereas A3 receptor activation is
harmful to ischemic preconditioning (Pugliese et al.,
2003), although it was claimed in a recent article that
A3 receptor agonists reduced brain ischemic injury and
inhibited inflammatory cell migration in rats (Choi
et al., 2011). Activation of A1 receptors has been shown
to promote postischemic electrocortical burst suppression (Ilie et al., 2009).
157
A2 receptor antagonists reduced brain ischemic injury (Gao and Phillis, 1994), and A2A receptor antagonists reduced brain injury in neonatal and adult
cerebral hypoxia-ischemia (Bona et al., 1997; Monopoli
et al., 1998; Pedata et al., 2005; Stone and Behan,
2007; Mohamed et al., 2012). The protective effects of
A2A antagonists in brain ischemia may be largely due
to reduced A2A receptor-mediated glutamate outflow
from neurons and glial cells (Pedata et al., 2007).
Moreover, adenosine, acting via A2A receptors, enhances glutamate release during ischemia (Marcoli et al.,
2004). A2A receptor deficiency reduces striatal glutamate outflow and attenuates brain injury induced by
transient focal ischemia in mice (Chen et al., 1999; Gui
et al., 2009), but another study claimed that there was
aggravated brain damage after hypoxic ischemia in
immature A2A knockout mice (Ådén et al., 2003). It has
been claimed that A2A receptor-stimulated cascade in
bone marrow-derived cells is an important modulator
of ischemic brain injury (Yu et al., 2004). A2A receptor
antagonism reduced JNK MAPK activation in oligodendrocytes after cerebral ischemia (Melani et al.,
2010). In A2A receptor knockout mice there was a decrease in early ischemic vascular injury after subarachnoid hemorrhage (Sehba et al., 2010). Nearly 50% of
cerebral hypoxic hyperemia was attenuated in A2A knockout mice (Miekisiak et al., 2008). In the CA1 area of the
hippocampus, stimulation of A2A receptors attenuates A1
receptor-mediated depression of synaptic transmission
induced by in vitro ischemia (Latini et al., 1999). Early
(onset within hours), but not late (duration of days)
neuroprotection due to preconditioning is associated with
upregulation of A3 receptor mRNA (von Arnim et al.,
2000). Thus, A1 receptor agonists and A2A and P2
receptor antagonists have protective effects against
cerebral ischemic injury.
3. Lung. Ischemia-reperfusion lung injury was
attenuated by ATP-MgCl2 in rats, although its effect
was in part mediated by its breakdown product,
adenosine, via A2 receptors, probably on leukocytes,
acting to prevent the production of damaging O2derived free radicals (Hsu et al., 1994; Hirata et al.,
2001; Chen et al., 2003). A 2A receptor agonists
attenuated cardiac dysfunction arising from pulmonary ischemia-reperfusion injury (Reece et al., 2005;
Ellman et al., 2008; Gazoni et al., 2008; Sharma et al.,
2009). It has been claimed that A2B receptors play a role in
mediating lung inflammation after ischemia-reperfusion
by stimulating cytokine production and neutrophil
chemotaxis (Anvari et al., 2010). Activation of A 3
receptors has also been claimed to attenuate lung
injury after in vivo reperfusion (Rivo et al., 2004;
Mulloy et al., 2013). A1 receptor antagonists have
been reported to block ischemia-reperfusion injury of
feline lung (Neely and Keith, 1995). In summary, A1, A2A,
A2B, and A3 receptor activation all ameliorate lung
ischemia-reperfusion injury (Gazoni et al., 2007, 2010;
158
Burnstock and Ralevic
Fernandez et al., 2013). CD39 and CD73 ectonucleotidase activities were severely impaired in the vasa
vasorum endothelial cells from pulmonary arteries of
chronically hypoxic neonatal calves, with increases in
extracellular ATP and ADP levels associated with higher
proliferative responses (Yegutkin et al., 2011).
4. Kidney. Adenosine levels are raised in ischemic
kidney after 10 minutes of ischemia (Miller et al., 1978)
but decreased after 30 minutes of ischemia (LópezMartí et al., 2003). It was suggested that tissue levels
of adenosine can modulate renal ischemia-reperfusion
injury via effects on NO and superoxide (López-Martí
et al., 2003). In contrast to most other vessels, extracellular adenosine produces vasoconstriction of the
renal vasculature via A1 receptors and hence is a
candidate for the decrease in renal blood flow and
gomerular filtration rate that occurs in ischemic kidneys. Theophylline, a P1 adenosine receptor antagonist,
reduced the vasoconstriction in response to arterial
occlusion and that to adenosine (and ATP) (Sakai et al.,
1979b). It was suggested that renal ischemic preconditioning can protect against ischemia-reperfusion injury
by decreasing the renal interstitial concentrations of
adenosine and ATP, and it was claimed that A1
receptor activation during ischemia-reperfusion injury
is detrimental to renal function (Li et al., 2005).
However, later articles claim short-term and delayed
protection against renal ischemia and reperfusion
injury with A1 receptor activation (Joo et al., 2007;
Moosavi et al., 2009). More recently, an A1 receptor
enhancer, PD-81723, was shown to be protective
against renal ischemia-reperfusion injury (Park et al.,
2012). A1 receptor activation has also been shown to
inhibit inflammation, necrosis, and apoptosis after
renal ischemia-reperfusion injury in mice (Lee et al.,
2004a). A1 receptor knockout mice exhibit increased
renal injury after ischemia-reperfusion (Lee et al.,
2004b), but Kim et al. (2009) shows the reverse effect.
Other studies showed that A2A receptor agonists
reduce renal injury after ischemia-reperfusion (Okusa
et al., 1999, 2001; Day et al., 2003). The A2A agonist
protective effect on ischemic-reperfusion injury was
blocked in macrophage-depleted A2A knockout mice
(Day et al., 2005a). ATL146 e[4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9Hpurin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid
methyl ester], an A2A receptor agonist, has been tested
in phase 3 clinical trials to treat acute kidney injury
due to ischemia (Li and Okusa, 2006). A2A receptormediated tolerized dendritic cells protect mouse kidney
from ischemia-reperfusion injury (Li et al., 2012b). A2A
receptors expressed in bone marrow-derived cells have
been claimed to contribute to the renal protective effect
of A2A receptor agonists in renal ischemia-reperfusion
injury (Day et al., 2006). Regulatory T cells, which
suppress inflammation and injury associated with
kidney ischemia-reperfusion injury, require A2A receptors
signaling (Kinsey et al., 2012). A2B as well as A2A
receptors have been claimed to mediate protection from
ischemic-reperfusion injury (Grenz et al., 2008). Inhibition of adenosine uptake into proximal tubule cells
by the equilibrative nucleoside transporter 1 is another
way to increase extracellular adenosine to act via A2B
receptors to protect the kidney against ischemiareperfusion injury (Grenz et al., 2012a). A3 receptor
antagonists are effective in protecting renal function in
ischemia-reperfusion injury (Lee and Emala, 2000).
Attenuation of renal ischemia-reperfusion injury by
postconditioning involves adenosine receptors and PKC
activation (Eldaif et al., 2010).
ATP depletion in kidney tubules after ischemic
injury leads to cell death (Lee, 2004). Adenosine uptake
mediates recovery of ATP content in postischemic
cultured renal tubular cells (Cadnapaphornchai et al.,
1991). Enhanced recovery from acute renal failure in
rats by postischemic infusion of ATP-MgCl2 was
described earlier (Osias et al., 1977; Glazier et al.,
1978; Siegel et al., 1980; Gaudio et al., 1982; Hirasawa
et al., 1983; Sumpio et al., 1984; Wang et al., 1992b,
1992d; Martin et al., 1992). Renal injury can arise as
a consequence of ischemia and reperfusion during
renal transplant surgery. Kidneys subjected to warm
ischemia before transplantation are salvaged by
addition of ATP-MgCl2 to the perfusate (Lytton et al.,
1981). The mechanism underlying the beneficial effects
of ATP is still not clear, although several mechanisms
have been proposed. The protective effect of ATPMgCl2 after warm ischemia in the kidney is not
mediated by adenosine (Sumpio et al., 1987). ATP
given after ischemia augmented the expression of
genes critical to cell proliferation that may underlie
its beneficial mechanism of action (Paller et al., 1998).
ATP-MgCl2 has been shown to be effective in preventing lipid peroxidation if given before reperfusion, but not
before ischemia, in rabbit kidneys (Mocan et al., 1999).
Trimetazidine is an antioxidant agent used to protect kidney grafts from ischemia-reperfusion injury;
tissue concentrations of ATP and ADP were significantly increased in kidneys from rats treated with
trimetazidine, and it was suggested that this drug
protects against dephosphorylation of nucleotides and
ischemic damage (Domanski et al., 2006). In an in vitro
model of ischemic injury involving severe depletion of
intracellular ATP in rabbit cultured proximal tubule
cells, P2Y receptor agonists were shown to be protective, and the mechanism involved reduced activation of NF-kB, an inducible transcription factor
associated with inhibitory proteins (Lee and Han,
2005). Suramin, a nonselective P2 receptor antagonist,
promotes recovery from renal ischemia-reperfusion
injury in mice; suramin-treated animals had a significant reduction in apoptosis and increase in proliferation
of tubular cells and infiltrating leukocytes (Zhuang
et al., 2009).
Purinergic Signaling and Blood Vessels
There was a robust and selective induction of ENTPDase 1/CD39 protein in mouse renal tissues after
renal ischemic preconditioning (Grenz et al., 2007b), as
observed after preconditioning in mouse heart (Köhler
et al., 2007). Transient overexpression of E-NTPDase
1/CD39 was shown to protect against renal ischemiareperfusion and transplant vascular injury in mice
(Crikis et al., 2010; see Roberts et al., 2013). Conversely, renal protection by ischemic preconditioning
was abolished in E-NTPDase 1/CD39 knockout mice,
whereas apyrase treatment (to hydrolyze nucleotides)
restored renal protection by ischemic preconditioning
in the knockouts; it was proposed that apyrase treatment may be a therapeutic strategy in treating acute
ischemic injury of the kidneys (Grenz et al., 2007b).
Ischemia, followed by reperfusion for durations of over
30 minutes, was associated with loss of glomerular
ATP diphosphohydrolase activity and potentiated the
deleterious effects of reperfusion (Candinas et al.,
1996). E-NTPD3 activity, located on the surface of
LLC-PK1 cells, was significantly inhibited by ischemia
(Ribeiro et al., 2012). Ecto-59-nucleotidase/CD73 is the
rate-limiting enzyme for extracellular adenosine formation, and increases in renal adenosine concentration
with ischemic preconditioning were attenuated in ecto59-nucleotidase/CD73 knockouts (Grenz et al., 2007a).
Moreover, renal ischemic preconditioning was shown
to induce ecto-59-nucleotidase/CD73 (Grenz et al.,
2007a). However, there is a lack of consensus about
the role of ecto-59-nucleotidase/CD73 in tissue protection during renal ischemia. In kidneys of ecto-59nucleotidase/CD73 knockout mice renal protection by
ischemic preconditioning was abolished and was completely restored after intraperitoneal injection of the
knockout mice with soluble 59-nucleotidase (Grenz
et al., 2007a). Moreover, renal injury after ischemia
in the knockouts was also attenuated by treatment
with soluble 59-nucleotidase (Grenz et al., 2007a).
Others have similarly shown that in kidneys of ecto59-nucleotidase/CD73 knockout mice there was greater
injury and lipid peroxidation, and free radical concentrations were higher than in wild-type kidneys, supporting the concept that ecto-59-nucleotidase/CD73 may
protect the kidney from ischemia-reperfusion injury
through adenosine production (Jian et al., 2012). However, there are other reports that ecto-59-nucleotidase/
CD73 knockout in mice has protective effects in renal
ischemia-reperfusion injury (Lu et al., 2008; Rajakumar et al., 2010a). It has been claimed that CD39 is
protective in kidney ischemia-reperfusion injury via
adenosine A2B receptor signaling (Rajakumar et al.,
2010b).
5. Gut. Superoxide dismutase is beneficial in restoring the ATP and GTP concentrations of rat small
intestine during postischemic reperfusion (Siems et al.,
1991). ATP-MgCl2 reduces intestinal permeability
during mesenteric ischemia (Kreienberg et al., 1996).
159
Both adenosine and ATP were reported to attenuate
intestinal dysfunction produced by ischemia but not
that caused by reperfusion (Taha et al., 2010a, 2010b).
A more recent study showed that treatment with
adenosine attenuated small bowel motor and neural
malfunctions produced by ischemia and reperfusion in
rats (Haddad et al., 2012). Extracellular adenosine
restores cellular ATP after intestinal epithelial ischemia (Mammen et al., 2004). External application of
ATP protects mucin in the mucosal barrier during
early periods of gut ischemia (Chang et al., 2012). A2B
receptor signaling is claimed to provide potent protection during intestinal ischemia-reperfusion injury
(Eltzschig et al., 2009; Hart et al., 2009). Pretreatment
with 59-N-ethylcarboxamidoadenosine, a nonselective
A1/A2 agonist, provides partial improvement in intestinal ischemia-reperfusion injury in rats (Özaçmak
et al., 2009). Ischemia-reperfusion of the rat intestine
causes a decrease in the expression of P2X2 receptors
on neurons of the myenteric and submucosal plexuses,
as well as a decrease in density and of neurons
immunoreactive for the P2X2 receptor (Paulino et al.,
2011). After intestinal ischemia-reperfusion injury,
P2Y2 receptor mRNA expression was increased in
murine lung and kidney and A3 receptor mRNA was
increased in lung but decreased in kidney, but there
was no change in mRNA expression of these receptors
in the intestine (Milano et al., 2008). Protection from
intestinal ischemia-reperfusion injury by hypoxiainducible factor-1a involves CD73 and A2B receptors
(Hart et al., 2011). The roles of ATP and adenosine in
hypoxia during intestinal ischemia and inflammation
are discussed in a recent review (Grenz et al., 2012b).
6. Liver. It was claimed many years ago that
infusion of ATP-MgCl2 improved hepatic function and
survival after hepatic ischemia (Hirasawa et al., 1980;
Ohkawa et al., 1983; Frederiks and Fronik, 1986;
Jeong and Lee, 2000) and after reperfusion (Clemens
et al., 1985b). It has been claimed that the beneficial
effect of ATP-MgCl2 treatment after trauma-hemorrhage
is associated with a downregulation of circulating
levels of the inflammatory cytokines TNF and IL-6
(Wang et al., 1992c). Another suggestion was that the
improvement in ischemic damage by ATP-MgCl2 infusion may be mediated through improvement in
mitochondrial energy metabolism (Jeong and Lee,
2000). There is a 90% ATP loss from hepatocytes
during 60 minutes of ischemia (Grune et al., 1997).
Ischemic preconditioning protects the liver against
necrosis, perhaps through protecting against tissue
ATP loss (Selzner et al., 2003). ATP treatment was
particularly effective for treatment of ischemia in old
mice (Selzner et al., 2007). Aging of the liver is
associated with mitochondrial dysfunction, resulting
in poorer tolerance against ischemic injury; improvement in intrahepatic ATP levels in old livers by glucose
injection protects the old liver against ischemic injury
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Burnstock and Ralevic
and restores the protective effect of preconditioning
(Selzner et al., 2007). Provision of adenosine during
reperfusion enhanced restoration of ATP concentrations in rat liver (Palombo et al., 1991).
P2Y2 receptors promote hepatocyte resistance to
hypoxia by downmodulating ERK1/2-mediated signals
that promote Na+ influx through the Na+/H+ exchanger
(Carini et al., 2001). A study demonstrated that administration of UTP before induction of ischemia can
attenuate, via P2Y2 and/or P2Y4 receptors, postischemic hepatocyte apoptosis and thereby reverse liver
damage (Ben-Ari et al., 2009). The authors suggest
that the UTP-mediated protective effect may be
regulated through NF-kB inactivation. P2Y receptor
antagonism prevents cold preservation-induced cell
death independent of cellular ATP levels in a human
hepatocyte cell line (Anderson et al., 2007). After
hepatic ischemia and reperfusion injury, vascular
NTPDase activity is lost and deletion of E-NTPDase
1/CD39 in mice leads to significantly increased injury
and decreased survival, consistent with a protective
role of endogenous nucleotides in ischemia-reperfusion
injury (Imai et al., 2000).
There is compelling evidence that adenosine can play
a protective role against ischemia-reperfusion injury
(Dunne et al., 1998; Nilsson et al., 2000). This probably
occurs through activation of A2 receptors (Peralta
et al., 1999) located on sinusoidal endothelial cells
(Arai et al., 2000) and in particular involving A2A
receptors (Carini et al., 2001; Lappas et al., 2006).
Protection is lost in A2A receptor knockout mice (Day
et al., 2004, 2005b). However, administration of an adenosine A1 receptor antagonist before ischemia attenuates ischemia-reperfusion injury (Magata et al., 2007;
Kim et al., 2008). Ozone oxidative preconditioning
is mediated by A1 receptors in a rat model of liver
ischemia-reperfusion (León Fernández et al., 2008).
Selective intrarenal human A1 receptor overexpression
reduced acute liver (and kidney) injury after hepatic
ischemia-reperfusion in mice (Park et al., 2010b). It is
claimed that ischemic preconditioning promotes liver
regeneration via A2 receptors on Kupffer cells (Arai
et al., 2007). Hepatic ischemia-reperfusion injury
induces expression of A2B receptors early after partial
portal occlusion and A2B receptor activation has a protective effect (Zimmerman et al., 2011). Hypoxic
preconditioning in vivo was reported to protect against
liver ischemia-reperfusion injury via A2B receptors
(Choukèr et al., 2012). Ischemia-driven expression of
59-nucleotidase/CD73 leads to increased adenosine
production conferring tissue protection during liver
ischemia-reperfusion (Hart et al., 2008b).
7. Bladder. Ischemia-reperfusion of the urinary
bladder may result in dysfunction of the contractile
response to nerve stimulation and NO may act as
a tissue damaging agent in ischemia-reperfusion injury
(Saito et al., 1998). Contractile responses to ATP were
similarly sensitive to ischemia (Bratslavsky et al.,
1999).
8. Umbilical Cord. Extracellular ATP attenuates
ischemia-induced caspase-3 cleavage in endothelial
cells from human umbilical veins (Urban et al., 2012).
9. Testis and Prostate. ATP-MgCl2 prevented reperfusion injury in testicular torsion (Abes et al., 2001). It
has been suggested that adenosine-induced vasodilation may be useful to prevent prostatic ischemia (Ribeiro
et al., 2011).
10. Pancreas. Adenosine ameliorates ischemic damaged canine pancreas (Kuroda et al., 1994). Adenosine
in the preservative solution may enhance the inflammatory response in rat pancreas transplantation
(Pi et al., 2001).
11. Skeletal Muscle. A very early article implicated
ATP in the responses to experimental limb ischemia
(Stoner and Green, 1945). Hagberg et al. (1985)
concluded that reduction in the glycogen available for
ATP resynthesis during rabbit skeletal muscle ischemia drastically reduces the ability of skeletal muscle to
withstand prolonged ischemia. Vascular injury in dog
gracilis nuclei during ischemia-reperfusion was attenuated by pretreatment with ATP-MgCl2 (Korthuis et al.,
1988; Hayes et al., 1990). Attenuation of apoptosis in
ischemia-reperfusion injury in vivo in mouse skeletal
muscle by P2Y6 receptor activation has been claimed
(Mamedova et al., 2008). Release of nucleotides in ischemic tissue may induce a pronounced activation of the
endogenous fibrinolytic system (Hrafnkelsdóttir et al.,
2001). ATP released from ischemic muscle works
together with acid by increasing the sensitivity of sensory fibers when P2X and acid sensing ion channel
receptors form a molecular complex resulting in ischemic pain (Birdsong et al., 2010). In young healthy
humans, oxygen delivery is matched to oxygen demand
during hypoxia and exercise by increases in skeletal
muscle blood flow. However, in aging humans there is
impaired vasodilation and functional sympatholysis in
response to hypoxia (Kirby et al., 2012).
Adenosine pretreatment applied prior to ischemia
protects against ischemia-reperfusion injury (Lee and
Lineaweaver, 1996). Intra-arterial adenosine administration during reperfusion preserves endotheliumdependent relaxation in the rabbit hindlimb (Farooq
et al., 1997). A2A receptors were not found to contribute
to the hyperemia after ischemia of skeletal muscle in
the hindlimb of anesthetized cats (Poucher, 1997).
Adenosine appears to act via A1 receptors during acute
ischemic preconditioning of pig skeletal muscle, protecting against infarction (Pang et al., 1997). A more
recent paper describes a protective role for A1, A2A, and
in particular A3 receptors in skeletal muscle ischemia
and reperfusion injury (Zheng et al., 2007a, 2007b).
Remote postconditioning may attenuate ischemiareperfusion injury in murine hindlimb via activation
of adenosine receptors (Tsubota et al., 2009). Mg-ATP
Purinergic Signaling and Blood Vessels
elicits a protective effect on ischemic skeletal muscle by
acting primarily through adenosine receptors (Maldonado et al., 2013).
12. Eye. The concentration of adenosine in rat
retina is elevated after retinal ischemia and during
reperfusion (Roth et al., 1997). It was proposed that
blockade of A2A receptors combined with stimulation of
A1 receptors may be potential strategies for the
prevention of ischemic damage of the retina (Li et al.,
1999). However, a more recent study suggested that
A2A receptors mediate the protective effect of adenosine on retinal ischemia-reperfusion injury (Konno
et al., 2006). Evidence was presented that glutamateevoked purinergic P2Y1 receptor signaling of glial cells
is involved in cell volume homeostasis of the retina,
and it was suggested that this mechanism may
contribute to the protective effect of purines in
ischemic tissue (Uckermann et al., 2006). Atrial
natriuretic peptide (ANP) inhibits osmotic glial cell
swelling in the ischemic rat retina; because ANP
evokes release of ATP from Müller glial cells, it was
suggested that P2Y1 receptors and also A1 receptors
(after ATP breakdown to adenosine) on glial cells are
involved in the protective actions of ANP (Kalisch
et al., 2006). It has been suggested that suppressing
neuronal necrosis using ATP-liposomes in ischemiareperfusion-challenged neuronal tissues could promote
a neuroprotective environment and reduce tissue
damage (Dvoriantchikova et al., 2010). P2X7 receptor
activation causes retinal ganglion cell death in a human retina model of ischemic neurodegeneration
(Niyadurupola et al., 2013).
D. Thrombosis and Stroke
Extracellular nucleotides are recognized as mediators of vascular inflammation and thrombosis (Robson
et al., 2001). ATP released from endothelial cells
during changes in blood flow (producing shear stress)
is broken down by ectonucleotidases to ADP, which
acts on P2Y1 and P2Y12 receptors on platelets to cause
aggregation. Clopidogrel is a P2Y12 antagonist that
inhibits platelet aggregation and has been used for the
treatment of thrombosis and stroke (Herbert et al.,
1993; see Sarafoff et al., 2012). Other P2Y12 antagonists have been developed to follow clopidogrel as
antithrombotics, such as ticlopidine, cangrelor, ticagrelor, prasugrel, elinogrel, BX 667, AZD6140, and
PSB 0739 (see Cattaneo, 2009; Khoynezhad et al.,
2009; Wallentin, 2009; Angiolillo and Ferreiro, 2010;
Nawarskas and Snowden, 2011; Ahmad and Storey,
2012). Evidence has been presented for an association
of haplotype H2 gene variants of the P2Y12 receptor
with lower risk of ischemic stroke and deep venous
thromboembolism/pulmonary disease (Zee et al., 2008).
P2Y1 receptor antagonists have also been proposed as
antithrombotic agents (see Gachet, 2008). Adenosine
has antithrombotic effects by blocking induction of
161
circulating tissue factor (Deguchi et al., 1998) via A2A
and A3 receptors (Sitkovsky et al., 2004). Ectonucleotidases are regulators of purinergic signaling in thrombosis (Deaglio and Robson, 2011). The ectonucleotidase
CD39 mediated resistance to occlusive arterial thrombus formation after vascular injury in mice (Huttinger
et al., 2012).
E. Diabetic Vascular Disease
In rats with streptozotocin diabetes there was
prejunctional impairment of sympathetic neurotransmission and impaired ATP-mediated endothelial vasorelaxant function in mesenteric arteries (Ralevic et al.,
1995a). Attenuated vasodilatation to ATP, UTP, and
adenosine in the skeletal muscle circulation of patients
with type 2 diabetes was demonstrated (Thaning et al.,
2010).
Red blood cells may stimulate vasodilatation via
release of ATP, which may be important in maintaining perfusion in the microcirculation. Interestingly, in
erythrocytes from humans with type 2 diabetes ATP
release is impaired, consistent with the hypothesis that
a defect in erythrocyte physiology could contribute to
the vascular disease associated with this clinical condition (Sprague et al., 2006). This group later showed
that the phosphodiesterase 3 inhibitor cilostazol rescues
low PO2-induced ATP release from erythrocytes of
humans with type 2 diabetes (Sprague et al., 2011).
High extracellular glucose releases ATP and/or UTP
in endothelial cells and pancreatic b-cells (Parodi et al.,
2002; Hellman et al., 2004). An increase in glucose
from 5 to 15 mM (equivalent to normal and hyperglycemic levels, respectively) results in a marked increase
in the pro-atherogenic nuclear factor of activated
T cells signaling pathway in vascular smooth muscle
cells (Nilsson et al., 2006). The effect is mediated via
glucose-induced release of ATP and UTP that subsequently activate P2Y2 but also P2Y6 receptors (after
degradation to UDP). Thus, nucleotide release is
a potential metabolic sensor for the arterial smooth
muscle response to high glucose. Diabetic patients
experience microvascular disease characterized by
increased wall-lumen ratio, mainly because of an
increase in vascular smooth muscle cells, and have
higher rates of restenosis after coronary angioplasty.
High-glucose-induced release of extracellular nucleotides acting on P2Y receptors to stimulate vascular
smooth muscle cell growth via nuclear factors of
activated T-cells may provide a link between diabetes
and diabetic vascular disease (Nilsson et al., 2006).
There is a recent review about adenosine-insulin
signaling in fetoplacental endothelial dysfunction in
gestational diabetes (Guzmán-Gutiérrez et al., 2013).
F. Migraine and Vascular Pain
There are two distinct cerebrovascular phases: an
initial vasoconstriction (not associated with pain)
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Burnstock and Ralevic
followed by vasodilatation (reactive hyperemia) associated with pain in migraine, with early hints of the
involvement of ATP. A “purinergic” hypothesis for
migraine was put forward in 1981 as a basis for the
reactive hyperemia and pain during the headache phase
(Burnstock, 1981). It was proposed that ATP and its
breakdown product adenosine were contenders for
mediating the vasodilatation after the initial vasospasm and subsequent hypoxia. It was also suggested
that ATP was implicated in migraine pain via
stimulation of primary afferent nerve terminals located in the adventitia of the cerebral microvasculature. Later studies have shown that ATP-induced
cerebral vasodilatation is endothelium dependent via
activation of P2X and P2Y receptors on endothelial
cells, with subsequent release of EDRFs, and that the
endothelial cells are the main local source of ATP
involved, although ADP and ATP released from
aggregating platelets may also contribute to this
vasodilatation. These findings have extended the
purinergic hypothesis for migraine in two ways. First,
they clarify the mechanism of purinergic vasodilatation during the headache phase of migraine. Second,
they suggest that a purinergic mechanism may also be
involved in the initial local vasospasm, via P2X
receptors on smooth muscle cells activated by ATP,
released either as a cotransmitter with NA from
perivascular sympathetic nerves or from damaged
endothelial cells (Burnstock, 1989b).
Evidence in support of the purinergic hypothesis was
reported where it was suggested that decreased
platelet ATP release was a marker for migraine,
reflecting hypofunction of the purinergic system,
resulting in a greater tendency for vasoconstriction,
which predisposes to migraine attacks (Joseph et al.,
1986). Further support was the identification of P2X3
receptors on primary afferent nerve terminals supplying cerebral vessels arising from trigeminal, nodose,
and spinal ganglia (Chen et al., 1995, Burnstock,
1996a, 2001b). Peripheral sensitization in the duravascular sensory pathway via P2X3 receptors in
migraine was also reported (Jennings and Cho, 2007).
P2X3 receptor antagonists were suggested as possible
candidates for antimigraine drug development (Waeber
and Moskowitz, 2003). CGRP, released during migraine
attacks from trigeminal neurons, leads to sensitization
of trigeminal P2X3 nociceptive receptors; thus it was
suggested that trigeminal P2X3 receptors may be
a potential target for the early phase of migraine
attacks (Fabbretti et al., 2006). The nonsteroidal antiinflammatory drug naproxen, which is widely used for
the treatment of migraine pain, has been shown to
block P2X3 receptor-mediated responses of rat trigeminal neurons (Hautaniemi et al., 2012). Migraine
may also involve a chronic sympathetic nervous system
disorder, with an increase in release of sympathetic
cotransmitters, including ATP (Peroutka, 2004), perhaps
contributing to the initial vasospasm. It has been
shown that neutralization of NGF induces plasticity of
ATP-sensitive P2X3 receptors of nociceptive trigeminal
ganglion neurons involved in migraine (D’Arco et al.,
2007). Familial hemiplegic migraine calcium channel
mutation R192Q enhances ATP-gated P2X3 receptor
activity of mouse sensory neurons mediating trigeminal pain, suggesting a role for P2X3 receptors in
migraine (Wirkner et al., 2007; Fabbretti, 2010; Nair
et al., 2010). According to Gnanasekaran et al. (2011),
it was shown that P2X3 receptors of trigeminal nerves
were preferentially localized to lipid rafts, which is
associated with a molecular phenotype characterized
by stronger responses to P2X3 receptor activation.
Cultures of the trigeminal ganglia from the knockin
mouse genetic model of familial hemiplegic migraine
had a neuroinflammatory profile that may facilitate
release of ATP to activate P2X3 receptors and amplify
nociceptive signals by trigeminal sensory neurons
(Franceschini et al., 2012, 2013). Vascular endothelial
cells mediate endothelium-induced hyperalgesia via
release of ATP to activate P2X2/3 nociceptive receptors
(Joseph et al., 2013).
Adenosine has also been implicated in migraine. For
example, during migraine, biosynthesis of ATP is
elevated and, after release, degrades to adenosine
and the blood level of adenosine increased by 47%
(Guieu et al., 1994). Infusion of adenosine causes
migraine-like symptoms; and withdrawal from caffeine
and theophylline (adenosine receptor antagonists)
addiction also causes migraine-like symptoms (Spencer
1996; Shapiro, 2007). Early clinical trials with dipyridamole, an adenosine uptake inhibitor that increases
extracellular adenosine, had to be stopped because of
increased migraine attacks in all patients (Hawkes,
1978). The efficacy of caffeine against migraine is poor
(Tokola et al., 1984), but it is effective when used in
combination with analgesics (Diener et al., 2005). An
A1 receptor agonist, GR79236 [(2R,3R,4S,5R)-2-(6{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)5-(hydroxymethyl)oxolane-3,4-diol], acting on the
trigeminovascular system, was claimed to be effective
against migraine, perhaps by reducing CGRP release
(Goadsby et al., 2001; Mehrotra et al., 2008). A2A
receptors facilitate the effects of CGRP and vasoactive
intestinal peptide, two neuropeptides claimed to be
involved in migraine pathophysiology and are a target
of caffeine, used in migraine treatment in combination
with analgesics; A 2A receptor gene variation may
contribute to the pathogenesis of migraine with aura
(Hohoff et al., 2007).
It has been suggested that in vascular pain, including angina, pelvic, and ischemic pain, as well as
migraine, ATP released from endothelial cells during
the reactive hyperemia after vasospasm (not associated
with pain) diffuses through the wall of microvessels to
reach P2X3 receptors on sensory perivascular nerves to
Purinergic Signaling and Blood Vessels
initiate impulses that travel via the spinal cord to pain
centers in the brain (Burnstock, 1996a). Data have been
presented to suggest that overactive glial P2Y receptors
may contribute to pain transduction in migraine (Ceruti
et al., 2011b; see Magni and Ceruti, 2013).
G. Sepsis and Septic Shock
An early theory was that degradation of adenine
nucleotides is related to irreversibility in hemorrhagic
shock, and a marked reduction in ATP contents of the
pancreas, liver, and duodenum was demonstrated
(Cunningham and Keaveny, 1977). It was suggested
that ATP prevented disruption of glucose homeostasis
and development of endotoxin shock by counteracting
insulin and blunting hypoglycemia (Chaudry et al.,
1976; Filkins and Buchanan, 1977). Treatment of
shocked animals with ATP-MgCl2 was reported to be
an effective therapy for experimental hemorrhagic
shock (Kraven et al., 1980; Machiedo et al., 1981;
Engelbrecht and Mattheyse, 1986; Zambon et al.,
1994), although this was debated (Schloerb et al.,
1981). In animal models of sepsis, treatment with ATPMgCl2 has been shown to prevent endothelial dysfunction, reduce organ damage, restore immune competence, and increase survival (Wang et al., 1999; Nalos
et al., 2003).
Human microvascular endothelial cells showed a
selective induction of the P2Y6 receptor after exposure
to inflammatory stimuli, and in vivo inflammatory
responses due to LPS treatment were attenuated in
P2Y6 knockout mice or after P2Y6 antagonist treatment, implicating the P2Y6 receptor as a therapeutic
target for systemic inflammatory responses (Riegel
et al., 2011). Glibenclamide reduced proinflammatory
cytokines in an ex vivo model of human endotoxinemia
under hypoxemic conditions (Schmid et al., 2011). It
was suggested that glibenclamide inhibition was dependent on P2X7 receptor activation of monocytes by
ATP-releasing erythrocytes during hypoxia. A role for
adenosine in the early hemodynamic changes associated with sepsis has been claimed (Conlon et al., 2005).
Regional hemodynamic responses to adenosine were
shown to be altered after LPS treatment in conscious
rats, such that renal and hindquarters vasodilator
responses were abolished (Jolly et al., 2008).
H. Hyperhomocysteinemia
Hyperhomocysteinemia is a risk factor for cardiovascular disease; the mechanisms causing the cardiovascular complications are not fully understood, although
endothelial dysfunction appears to be involved. In this
condition, there is evidence that constitutive and evoked
adenosine release is decreased, and it has been suggested that as a consequence the cardio- and vasoprotective actions of adenosine are attenuated, identifying
a key role for adenosine in the pathogenesis of hyperhomocysteinemia (Riksen et al., 2003).
163
I. Calcific Aortic Valve Disease
ATP acts as a survival signal and prevents mineralization of aortic valve that occurs in calcific aortic
valve disease (Osman et al., 2006; Côté et al., 2012b).
Released ATP promoted the survival of valvular
interstitial cells in the aortic valve via P2Y2 receptors,
and it was also shown that a high level of membranebound ectonucleotidase ENPP1 was expressed in
calcific aortic valve disease. Inhibition of ectonucleotidase with ARL67156 prevented the development of
calcific aortic valve disease in warfarin-treated rats
(Côté et al., 2012a).
J. Metabolic Syndrome
Metabolic syndrome is an obesity disorder in which
abnormal metabolism of glucose and lipid is associated
with the development of chronic inflammatory diseases. Metabolic syndrome has pronounced effects on
small blood vessels, and these result in many chronic
complications in other organ systems (Sparks and
Chatterjee, 2012).
VI. Conclusions and Future Directions
Several important conclusions can be drawn from
this review:
1. Purinergic signaling plays a major role in control
of both vascular tone and remodeling. Vascular
tone is regulated by moment-to-moment changes
in sympathetic nerve activity that coordinates
with endothelium-mediated vasorelaxation (or less
commonly contraction). ATP has a pivotal role as
it is released as a cotransmitter with NA from sympathetic nerves to contract vascular smooth muscle
and is also released from endothelial cells in
response to changes in blood flow (producing shear
stress) and hypoxia to act on adjacent endothelial
cells with subsequent vasodilation. Vascular tone
is also regulated by the actions of other locally
released purine and pyrimidine nucleotides (ADP,
UTP, and UDP) and by adenosine.
2. P1 adenosine receptors: Adenosine is predominantly a vasodilator, acting via A2A and/or A2B
receptors on the endothelium and smooth muscle, but mediates vasocontraction, mainly via A1
receptors, in pulmonary arteries, renal afferent
arterioles and some aortae.
3. P2 receptors for purine and pyrimidine nucleotides: Contractile P2X1 receptors appear to be
expressed on the smooth muscle of all blood
vessels. Vascular smooth muscles also express
contractile P2Y2, P2Y4, and P2Y6 receptors activated by ATP, UTP, and UDP (Table 3). Some
blood vessels express vasorelaxant P2Y receptors
on their smooth muscle (hepatic veins and aortae
and coronary arteries from some species), but in
164
Burnstock and Ralevic
most blood vessels vasorelaxant P2Y receptors are
expressed on the endothelium.
4. Adenosine and purine and pyrimidine nucleotides elicit long-term (trophic) signaling, modulating cell proliferation, differentiation, and death
in angiogenesis and regeneration of damaged
vessels (see Table 4). In summary, A2 and P2Y1
receptors mediate proliferation of endothelial
cells, whereas A2 and P2Y2/P2Y4 receptors stimulate proliferation of smooth muscle cells.
5. Significant changes in purinergic signaling pathways occur in pathologic conditions (see Table 5).
Thus, the field of purinergic signaling in the vasculature is complex, but major patterns are emerging,
which we have summarized in the figures. Within
blood vessels, the effects of purines are influenced by
the sources of purine release and endothelial integrity.
In general, purines released at the adventitia (e.g.,
ATP from sympathetic nerves) are vasocontractile,
whereas those released at the intima (e.g., from erythrocytes, endothelial cells) mediate endothelium-dependent
vasodilatation or contraction where there is endothelial damage. A balance between purine release and the
activities of ectonucleotidases will determine the
extracellular levels of ATP, ADP, UTP, and adenosine
and consequently the prevailing target effects.
Clearly, purines contribute to a number of processes
involved in normal vascular function, and disturbances
in purinergic signaling are involved in some vascular
diseases. As all cells in the vascular system express one
or more types of purine receptor, this raises the possibility that purine receptors may be potential targets
in vascular disease (see Schuchardt et al., 2012). Purine
release mechanisms, receptors, and ectonucleotidases
are all potential targets for drug development. Drugs
against purinergic receptors already exist, giving
reason for optimism. Clopidogrel is a widely used
antithrombotic drug; the active metabolites of this
prodrug bind to platelet P2Y12 receptors to inhibit
aggregation. The success of this compound owes much
to the fact that P2Y12 receptors are found mainly on
platelets. However, purine receptors within the vasculature are also expressed elsewhere in the body, and
this is a major drawback to the development of drugs
targeting these receptors; as with all established/
potential drugs, target selectivity is not guaranteed.
Of some promise may be the development of A3
agonists to protect against ischemia-reperfusion injury. The A3 receptor has a relatively limited expression, and it has been shown to be cardioprotective and
adenosine can safely be administered to humans. An
increased importance of ATP as a sympathetic cotransmitter in arteries of spontaneously hypertensive and
obese rats (Haddock and Hill, 2011; Goonetilleke et al.,
2013 and references therein) suggests that antagonists
at smooth muscle P2X1 receptors could be beneficial in
these diseases. The drawbacks are that P2X1 receptors
are widely distributed, and P2X 1 knockout mice
showed male infertility and an increase in blood
pressure (Mulryan et al., 2000). E-NTPDase1 knockout
augmented purinergic vasorelaxation in vitro and the
hypotensive effects of purines in vivo (Kauffenstein
et al., 2010b), and thus enzyme inhibition might be
useful in conjunction with purinergic vasodilator
drugs, especially those targeting the endothelial P2Y1
receptor; potential pitfalls are an increased desensitization of the P2Y1 receptor (Kauffenstein et al., 2010b)
and prothrombotic effects. An area with future potential involves the characterization of vascular smooth
muscle and endothelial P2Y2, P2Y4, and P2Y6 receptors because there is evidence of profound species
differences and some restriction in their expression
within blood vessels. However, the development and
use of ligands with good subtype specificities that are
orally bioavailable and do not degrade in vivo is needed
to exploit this. The considerable efforts of the clinical
biochemists working in this field are leading to a
promising emergence of subtype-specific P2 ligands.
This will open up new avenues for research into the
physiologic roles of purine receptors and their therapeutic potential for the treatment of vascular disorders.
Acknowledgments
The authors thank Dr. Gillian E. Knight for outstanding help with
the preparation of this manuscript.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Burnstock,
Ralevic.
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