Am J Physiol Heart Circ Physiol 306: H163–H172, 2014.
First published November 1, 2013; doi:10.1152/ajpheart.00493.2013.
Review
Smooth muscle contractile diversity in the control of regional circulations
John J. Reho, Xiaoxu Zheng, and Steven A. Fisher
Division of Cardiology, School of Medicine, University of Maryland, Baltimore, Maryland
Submitted 20 June 2013; accepted in final form 23 October 2013
vascular smooth muscle; contractile; myosin; isoforms; renal; hepatic; pulmonary
cardiac output to the regional circulations is determined by the local resistance to blood flow, a
function that is dynamically regulated by the state of contraction of the vascular smooth muscle. Each regional circulation
has unique requirements for blood flow and thus unique mechanisms by which it is regulated. As the resistance to flow
through a vessel is inversely proportional to the fourth power
of its radius, the primary resistance to blood flow, and thus site
of regulation, is the small arteries and arteriolar network. It is
well recognized that the large (conduit) and small (resistance)
arteries are phenotypically and functionally distinct in both the
systemic and pulmonic circulations (20, 29, 40, 110). The
smooth muscle of large arteries and veins express the slow
contractile gene program characteristic of the tonic phenotype.
The smooth muscle of the small resistance arteries in the
systemic circulation express components of the fast contractile
gene program characteristic of the phasic phenotype. At its
simplest smooth muscle contraction is determined by calcium
influx, activation of myosin light chain (MLC) kinase (MLCK)
and phosphorylation of myosin regulatory light chain, and
relaxation by calcium efflux, regulation of myosin phosphatase
(MP) activity, and dephosphorylation of myosin regulatory
THE DISTRIBUTION OF THE
Address for reprint requests and other correspondence: S. A. Fisher, S012c,
HSF II, Div. of Cardiology, School of Medicine, Univ. of Maryland, Baltimore, 20
Penn St., Baltimore, MD 21201 (e-mail: [email protected]).
http://www.ajpheart.org
light chain (Fig. 1). While these same basic mechanisms apply
to tonic and phasic smooth muscle, how they are controlled in
each is quite distinct [reviewed in (53, 70)]. This review will
focus on vascular smooth muscle phenotypic and functional
differences within select circulations to highlight unique properties in the control of each regional circulation. Other aspects
of unique control mechanisms of regional circulations, such as
differences in controlling signals, are beyond the scope of this
review [see recent reviews (5, 14, 15, 30)]. The significance of
these differences with respect to the dysregulation of blood
flow in disease and the potential for specificity in pharmacological targeting will also be discussed.
Smooth Muscle Contractile Phenotypes: Fast and Slow Gene
Programs
It was almost 50 years ago that Somlyo and Somlyo (106)
and Hermsmeyer (59) recognized functional differences between vascular tissues which they termed pharmacomechanical
versus electromechanical coupling. In the intervening years, it
became apparent that smooth muscle contractile function in the
different organ systems is incredibly diverse and difficult to
capture with a single simple classification scheme. The classification most relevant to organ system function is that of phasic
versus tonic contractile activities which loosely corresponds to
the dichotomy of electro- versus pharmacomechanical coupling. Phasic or fast rhythmic contracting smooth muscle is a
0363-6135/14 Copyright © 2014 the American Physiological Society
H163
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Reho JJ, Zheng X, Fisher SA. Smooth muscle contractile diversity in the
control of regional circulations. Am J Physiol Heart Circ Physiol 306: H163–H172,
2014. First published November 1, 2013; doi:10.1152/ajpheart.00493.2013.—Each
regional circulation has unique requirements for blood flow and thus unique
mechanisms by which it is regulated. In this review we consider the role of smooth
muscle contractile diversity in determining the unique properties of selected
regional circulations and its potential influence on drug targeting in disease.
Functionally smooth muscle diversity can be dichotomized into fast versus slow
contractile gene programs, giving rise to phasic versus tonic smooth muscle
phenotypes, respectively. Large conduit vessel smooth muscle is of the tonic
phenotype; in contrast, there is great smooth muscle contractile diversity in the
other parts of the vascular system. In the renal circulation, afferent and efferent
arterioles are arranged in series and determine glomerular filtration rate. The
afferent arteriole has features of phasic smooth muscle, whereas the efferent
arteriole has features of tonic smooth muscle. In the splanchnic circulation, the
portal vein and hepatic artery are arranged in parallel and supply blood for
detoxification and metabolism to the liver. Unique features of this circulation
include the hepatic-arterial buffer response to regulate blood flow and the phasic
contractile properties of the portal vein. Unique features of the pulmonary circulation include the low vascular resistance and hypoxic pulmonary vasoconstriction,
the latter attribute inherent to the smooth muscle cells but the mechanism uncertain.
We consider how these unique properties may allow for selective drug targeting of
regional circulations for therapeutic benefit and point out gaps in our knowledge
and areas in need of further investigation.
Review
H164
SMOOTH MUSCLE DIVERSITY IN REGIONAL CIRCULATIONS
NO
PKC
cGMP
RhoA
CPI-17
Variants
ROCK1
ROCK2
–
PKG1α
ROCK
+
PP1c
MYPT1
LZ
Variants
E24 + (LZ–) (fast)
E24 – (LZ+) (slow)
P
Constriction
Myosin
Myosin
MLCK
Ca-Calmodulin
hallmark of the gastrointestinal and urinary systems that require highly coordinated unitary muscle function. Tonic or
slow-sustained contracting smooth muscle is characteristic of
the large arteries and veins involved in conduit and capacitance
roles that function primarily as independent units. The advent
of the molecular era of basic cardiovascular research in the
1990s led to the discovery of some of the molecular mechanisms underlying these contractile differences [reviewed in
(40)]. In all muscle lineages (striated and smooth muscle),
myosin isoforms are primary determinants of fast versus slow
contractile properties (101). In smooth muscle, a 21 nucleotide
alternative exon coding for a seven amino acid insert in the
head of the myosin heavy chain was identified and conferred
threefold increased myosin ATPase activity and shortening
velocity in phasic smooth muscle (66) (Fig. 2A). Isoforms of
the essential MLC (MLC17) generated by alternative splicing
of a 39 nucleotide alternative exon were also identified and
proposed to determine myosin and smooth muscle contractile
kinetics (41, 54, 58, 78). These studies were predominately
based on comparisons of tonic vascular smooth muscle and
phasic visceral smooth muscle or experiments in vitro. In a
landmark study, DiSanto and coworkers (28) showed that the
fast isoforms of myosin heavy and light chain are selectively
expressed in the small muscular arteries of the rat and rabbit
(femoral, saphenous, caudal) correlating with 1.7-fold higher
myosin ATPase activity and velocity of shortening compared
with the tonic smooth muscle of the aorta. This provided the
Relaxation
Ca2+
first demonstration of a molecular basis for fundamental differences in smooth muscle contractile properties throughout
the arterial tree.
A similar story has unfolded with regard to the expression of
the regulatory proteins MLCK and MLC phosphatase (MLCP)
that activate and deactivate the myosin motor, thereby mediating vasoconstriction and vasodilation, respectively. Severalfold increased expression and activity of MLCK and MLCP in
phasic versus tonic smooth muscle were proposed to confer
faster rates of contraction and relaxation (46) (Fig. 2B). Many
of the signals that regulate vascular smooth muscle tone were
subsequently shown to do so by controlling the activity of MP
[reviewed in (47, 53)]. We and others have proposed that the
regulated expression of two subunits of MP, the inhibitory
subunit C-kinase potentiated protein phosphatase-1 inhibitor
(CPI-17; PPP1R14a) and the regulatory subunit [PPP1R12a;
myosin phosphatase targeting subunit 1 (Mypt1)], determine
tissue and vessel-specific responses to vasoconstrictors and
vasodilators (Fig. 2C). The level of expression of CPI-17
relative to MP is proposed to determine the sensitivity to
agonist-mediated inhibition of MP and thus force production
[reviewed in (32)]. The alternative splicing of a 31 nt exon 24
(E24) generates isoforms of Mypt1 that contain or lack a
COOH-terminal leucine zipper motif (LZ) that is required for
nitric oxide (NO)/guanosine-cyclic monophosphate (cGMP)mediated activation of MP and relaxation [reviewed in (40)]. In
this review we will examine their patterns of expression of the
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Fig. 1. Relationship of protein isoforms to
signaling pathways that control vascular
smooth muscle contraction. Rho kinase isoforms ROCK1 and ROCK2 derive from separate genes and inhibit myosin phosphatase
(MP) activity via phosphorylation of Mypt1.
The expression of the inhibitory subunit of
MP C-kinase potentiated protein phosphatase-1 inhibitor (CPI-17; PPP1R14a) is controlled at the level of transcription. Its relative
level of expression is proposed to determine
sensitivity to agonist and PKC mediated vasoconstriction. Isoforms of the MP targeting subunit (Mypt1 ⫽ PPP1R12a) are generated by
alternative splicing of a 31 nucleotide exon
generating isoforms with variable presence of
a COOH-terminal leucine zipper (LZ) motif.
The LZ motif is required for cGMP-mediated
activation of MP and vasorelaxation. It is not
present in the phasic smooth muscle. These
smooth muscle cell phenotype-specific signaling pathways determine the inhibition or
activation of MP which in combination with
calcium-calmodulin activation of myosin
light chain kinase determine smooth muscle
force production. NO, nitric oxide; E24,
exon 24; P, phosphate.
Review
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SMOOTH MUSCLE DIVERSITY IN REGIONAL CIRCULATIONS
B
A
Actin
Phasic (Fast) Contractions
Tonic (Slow) Contractions
Variants
SM-A (slow)
SM-B (fast)
Myosin Light Chain
Force
Myosin Heavy Chain
Myosin
head
Force
Variants
α-actin
γ-actin
Variants
MLC17a (fast)
MLC17b (slow)
Time
Time
C
Vascular Smooth Muscle Contractile Isoform Diversity
Gene
Fast vs. Slow
Biochemical
significance
Physiological
significance
Myosin Heavy Chain
(MYH11)
F – (E8 included; SM-B)
S – (E8 excluded; SM-A)
Myosin ATPase activity
Velocity of Shortening
Myosin Light Chain
(MYL6)
F – (E6 excluded; MLC17a)
S – (E6 included; MLC17b)
Myosin ATPase activity
Velocity of Shortening
MYPT1
(PPP1R12a)
F – (E24 included)
S – (E24 excluded)
cGK activation
NO/cGMP vasorelaxation
Fig. 2. A: actin and myosin variants of the smooth muscle contractile apparatus. Alternative splicing of the myosin heavy and light chain transcripts generates
isoforms with differential ATPase and shortening velocities. Variants of actin arise from separate gene products; however, the functional significance of these
variants is unknown. B: phasic and tonic smooth muscle contractions and fast and slow gene programs. Phasic (fast) smooth muscle demonstrates relatively rapid
cycling of force, whereas tonic (slow) smooth muscle demonstrates resting tone and slow modulation of force. C: isoforms of the myosin and MP subunits are
generated by alternative splicing and specific to phasic and tonic smooth muscle. MLC, myosin light chain; F, fast; S, slow; E, exon; cGK, cGMP protein kinase.
contractile machinery in different regional circulations and
review progress that has been made in determining the role of
unique smooth muscle contractile properties in conferring the
unique properties of the highlighted regional circulations.
Renal Circulation
A unique aspect of the renal circulation is the arrangement of
afferent and efferent arterioles in series separated by the
glomerulus through which the blood is filtered (Fig. 3A). The
tone of the afferent and efferent arterioles is a key determinant
of the glomerular filtration rate and thus kidney function as
well as renal vascular resistance and blood flow [reviewed in
(85)]. Differences between the afferent and efferent arterioles
are well described, whereas the significance of these differences remains conjectural. The afferent arteriole responds
rapidly to changes in pressure and flow with a myogenic
contractile response that autoregulates blood flow as well as a
tubuloglomerular feedback mechanism that also autoregulates
blood flow in the kidney. The myogenic response is characteristic of resistance arteries and absent in the tonic smooth
muscle of conduit vessels. It is also absent in the efferent
arteriole, which maintains tone and regulates glomerular filtration through changes in tone. Consistent with these functional
differences, the fast (phasic) isoform of the smooth muscle-
specific myosin heavy chain (MYH11) is expressed in the
afferent arteriole, whereas only the slow (tonic) isoform is
expressed in the efferent arteriole (104). The fast isoform is
generated by the inclusion of a 21-nucleotide alternative exon
(E8) in the myosin head (SM-B) and increases myosin ATPase
activity and maximum velocity of shortening severalfold (Fig.
2A) (66). This correlates with the higher myosin ATPase
activity and shortening velocity of agonist (angiotensin II and
norepinephrine)-induced contractions of rat and mouse afferent
versus efferent arterioles. However, inactivation of the fast
(SM-B) exon did not equalize contraction velocities in mouse
afferent and efferent arterioles, suggesting other undefined
molecular differences as contributory to these functional differences (90). Isoforms of the actin filaments could also be
involved in the functional differences between afferent and
efferent arterioles. Expression of smooth muscle-specific ␣-actin has been demonstrated to be similar in afferent and efferent
smooth muscle (67). Currently, there are no data regarding the
expression of the ␥-actin isoform, which is more highly expressed in phasic (visceral) smooth muscle (35). Isoforms
generated in the Rho kinase signaling pathway (ROCK-1 and
ROCK-2) may also play a contributory role in the functional
differences noted in the afferent and efferent arterioles by
regulating the activity of the MP. Indeed, Inscho and col-
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Myofilament
Review
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SMOOTH MUSCLE DIVERSITY IN REGIONAL CIRCULATIONS
A
Afferent
arteriole
Variable pressure
Fast gene program
Myogenic response
Glomerulus
Glomerular
Filtration
Rate
Efferent
arteriole
Constant pressure
Slow gene program
Tone maintenance
Hepatic
artery
High pressure
Slow gene program
Tonic contractile activity
Portal
vein
Low pressure
Fast gene program
Phasic contractile activity
Hepatic Arterial Buffer Response
(HABR)
Metabolism
Detoxification
Intestinal
nutrient
delivery
C
Pulmonary
arteries
Low resistance
Low pressure
Hypoxia
Hypoxic Pulmonary
Vasoconstriction (HPV)
Fig. 3. Smooth muscle contractile diversity in regional circulations. A: afferent
and efferent arterioles of the renal circulation are arranged in series and
determine glomerular filtration rate. Afferent arterioles express components of
the fast smooth muscle gene program involved in the myogenic contractile
response, whereas efferent arterioles express a slow gene program and maintain tone and constant perfusion pressure. B: portal vein and hepatic artery are
arranged in parallel to form a dual blood supply for delivery of oxygen and
nutrients and toxins from the intestine. The low-pressure portal vein expresses
a purely fast gene program and displays phasic contractility, whereas the
high-pressure hepatic artery expresses a slow gene program and tonic contractile activity. The hepatic arterial buffer response (HABR) describes changes in
blood flow through the hepatic artery to buffer changes in portal venous blood
flow and maintain total blood flow to the liver constant. C: pulmonary arteries
provide a low-pressure, low-resistance circulation for the oxygenation and
delivery of blood to the heart. Pulmonary arteries constrict to hypoxia [hypoxic
pulmonary vasoconstriction (HPV)] to match regional perfusion and ventilation and maximize oxygen uptake.
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B
leagues (64) demonstrated greater expression of the ROCK-1
versus ROCK-2 isoform in the afferent arterioles. There are no
data regarding the relative expression of these isoforms in the
efferent arterioles. The contribution of the ROCK signaling
pathway to the regulation of afferent and efferent arteriolar
function is controversial. Several studies have suggested equal
contributions of the ROCK signaling pathway in afferent and
efferent arterioles (19, 97). However, Nakamura and colleagues (84) suggest the inhibition of the ROCK pathway
preferentially dilates the afferent arteriole.
There is also evidence for differences in ionic fluxes regulating the activation and deactivation of the contractile apparatus in afferent versus efferent arteriolar smooth muscle.
Membrane depolarization and opening of voltage-gated calcium channels occurs with agonist or potassium chlorideinduced force production in the afferent arterioles, whereas the
efferent arterioles do not significantly depolarize and only
release calcium from internal stores (16, 73). Similarly, the
afferent arteriole is dilated by endothelium-derived hyperpolarizing factor (extracellular potassium) and hyperpolarization,
whereas the efferent arteriole is not (21, 115). In other circulations, a greater role of endothelium-derived hyperpolarizing
factor versus endothelium-derived relaxing factor (NO) in
resistance versus larger conduit arteries has been attributed to
increased expression of inward rectifier potassium channels
(Kir2.1) (94). However, no difference in Kir2.1 expression was
observed between afferent and efferent arterioles (21), and the
molecular basis for these differing responses remains undefined. The large conductance calcium-activated potassium
channel BKCa also appears to play more of a functional role in
the afferent versus efferent arterioles, as chemical activators
and inhibitors cause dilation and constriction of the former but
not the latter in ex vivo preparations (34). BKCa is also a
mediator of NO/cGMP-dependent vasodilation in the renal
afferent arteriole (105). NO regulates afferent and efferent
arteriole tone (105, 118), while it is controversial as to whether
it has different roles or targets in the two vessels (87). Interestingly, NO/cGMP increases intracellular calcium in the afferent arteriole when BKCa is blocked (37) (the efferent arteriole was not studied), reminiscent of the ability of cGMP to
induce phasic contractile activity (vasomotion) in resistance
arteries, possibly through activation of chloride channels [reviewed in (49)], whereas NO/cGMP only relaxes conduit
artery tonic smooth muscle. L-type calcium currents are evident in afferent but not efferent arterioles (17, 38, 72) [reviewed in (56)], correlating with the expression of the L-type
channel subunit voltage-dependent calcium channel 1.2 (52).
However, there remains controversy as to the expression and
activity of L- and T-type calcium channels in afferent and
efferent arterioles, perhaps a function of regional (cortical vs.
medullary) specialization within the kidney or differences
between species. Prostanoids may also be involved in the
functional differences between the afferent and efferent arteriole system. Thromboxane has been demonstrated to preferentially constrict the afferent arteriole with nominal effects on the
efferent arteriole (55). Additionally, prostaglandin E2 dilates
the afferent arteriole via the prostaglandin E2 receptor (63).
Localized production of 20-hydroxyeicosatetraeonic acid
seems to act as a vasoconstrictor to the afferent arteriole and
modulates the myogenic response (45).
Review
SMOOTH MUSCLE DIVERSITY IN REGIONAL CIRCULATIONS
Splanchnic Circulation
The liver has a dual blood supply arranged in parallel in
contrast to the kidney’s in-series arrangement (Fig. 3B). Similar to the kidney, this arrangement is integral to its function.
The low-resistance/low-pressure portal vein (PV) provides
⬃75% of the blood flow to the liver for the purpose of first pass
metabolism and detoxification of substances absorbed by the
intestine [reviewed in (31, 114)]. The hepatic artery perfuses
the liver under systemic pressures and provides ⬃25% of the
blood flow to the liver, which unlike the portal venous blood is
fully oxygenated. The perfusion of the liver by the lowpressure (6 –10 mmHg) portal venous system reflects the low
resistance and pressure (2– 4 mmHg) of the sinusoidal bed.
Another unique feature of the hepatic circulation is the hepatic-
arterial buffer response (HABR), in which blood flow through
the hepatic artery is adjusted in response to altered flow
through the PV to maintain constant perfusion to the liver. The
mechanism of the HABR is not defined but may involve
adenosine (69). Perhaps relating to the HABR, resting blood
flow is high as the liver receives ⬃25% of the cardiac output
while comprising only ⬃2.5% of the total body weight, such
that unlike other systemic beds, oxygen demand is primarily
met by increased oxygen extraction rather than increased blood
flow (12, 13), as for example in a model of endotoxic shock
(98) [see review (31)]. In contrast to this cross regulation,
autoregulation of blood flow does not occur in the portal
venous system and is weak or inconsistent in the hepatic
arterial system.
Portal venous smooth muscle is unique among vascular
tissues in that it exhibits spontaneous phasic contractile activity
(Fig. 2B) and expresses exclusively the fast contractile gene
program (24, 80, 81). This includes the fast isoforms (splice
variants) of myosin heavy and light chains (79), and levels of
the MLCK and MLCP, required for activation and deactivation
of the myosin motor unit, that are severalfold higher compared
with the tonic smooth muscle (Fig. 2C) (91). The MP targeting
subunit Mypt1 is nearly exclusively the E24-included (fast)
variant coding for the isoform that lacks the COOH-terminal
LZ motif (91). The ratio of ␥-actin to ␣-actin protein is higher
in PV (45:55) compared with aorta, similar to other phasic
smooth muscle, and increases further in pressure-overload
hypertrophy (79). With regard to ion fluxes that activate and
deactivate the contractile apparatus, there is limited description
of the channels that are expressed and active in portal venous
smooth muscle and limited comparisons with the tonic smooth
muscle of the large vessels or other tissues and cell types. A
number of voltage-dependent potassium channels (KCNQ) are
expressed in cultured mouse PV myocytes (111). A splice
variant of KCNQ1 (KCNQ1b) was identified that comprised
50% of transcripts and was not identified in heart or brain
transcripts (86).
The role of the phasic contractile activity of the PV in the
perfusion of the liver under normal conditions has not been
experimentally tested. A reasonable speculation is that it serves
as a low-pressure venous pump in series with the heart to
propel blood to the liver. With regard to mechanisms, the fast
isoforms of myosin and higher MLCK and MLCP expression
and activity are likely required for the more rapid cycling of
force production compared with tonic smooth muscle. PV, like
other phasic smooth muscle, expresses the LZ⫺ isoform of
Mypt1 not activated by NO/cGMP, consistent with portal
venous smooth muscle resistance to NO-mediated dilation in
vivo (88) and ex vivo (36). With regard to ion fluxes, KCNQ1b
variant contributes to the delayed outward rectifying potassium
currents required for repolarization of this smooth muscle,
whereas L-type calcium currents and internal stores provide
calcium for force activation (4, 107). However, the source of
the portal venous pacemaker current has not been defined with
certainty. A calcium-activated chloride channel has been proposed to serve this function (26, 39). A different study proposed that a hyperpolarization-activating current pacemaker
current carried by hyperpolarization-activated cyclic nucleotide-gated channel 2– 4 triggers phasic contractile activity of
rabbit PV myocytes (48). There is also evidence for and against
dedicated pacemaker cells (interstitial cells of Cajal), as in the
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In summary the afferent arteriole has properties typical of
phasic smooth muscle and a resistance artery, whereas the
efferent arteriole has properties more typical of a tonic smooth
muscle. These paradigms, while useful, likely represent an
oversimplification of their unique properties. A more complete
analysis of the afferent versus efferent arteriole gene programs
is hindered by their small size, inaccessibility, and mixed cell
populations, as is true throughout the microcirculation (discussed further in Conclusions and Perspectives).
Efferent vasoconstriction increases glomerular capillary pressure and preserves glomerular filtration when renal perfusion is
reduced, whereas afferent arteriolar constriction reduces glomerular pressures and protects the kidney from increases in perfusion pressure. Reduced renal perfusion and its effect on
glomerular filtration and kidney function is a vexing problem
in the management of heart failure and a major contributor to
heart failure morbidity and mortality. Therapy directed at heart
failure may exacerbate or improve the renal dysfunction for
reasons that are unknown [reviewed in (8, 9)]. The L-type
calcium channel blockers selectively dilate the afferent arteriole and thus improve glomerular filtration rate (1, 57), though
whether this increased perfusion would improve the outcome is
uncertain and confounded by effects on the heart and other
blood vessels. Additionally, the action and efficacy of calcium
channel blockers vary considerably in efferent arteriolar
smooth muscle based on localization within the kidney (120).
Pharmacological analysis of L- and T-type calcium channels in
the kidney has been extensively reviewed elsewhere (56).
Other vasodilator drugs that open potassium channels and
inhibit LTCC via hyperpolarization, such as pinacidil (ATPdependent potassium channel agonist) (96) and minoxidil
(Kir6.1 agonist, as is diazoxide) (42), also preferentially dilate
the afferent arteriole, as does hydralazine (42), a vasodilator
commonly used to treat hypertension and heart failure. In
contrast, inhibitors of angiotensin signaling cause balanced
dilation of afferent and efferent arterioles and are highly
beneficial in the treatment of heart failure and other cardiovascular diseases. Yet the use of these drugs in advanced heart
failure and other vascular diseases is also limited by renal
insufficiency. Unlike other vascular beds (51, 91, 119), there is
currently little information as to how afferent and efferent
arteriolar smooth muscle gene expression and function may be
altered in disease, a foundation that would likely help to
improve on the many pharmacological treatments that target
the vascular smooth muscle contractile state.
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SMOOTH MUSCLE DIVERSITY IN REGIONAL CIRCULATIONS
in the disease process but do not exist. At later stages of the
disease, systemic vasoconstrictors and nonselective ␤-blockers
may be used to reduce portal blood flow and limit variceal
bleeding [reviewed in (6)]. Organic nitrates as vasodilators are
no longer recommended. Some but not all studies have found
that phosphodiesterase-5 inhibitors (sildenafil) may improve
sinusoid flow in the hepatic microcirculation (22, 50) and are
being tested in clinical trials.
Pulmonary Circulation
The pulmonary circulation is unique in that resistance to
blood flow is ⬃1/5th of that in the systemic circulation such
that the entire cardiac output (minus the bronchial component)
is delivered with low perfusion pressures (Fig. 3C). In addition
to unique anatomic features, low vascular resistance may be
due to the low basal tone of the pulmonary arterioles. This
could reflect differences between signals that control tone in
the pulmonary and systemic circulations (7, 18, 23, 71, 75), or
differences within the vascular smooth muscle (43, 77, 113). In
contrast to the systemic circulation, there appears to be low
adrenergic tone at rest or with exercise in the pulmonary
circulation (68, 108), in part accounting for the ability to
accommodate increases in cardiac output with exercise with
minimal increases in right heart pressures. It is also possible
that the vascular smooth muscle response to neural or other
signals is different from systemic arterioles and requires further
investigation.
A particularly unique feature of the pulmonary circulation is
hypoxic pulmonary vasoconstriction (HPV) (11, 109). HPV
ensures that blood flows to the most ventilated regions of the
lung to maximize oxygen uptake and thus delivery to the
systemic tissues. In contrast, systemic arterioles dilate in response to reduced oxygen concentrations to maintain oxygen
supply to the tissues. HPV is maintained in ex vivo preparations and isolated pulmonary artery SMCs (PASMCs), suggesting it is an intrinsic property of these cells [reviewed in
(11, 109)]. Hypoxic contraction of PASMCs appears to involve
calcium activation of MLCK (76, 83, 116) as well as increased
calcium sensitivity of the myofilaments (25, 33, 61, 76),
implicating inhibition of the MP, each of which are more
prominent in distal (77, 102) versus proximal PASMCs (10,
74, 77), correlating with the magnitude of the HPV [reviewed
in (11, 109)]. In contrast rat carotid artery SMCs relax to
hypoxia and phosphorylation of myosin decreases (77), demonstrating that the sensor and mediator for hypoxic vasoconstriction are unique to and contained within the PASMCs. It
has been suggested that hypoxic inhibition of voltage-potassium channels initiates HPV (95). These channels are enriched
in distal versus proximal PASMCs (3, 11, 102), analogous to
differences in Kir channel distribution in systemic circulations
(2, 62, 82, 117). However, because these channel activities are
also present in systemic arterioles, it seems less likely, though
still possible, that they are responsible for the discordant
hypoxic responses. A role for prostanoids has been suggested
in mediating the HPV response in the pulmonary circulation.
Chronic hypoxia increases expression of cyclooxygenase-2 and
increases endothelium-independent thromboxane-induced contraction in pulmonary arteries (27), as well as sensitivity of
pulmonary artery myocytes to thromboxane (60). The specific
mechanisms for sensing and mediating HPV must be better
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gut (100). The hyperpolarization-activating current is specifically inhibited by the bradycardic agent ZD-7288 (Zeneca). It
would be of interest to determine the effect of inhibition of
phasic smooth muscle cell (SMC) contractile activity on blood
flow in the portal and other regional circulations. However,
ZD-7288 also increases basal tone in PV and other smooth
muscle preparations (48), which along with its bradycardic
effect on the heart would confound interpretation of its effects
on vascular function in whole animal preparations.
Additionally, a role for prostanoids have been suggested in
this phasic contractile activity as inhibition of the cyclooxygenase pathway decreases the amplitude of spontaneous phasic
contractions in the PV (103). This vascular phasic pumping
action is not unique to the PV as most small arteries exhibit
some phasic contractile activity termed vasomotion (49, 92)
and express components of the fast gene program, the functional significance of which is also not determined. In summary, the PV is unique among vessels as a prototypical phasic
smooth muscle and may be useful for defining the full extent of
differences between vascular fast and slow muscle gene programs.
Resistance vessels of the mesenteric circulation are the
prototypical vessels to study vascular function as the small
artery/arteriole network is an important determinant of systemic vascular resistance. The smooth muscle of first order-tothird order mesenteric arteries displays a phenotype intermediate to that of the phasic smooth muscle of the PV and tonic
smooth muscle of the hepatic artery. This includes predominant expression of the Mypt1 E24⫹/LZ⫺ isoform and mixtures
of fast and slow isoforms (splice variants) of the myosin heavy
and light chains (91). This is consistent with the mixed contractile patterns of these arteries including phasic contractile
activity (vasomotion) and tonic contractions. Interestingly, the
gene program of the smooth muscle of mesenteric arteries also
modulates in disease. In models of portal hypertension (91) and
flow-induced vascular remodeling (93, 119), there are shifts to
Mypt1 E24⫺/LZ⫹ isoforms and slow gene program associated
with increased sensitivity of vasorelaxation to NO donors and
cGMP.
Increased pressure in the hepatic circulation, i.e., portal
hypertension, is a vexing sequelae of liver injury and cirrhosis
and is associated with high morbidity and mortality. While the
resistance to blood flow and normally low portal pressures are
increased, upstream mesenteric arterial resistance is low with
portosystemic shunting of blood, resulting in a low systemic
vascular resistance/high cardiac output state [reviewed in
(114)]. Other regional circulations may also be affected, referred to as hepatorenal and hepatopulmonary syndromes, the
bases of which are not well understood. In animal models of
portal hypertension induced by ligature of the PV, there is
reduced phasic activity of the PV (112) and partial switching
from fast to slow smooth muscle gene programs in the PV and
the upstream mesenteric arteries (91). The significance of this
switch in the smooth muscle contractile phenotype has not
been determined but would be predicted to increase sensitivity
to NO/cGMP-mediated vasodilation, consistent with the increased role of NO in the splanchnic circulation in animal
models of cirrhosis (65). These antithetical and complex
changes in portal and systemic hemodynamics make vascular
drug therapies problematic. Drugs that specifically target the
portal hypertension would be especially desirable for use early
Review
SMOOTH MUSCLE DIVERSITY IN REGIONAL CIRCULATIONS
H169
defined before determining the molecular bases for the differing responses of pulmonary and systemic circulations.
Pulmonary arterial hypertension may be due to structural or
functional changes in the blood vessels. “Muscularization” of
the pulmonary arterioles (⬍300 ␮m) is thought to be a key
contributor to the increased vascular resistance to blood flow
(99). The drugs used to reduce vascular resistance in pulmonary hypertension are different from those used for this purpose in systemic hypertension, e.g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostaglandins in the
former and ␣-adrenergic and calcium channel blockers in the
latter [reviewed in (44)]. Whether this is merely a reflection of
historical bias in drug development and testing or reflects true
differences between pulmonary and systemic hypertensive vascular smooth muscle requires further study. Clearly a better
understanding of differences between pulmonary and systemic
microvascular smooth muscle, especially in disease, is needed
to develop targeted therapies for hypoxic, inflammatory, and
other causes of pulmonary hypertension.
native splicing of exons. A second useful technology is reporterbased cell purification, as for example green fluorescent protein
labeling of SMCs (89), facilitating sorting of a relatively
purified population of SMCs from a tissue for downstream
applications such as RNASeq. These approaches should overcome barriers to definition of smooth muscle gene programs in
the physiologically relevant tissue for control of blood flow and
pressure, the microvasculature, in developmental and disease
contexts. It is our hope that this information, as well as studies
of unique attributes of human genomes, will lead to more
rationale and mechanistic drug targeting in individuals with
sundry vascular diseases.
Conclusions and Perspectives
DISCLOSURES
We thank Dr. Tom Pallone for insightful comments and constructive
feedback on the manuscript.
GRANTS
This study was supported by National Heart, Lung, and Blood Institute
Grants RO1-HL-066171 and T32-HL-072751.
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
J.J.R., X.Z., and S.A.F. prepared figures; J.J.R., X.Z., and S.A.F. drafted
manuscript; J.J.R., X.Z., and S.A.F. edited and revised manuscript; J.J.R., X.Z.,
and S.A.F. approved final version of manuscript.
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Vascular smooth muscle is highly specialized both between
and within regional circulations for organ-specific functions.
This includes the afferent versus efferent arteriole in determining glomerular filtration in the kidney, PV and hepatic artery
for delivery of oxygen, nutrients and toxins from the intestine,
and pulmonary arterioles to maintain low vascular resistance
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vascular smooth muscle contractile diversity, when and how it
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Newer technologies should facilitate rapid progress in defining
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more recently deep RNA sequencing (RNASeq). In RNASeq
mRNAs present within a sample are exhaustively sequenced
and matched back to the reference genome, providing both
absolute counts of transcripts and isoforms generated by alter-
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