Physiol Rev 89: 1177–1215, 2009;
doi:10.1152/physrev.00024.2009.
Peptide Hormone Regulation of Angiogenesis
CARMEN CLAPP, STÉPHANIE THEBAULT, MICHAEL C. JEZIORSKI,
AND GONZALO MARTÍNEZ DE LA ESCALERA
Instituto de Neurobiologı́a, Universidad Nacional Autónoma de México, Campus UNAM-Juriquilla,
Querétaro, Qro., México
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I. Introduction
II. Angiogenesis Overview
III. Hormones With Effects on Angiogenesis Altered by Proteolysis
A. The growth hormone/prolactin/placental lactogen family
B. The renin-angiotensin system
C. The plasma kallikrein-kinin system
IV. Hormonal Regulation of Physiological Angiogenesis
A. Female reproductive organs
B. Nonreproductive organs
V. Hormonal Contribution to Angiogenesis-Dependent Diseases
A. Preeclampsia
B. Diabetic retinopathy
C. Rheumatoid arthritis
D. Cancer
VI. Conclusions and Future Directions
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Clapp C, Thebault S, Jeziorski MC, Martı́nez de la Escalera G. Peptide Hormone Regulation of Angiogenesis.
Physiol Rev 89: 1177–1215, 2009; doi:10.1152/physrev.00024.2009.—It is now apparent that regulation of blood vessel
growth contributes to the classical actions of hormones on development, growth, and reproduction. Endothelial cells
are ideally positioned to respond to hormones, which act in concert with locally produced chemical mediators to
regulate their growth, motility, function, and survival. Hormones affect angiogenesis either directly through actions
on endothelial cells or indirectly by regulating proangiogenic factors like vascular endothelial growth factor.
Importantly, the local microenvironment of endothelial cells can determine the outcome of hormone action on
angiogenesis. Members of the growth hormone/prolactin/placental lactogen, the renin-angiotensin, and the kallikreinkinin systems that exert stimulatory effects on angiogenesis can acquire antiangiogenic properties after undergoing
proteolytic cleavage. In view of the opposing effects of hormonal fragments and precursor molecules, the regulation of
the proteases responsible for specific protein cleavage represents an efficient mechanism for balancing angiogenesis. This
review presents an overview of the actions on angiogenesis of the above-mentioned peptide hormonal families and
addresses how specific proteolysis alters the final outcome of these actions in the context of health and disease.
I. INTRODUCTION
Blood vessels influence the metabolic effects of hormones by transporting fluid, nutrients, oxygen, and waste
material. In addition, the vascular system delivers hormones from other parts of the body, allowing them to
perform their local actions, which can include the production of another hormone that has to be transported to
other specialized cells. Likewise, the function of blood
vessels depends on hormones that regulate blood pressure, blood coagulation, and inflammation. To favor hormone delivery or blood transport into growing tissues,
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hormones promote angiogenesis, the proliferation of new
blood vessels from preexisting vasculature. By acting systemically, hormones coordinate and integrate angiogenesis with other functions throughout the body. They also
regulate blood vessel growth by controlling the production of local chemical mediators, often other hormones,
but also growth factors, cytokines, enzymes, receptors,
adhesion molecules, and metabolic factors, by vascular
endothelial cells and other cells within the vicinity of
capillaries. Notably, hormones can acquire angiogenic or
antiangiogenic properties after undergoing proteolytic
cleavage within the tissue microenvironment.
0031-9333/09 $18.00 Copyright © 2009 the American Physiological Society
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II. ANGIOGENESIS OVERVIEW
The formation of new blood vessels is essential for
organogenesis and successful embryonic and fetal development (139). In the adult organism, the proliferation of
blood vessels is key for the growth and function of female
reproductive organs, such as the ovary and endometrium
during the menstrual cycle and the placenta and mammary gland during pregnancy (219). However, in most
adult tissues, physiological angiogenesis is highly restricted, and capillary growth occurs only rarely and in
association with repair processes such as wound and fracture healing. Disruption of the mechanisms controlling physiological angiogenesis has a major impact on health, as it
underlies the pathogenesis of a growing list of diseases
characterized by the overproliferation of blood vessels, including cancer, psoriasis, arthritis, retinopathies, obesity,
asthma, and atherosclerosis. In addition, insufficient angiogenesis and abnormal vessel regression can lead to heart
and brain ischemia, neurodegeneration, hypertension, osteoporosis, respiratory distress, preeclampsia, endometriosis, postpartum cardiomyopathy, and ovarian hyperstimulation syndrome (74, 75).
Hypoxia is an important stimulus for the physiological and pathological growth of blood vessels (449). It
connects vascular oxygen supply to metabolic demand.
Cells are normally oxygenated by diffused oxygen, but
when tissues grow beyond the limit of oxygen diffusion,
Physiol Rev • VOL
hypoxia triggers vessel growth by signaling through hypoxia-inducible transcription factors that upregulate and
downregulate the expression of proangiogenic and antiangiogenic factors, respectively (449).
In the embryo, blood vessels originate from endothelial cell progenitors that migrate into avascular areas and
form a primitive vessel network. This de novo formation
of blood vessels, termed vasculogenesis, is followed by
sprouting, branching, and stabilization in the process
known as angiogenesis that utilizes existing vasculature
to generate new vessels. Even though both vasculogenesis and angiogenesis have long been known to initiate a
functional circulatory system during embryogenesis
(267), that vasculogenesis also operates in the adult has
been clarified only recently. In adults, endothelium-derived circulating cells and stem cell precursors of endothelial cells contribute to vessel growth in both physiological and pathological conditions (139, 451).
Vascular endothelial growth factor (VEGF) and angiopoietin-1 and -2 are probably the most important factors promoting angiogenesis, but the regulation of this
process is complex and involves an extensive interplay
between cells, multiple soluble factors, and ECM components (Fig. 1), which has been the focus of detailed reviews (5, 74, 267, 303). The following is a brief summary
of the angiogenesis process illustrating some of the relevant molecular interactions.
Angiogenesis is stimulated by hypoxia, which upregulates the expression of several genes involved in different steps of angiogenesis, including VEGF, angiopoietin-2, and nitric oxide synthases (NOS) (449). Vessels
dilate in response to nitric oxide (NO), and VEGF disrupts
endothelial cell contacts causing vasopermeability (26).
Endothelial cells are then free to migrate out of the basement membrane and through the softened perivascular
space using leaked plasma proteins as a provisional matrix.
However, only a subset of endothelial cells is selected for
sprouting and respond to proangiogenic signals by mechanisms involving Notch receptors and their Delta-like 4 ligand
(217). The directional migration of endothelial cells is primarily driven by VEGF, angiopoietin-1, angiopoietin-2, and
basic fibroblast growth factor (bFGF). Other contributing
cytokines include platelet-derived growth factor (PDGF),
epidermal growth factor (EGF), transforming growth factor-␤ (TGF-␤), and the guidance molecules ephrins, semaphorins, and netrins (5, 303). Proteases released by endothelial cells, including plasminogen activators, matrix metalloproteases (MMPs), heparinases, chymases, tryptases, and
cathepsins, degrade and alter the composition of the
ECM, allowing adequate support and guidance for endothelial cell migration. In addition to migration, sprout
extension involves the proliferation of endothelial cells
induced primarily by VEGF and angiopoietin-2 (in the
presence of VEGF). Proteases facilitate vessel sprouting
by releasing ECM-bound angiogenic activators (bFGF,
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Proteolytic cleavage is a mechanism used frequently
to generate proangiogenic and antiangiogenic protein mediators at specific sites. Proteolytic cleavage of extracellular matrix (ECM) components releases smaller proangiogenic fragments from larger proteins, as well as sequestered proangiogenic growth factors and cytokines
(380). Similarly, antiangiogenic peptides are generated via
proteolysis of components of the ECM and the coagulation and fibrinolytic systems (404, 519). Although proteolytically processed antiangiogenic fragments have long
been known (160, 404), little attention has been given to
proteolytic cleavage as an important mechanism controlling hormone action on angiogenesis.
Here, we review the regulation of angiogenesis by
representative peptide hormones that are converted to
proangiogenic or antiangiogenic molecules by proteolytic
cleavage. The properties of these fragments versus those
of their precursors, the regulation of the protease(s) responsible for specific protein cleavage, and the selective
expression of specific receptors and associated signaling
pathways for each hormonal isoform are discussed within
a wider context of health and disease, with the expectation that understanding the role of hormones in angiogenesis could open new therapeutic perspectives for diseases
resulting from angiogenic dysregulation.
PEPTIDE HORMONES AND ANGIOGENESIS
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VEGF, TGF-␤) and activating angiogenic cytokines like
interleukin (IL)-1␤. The degraded ECM enables integrinmediated endothelial cell adhesion and the signaling of
integrins, such as ␣V␤3 and ␣V␤5, that participate in crosstalk with VEGF and bFGF receptors to either promote or
inhibit endothelial cell proliferation (491). Eventually, the
sprouts join together and convert into tubes first by intracellular and then intercellular fusion of large vacuoles
(273). Vascular endothelial statin, a secreted ECM-associated protein, participates in lumen formation (427). The
subsequently enhanced delivery of oxygen by the onset of
blood flow lowers local VEGF expression, thereby reducing
endothelial cell proliferation. These events together with the
recruitment of pericytes and the deposition of a subendothelial basement membrane promote vessel maturation and
quiescence. These processes are regulated by angiopoietin-1
and its receptor Tie 2, PDGF and PDGF receptor ␤, Notch
signaling (25), sphingosine-1-phosphate-1 (S1P1)/endothelial
differentiation sphingolipid G protein-coupled receptor (16),
and TGF-␤ (53). Proteases can also modulate and finalize
the angiogenesis process by liberating ECM-bound antiangiogenic factors such as thrombospondin-1, canstatin, arPhysiol Rev • VOL
resten, tumstatin, and endostatin and non-matrix-derived
inhibitors of vessel formation including angiostatin, vasoinhibins, antithrombin III, prothrombin kringle-2, plasminogen
kringle-5, and vasostatin (404).
III. HORMONES WITH EFFECTS ON
ANGIOGENESIS ALTERED BY
PROTEOLYSIS
While tremendous efforts have been devoted to the
study of factors that primarily regulate angiogenesis, the
contributions of broadly acting agents like hormones remain more difficult to interpret due to the quantity and
diversity of their targets and actions. Hormones represent
an appropriate system for regulating the angiogenesis
process throughout the body. Indeed, the endocrine nature of antiangiogenic hormones enables the efficient delivery required, for example, to maintain the quiescent
state of blood vessels that normally exists in adult tissues.
By acting directly on endothelial cells or indirectly by
recruiting other cell types to produce angiogenesis regu-
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FIG. 1. The cellular steps involved in angiogenesis. Hypoxia induces the production of nitric oxide (NO) and the expression of vascular
endothelial growth factor (VEGF) and angiopoietin-1 and -2 (Ang 1 and Ang 2), which interact with extracellular matrix (ECM) proteases to increase
permeability of the capillary vessel wall. Destabilization then allows endothelial cells to migrate and proliferate to form tubules, aided by VEGF,
angiopoietins, guidance molecules, growth factors, cytokines, and degradation of the ECM. Maturation of the newly formed vessel is accompanied
by increased expression of antiangiogenic factors, many released as a result of proteolysis. PDGF, platelet-derived growth factor; S1P1, sphingosine1-phosphate-1; TGF␤, transforming growth factor-␤.
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TABLE 1. Hormones with angiogenic and
antiangiogenic actions
Hormone
Reference Nos.
Angiogenic
ACTH
Adrenomedullin
Angiotensin II
Bradykinin
Calcitonin
Endothelin
Erythropoietin
Gastrin
Gonadotropins
Growth hormone/prolactin/placental lactogen
Growth hormone-releasing hormone
Insulin
IGF-I
Leptin
Neuropeptide Y
Oxytocin
Parathyroid hormone
Relaxin
Thrombopoietin
Thyroid-stimulating hormone
Vasopressin
263
460
236
236
89
218
23
212
457
109
274
270
129
233
300
79
389
202
17
457
13
Antiangiogenic
Angiotensin-(1–7)
Angiotensinogen
Cleaved high-molecular-weight kininogen
des关ANG I兴angiotensinogen
Ghrelin
Gonadotropin-releasing hormone
Natriuretic peptides
Somatostatin
Vasoinhibins
20
80
640
80
29
551
459
223
92
Pro- and antiangiogenic actions
Adiponectin
Corticotropin-releasing hormone
459
405
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for each hormonal isoform and their related signaling
pathways also play a critical role.
The following is an overview of the actions on angiogenesis of members of the growth hormone (GH)/prolactin (PRL)/placental lactogen (PL) family, the renin-angiotensin system (RAS), and the kallikrein/kinin system
(KKS), all of which are regulated by proteolysis.
A. The Growth Hormone/Prolactin/Placental
Lactogen Family
GH, PRL, and PL are produced in the anterior pituitary gland as well as in the uteroplacental unit and other
nonpituitary sites. They are structurally and functionally
related and evolved from a common ancestral gene some
400 million years ago (107, 364, 588). They vary between
22 and 23 kDa and comprise 190 –200 amino acids organized in a four-␣-helix configuration stabilized by two (GH
and PL) or three (PRL) disulfide bonds (Fig. 2). The
relationship between their structural similarities and biological properties is unclear. Human PL and GH are remarkably similar in amino acid sequence (86% homology),
size (191 amino acids), and disulfide bond number and
position, whereas human PRL has 199 amino acids and 3
disulfide bonds and shares only 25% sequence identity
with the other two hormones (399). Nevertheless, all
three human hormones are potent agonists of the PRL
receptor (204, 399), but only GH activates the GH receptor
(330, 591).
GH, PRL, and PL are proangiogenic and upon proteolytic cleavage are converted to peptides with potent inhibitory effects on blood vessel growth and function, forming a
family recently named vasoinhibins (Fig. 2) (92).
1. Growth hormone
GH is best known as a major regulator of linear
postnatal growth, energy metabolism, muscle expansion
and performance, and immune function (88, 455, 577). GH
acts by stimulating insulin-like growth factor I (IGF-I)
production both systemically and locally, and also by
directly activating the JAK/STAT pathway in target cells
(304, 309). Accumulating evidence indicates that GH
helps regulate vascular growth and function. GH receptors have been detected in blood vessels from different
vascular beds (296, 326, 494, 550, 603) and in cultured
endothelial cells (320, 555), where GH stimulates endothelial cell proliferation (478, 529) and tube formation (67,
178). The proangiogenic effects of GH have also been
demonstrated in vivo. Treatment with GH increases the
number of cerebral cortical arterioles in aging rats (515),
augments VEGF expression and angiogenesis in the rat
myocardium after infarction (302, 468), stimulates wound
angiogenesis in diabetic rats (191) and in mice (553), and
may enhance vascularization by promoting mobilization
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lators, proangiogenic hormones can help turn on the angiogenesis switch to promote the growth and metabolism
of target tissues. Moreover, by interacting with local factors, hormones may regulate angiogenesis differentially at
specific sites.
Multiple peptide hormones regulate angiogenesis by
acting as either stimulatory or inhibitory factors (Table 1).
Others contain, within the same molecule, the ability to
exert distinct or even opposite effects on angiogenesis:
proteolysis converts the original hormone to either proangiogenic or antiangiogenic peptides. The presence of opposing activities within the same hormonal precursor provides an efficient mechanism for fine-tuning angiogenesis
and implies that specific proteolytic cleavage controls a
shift toward a proangiogenic state or an angiostatic condition. Clearly, the selective expression of the receptors
PEPTIDE HORMONES AND ANGIOGENESIS
of bone marrow-derived endothelial progenitor cells into
the bloodstream (134, 554). Consistent with these findings, the skin of adult, GH-deficient patients shows reduced capillary density and permeability that improves
after treatment with GH (418), and GH-deficient adults
and children have reduced retinal vascularization (238,
239).
The retina has been considered a major target for the
proangiogenic actions of the GH/IGF-I axis (for a review,
see Ref. 180). Proliferative diabetic retinopathy is rare in
dwarfs who are deficient for GH and IGF-I (359). Lowering circulating GH with a somatostatin analog decreases
ischemia-induced retinal neovascularization in mice
(510), which is also reduced by blocking GH receptor
expression with antisense oligonucleotides (610) or by
genetic silencing of the GH receptor in transgenic dwarf
mice (510). GH action on retinal angiogenesis is mediated
primarily through circulating or locally produced IGF-I
(87). Administration of IGF-I to somatostatin analogtreated mice normalizes serum IGF-I levels, but not GH
levels, and promotes ischemia-induced retinal neovascularization (510). Furthermore, deletion of the IGF-I recepPhysiol Rev • VOL
tor in vascular endothelial cells partially protects against
retinal neovascularization (297), and IGF-I antagonists
interfere with the actions of VEGF (511), the essential
cytokine mediating proliferative retinopathies (68). Indeed, IGF-I is necessary for maximal VEGF activation of
the mitogen-activated protein kinase (MAPK) and Akt
pathways in the retina (511), and IGF-I induces the expression of retinal VEGF by activating the phosphatidylinositol 3-kinase (PI3-K)/Akt, hypoxia inducible factor-1
(HIF-1), NF␬B, and JNK/AP-1 pathways (443).
IGF-I may also mediate the proangiogenic actions of
GH at other sites, as IGF-I receptors are widely expressed
in endothelial cells, and IGF-I has been shown to stimulate angiogenesis in vivo and in vitro (for a review, see
Ref. 129). However, some actions of GH on endothelial
cells may be independent of IGF-I. For example, GH is
unable to increase the transcription of IGF-I in endothelial
cells. Instead, it promotes the expression and activity of
endothelial NOS (eNOS) (555), and eNOS-derived NO
stimulates vasorelaxation, vasopermeability, and angiogenesis (586). In addition, systemic (320) or local infusions
of GH (390) acutely increase forearm blood flow and NO
release in healthy humans without significantly raising
plasma IGF-I levels or muscle IGF-I mRNA expression.
While these observations argue in favor of an autonomous
GH action mediated by NO, IGF-I is also vasoactive due to
its activation of eNOS (for a review, see Ref. 129), and more
information is required to clarify this issue. The relevance of
the vascular actions of GH is emphasized by clinical data
showing that patients with GH deficiency have increased
risk of cardiovascular death (206). Loss of GH production
in humans leads to increased peripheral resistance, reduced cardiac output, decreased blood flow in response
to vasodilators, and reduced systemic NO levels, whereas
GH replacement restores these responses to normal (58,
73, 391). Interestingly, some vasoconstrictive effects of
GH via NO inhibition have also been reported in experimental settings (370).
The complexity of GH vascular effects is further
illustrated by the fact that elevated GH levels are not
always associated with angiogenesis. Overexpression of
GH in transgenic mice (gigantic phenotype) does not
result in increased retinal neovascularization (510), acromegaly has no correlation with retinopathy (36, 167), and
long-term GH replacement therapy does not appear to
increase the risk of retinopathy in children or adults
(239). Interestingly, in the chick embryo chorioallantoic
membrane, GH is proangiogenic only during the more
differentiated, nongrowing state of blood vessels (211,
529), and not in their less differentiated, proliferative
phase (529). Furthermore, treatment with GH does not
stimulate the proliferation of some endothelial cells in
culture (67, 478). These contrasting findings imply that
GH has context-dependent vascular actions influenced by
other angiogenic agents, including IGF-I, NO, and VEGF,
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FIG. 2. The formation of antiangiogenic vasoinhibins from proangiogenic human growth hormone (GH), placental lactogen (PL), and
prolactin (PRL). Each protease cleaves within the loop connecting helix
III and IV (except for one cleavage site of PRL by cathepsin D), at
positions indicated in amino acids, thereby generating an NH2-terminal
fragment of the indicated length in amino acids that corresponds to
vasoinhibins. Vasoinhibins thus represent a heterogeneous group of
antiangiogenic proteins ranging between 14 and 17 kDa. BMP1, bone
morphogenetic protein 1; MMPs, matrix metalloproteases; N, amino
terminal; C, carboxy terminal. Molecules are color coded in green for
their angiogenic properties and in red for their anti-angiogenic effects.
[Modified from Clapp et al. (92).]
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and GH itself. GH is produced by endothelial cells, and
endothelium-derived GH stimulates the proliferation, migration, survival, and capillary formation of endothelial
cells in an autocrine manner (67). Therefore, the lack of
action of exogenous GH may relate to endothelial cell GH
receptors being already occupied by the endogenous hormone. Other important factors affecting GH actions on
angiogenesis include its local proteolysis to vasoinhibins
(see below) and the relative contribution of other related
hormones. Human GH, the form used therapeutically and
in most experimental work, has the ability to activate PRL
receptors, which can also mediate proangiogenic signals.
PRL was named for one of its first known functions,
the initiation and maintenance of lactation, but this hormone is remarkably versatile, as it regulates various
events in reproduction, osmoregulation, growth, energy
metabolism, immune response, brain function, behavior
(44, 59), and angiogenesis (96). In vivo studies show that
treatment with PRL stimulates the proliferation of endothelial cells in the corpus luteum (195), in the testis (291),
and in the myocardium (243). During pregnancy, PRL
receptor deficiency interferes with the vascularization of
the corpus luteum (220), and defective mammary gland
development in PRL (249) and PRL receptor (419) null
mice can be associated, in part, with subnormal neovascularization (96). However, several inconsistencies reflect
the complexity of PRL action. Like GH, PRL is proangiogenic in the chick embryo chorioallantoic membrane assay only during the nongrowing stage of blood vessels
(529), and not during their proliferative phase (94, 196,
529, 567). Also, PRL is unable to stimulate blood vessel
growth in the corneal angiogenesis assay (567), and targeted disruption of the PRL gene is associated with highly
vascularized pituitary tumors in aged mice (116). A major
unresolved issue is whether PRL directly or indirectly
stimulates endothelial cell proliferation. The PRL receptor has been detected, albeit at low levels, in some endothelial cells (360, 461, 567) but not in others (410), and the
preponderance of evidence shows no mitogenic effect of
PRL on cultured endothelial cells (94, 160, 410, 461, 529,
567). Nonetheless, lack of an effect could reflect the fact
that endothelial cells produce and release PRL able to
promote proliferation in an autocrine manner (93, 461).
One study reported a direct effect of PRL on endothelial
cell growth that was dependent on the expression of
heme oxygenase-1 (346), an enzyme that promotes cell
cycle progression and prevents apoptosis by producing
bilirubin and carbon monoxide (65, 132).
On the other hand, PRL can stimulate angiogenesis
indirectly by inducing the synthesis of proangiogenic factors in other cell types. PRL promotes VEGF or bFGF
expression in decidual cells (517), immune cells (207, 345,
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3. Vasoinhibins
Vasoinhibins are a family of peptides derived by proteolytic cleavage from PRL, GH, and PL that inhibit blood
vessel dilation, permeability, growth, and survival (reviewed in Refs. 92, 96). Cleavage by various proteases
occurs near or within the large loop connecting the third
and fourth ␣-helices in all three hormones (Fig. 2). Cathepsin D (35, 438), MMPs (MMP-1, MMP-2, MMP-3,
MMP-8, MMP-9, and MMP-13) (339), and bone morphogenic protein-1 metalloprotease (BMP-1) (196) cleave
PRL to generate vasoinhibins, whereas thrombin and plasmin cleave PL (477, 529) and BMP-1, thrombin, plasmin,
subtilisin, and chymotrypsin cleave GH (196, 319, 615).
Since only one study has addressed the actions of vasoinhibins derived from GH and PL (529), most of the following information concerns vasoinhibins originating from
PRL.
Vasoinhibins decrease angiogenesis in the chick embryo chorioallantoic membrane (94, 196, 529) and in the
cornea (141); inhibit blood vessel growth and survival,
vasodilation, and vasopermeability in the retina (22, 140,
192); impair growth and function of coronary vessels
(243); and reduce the growth, metastasis, and neovascularization of tumors (49, 285, 398). Vasoinhibins act directly on endothelial cells to reduce the mitogenic effects
of VEGF and bFGF (94, 529); inhibit bFGF- and IL-1␤-
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2. Prolactin and placental lactogen
559), and mammary epithelial cells (207). The PRL-induced release of VEGF by mammary epithelial cells and
the Nb2 lymphoma cell line (207) depends on the JAK2/
MAPK/early growth response gene-1 pathway, whereas
the activation of heme oxygenase-1 mediates PRL-stimulated VEGF transcription in macrophages (346). Evaluating PRL action is rendered more difficult because human
GH and PL can also activate PRL receptors. In fact, PL
signals through the PRL receptor and may be an important contributor to increased blood vessel growth during
pregnancy. Like PRL, PL stimulates in vivo angiogenesis
in the chick embryo chorioallantoic membrane during the
nonproliferative stage of blood vessels and is unable to
stimulate the in vitro proliferation of certain endothelial
cells (529).
PRL can affect the function of blood vessels during
injury and inflammation. PRL alters the cytoskeleton and
adhesion properties of endothelial cell monolayers after
mechanical injury (360) and promotes the infiltration of
leukocytes (415, 547) via their integrin-mediated adhesion
to vascular endothelial cells (371). Also, PRL can have
stimulatory or inhibitory effects on vascular resistance,
blood volume, and blood flow depending on the experimental model and condition (for a review, see Ref. 96).
Importantly, the vascular actions of PRL and PL, like
those of GH, can be counteracted by their proteolytic
conversion to vasoinhibins.
PEPTIDE HORMONES AND ANGIOGENESIS
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sis (M. Cruz-Soto and C. Clapp, unpublished observations). Notably, vasoinhibins were not detected in the
anterior pituitary glands of cathepsin D-null mice, arguing
in favor of cathepsin D being the physiologically relevant
protease at this site (Cruz-Soto and Clapp, unpublished
observations). Understanding the mechanisms regulating
the generation of pituitary vasoinhibins could help clarify
conflicting data, such as the presence of highly vascularized pituitary tumors in PRL-null mice (116). Indeed, because the pituitary gland may be an important site for the
cleavage of PRL into vasoinhibins (92), it is possible that
the absence of vasoinhibins, rather than the lack of PRL,
accounts for the upregulation of angiogenesis in pituitary
tumors.
Vasoinhibins are not the only members of the PRL/
GH/PL family that inhibit angiogenesis. S179D PRL, a
molecular mimic of naturally occurring phosphorylated
PRL, was recently shown to inhibit angiogenesis by interfering with endothelial cell migration, proliferation, survival, and growth factor signaling (567, 568). Phosphorylation of PRL at Ser-179 alters the charge of the molecule,
and it will be useful to examine the structural properties
of phosphorylated PRL for common features with vasoinhibins.
B. The Renin-Angiotensin System
The RAS encompasses various peptide hormones
that act systemically and locally to control blood pressure
and body fluid homeostasis. Over the last two decades,
RAS has been a key target for the development of drugs
effective for the treatment of cardiovascular diseases,
including hypertension, renal diseases, cardiac hypertrophy, congestive heart failure, and ischemic heart disease
(235, 349, 602).
RAS members result from stepwise enzymatic processing (Fig. 3) that starts with the cleavage of circulating
angiotensinogen (AGT) by the aspartyl protease renin,
forming the inactive decapeptide angiotensin I (ANG I)
and the COOH-terminal protein des[ANG I]AGT. Subsequently, angiotensin-converting enzyme (ACE) cleaves
ANG I to generate the main effector of RAS, the octapeptide angiotensin II (ANG II). Other endopeptidases, like
neprilysin, prolylcarboxypeptidase (PrCP), and angiotensin converting enzyme-related carboxypeptidase (ACE2),
cleave ANG I and ANG II to generate the heptapeptide
ANG-(1–7) (311), while ACE2 also converts ANG I into the
nonapeptide ANG-(1–9). Systemic ANG II is primarily produced within the pulmonary circulation, and its formation
is limited by the availability of circulating renin released
by the juxtaglomerular cells of the kidney. All components of RAS are present in many tissues, where ANG I
and ANG II can also be produced by enzymes other than
renin and ACE, including tonin, cathepsin G, chymostatin-
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stimulated endothelial cell migration (312, 313) and tube
formation (94, 313); block VEGF-induced vasopermeability
(192); and prevent VEGF-, bradykinin (BK)-, and acetylcholine-stimulated vasodilation (192, 209). Vasoinhibins also
promote vessel regression by stimulating apoptosis in endothelial cells (351, 537). The receptors for vasoinhibins have
not been identified (97), but portions of their signaling pathways have been defined (for a review, see Ref. 96). Vasoinhibins arrest endothelial cells at G0 and G2 by inhibiting
cyclin D1 and cyclin B1 and stimulating the cyclin-dependent kinase inhibitors p21cip1 and p27kip1 (535). This regulation may involve the inhibition of MAPK activation (117,
118) and of eNOS-dependent proliferative pathways (209,
649). Vasoinhibins also interfere with endothelial cell migration by upregulating plasminogen activator inhibitor type-1
(312) and blocking the Ras-Tiam1-Rac1-Pak1 signaling pathway (313). Vasoinhibins inhibit endothelial cell survival by
activating proapoptotic proteins of the Bcl-2 family (351)
and the NF␬B-mediated activation of caspases (537). Finally, vasoinhibins block vasodilation and vasopermeability
by interfering with the Ca2⫹-dependent activation of eNOS
(209) and by activating protein phosphatase 2A, which dephosphorylates and inactivates eNOS (192).
The extensive influence of vasoinhibins on vascular
endothelial cells includes proinflammatory actions. Vasoinhibins act on endothelial cells to promote the expression of cell adhesion molecules (ICAM-1, VCAM-1, Eselectin) and of chemokines from the CXC and the CC
families (536). Consequently, they stimulate the NF␬Bmediated adhesion of leukocytes to endothelial cells and
the infiltration of leukocytes into tumors (536). Also, vasoinhibins act as proinflammatory mediators on other cell
types, like pulmonary fibroblasts, where they promote the
NF␬B-mediated expression of inducible NOS (iNOS) with
potency comparable to the combination of IL-1␤, tumor
necrosis factor (TNF)-␣, and interferon (IFN)-␥ (110,
340).
Vasoinhibins are emerging as natural inhibitors of the
angiogenic process. They have been identified in the retina (22) and cartilage (339), where angiogenesis is highly
restricted, and blocking the expression and action of
vasoinhibins by siRNA targeting PRL or neutralization
with antibodies results in stimulation of retinal angiogenesis and vasodilation (22). In addition, interfering with the
formation of vasoinhibins by pharmacologically blocking
pituitary PRL secretion prevents postpartum cardiomyopathy in mice (243). In chondrocytes, vasoinhibins appear
to be generated mainly by MMPs (339), whereas other
proteases predominate at different sites. Genetic deletion
of two genes encoding BMP-1-like metalloproteases prevents the generation of GH- and PRL-derived vasoinhibins
in mouse fibroblasts (196). Recently, cathepsin D has
been shown to generate vasoinhibins within PRL secretory granules in the anterior pituitary, suggesting that
vasoinhibins are released during the process of exocyto-
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ANG
ANG
ANG
ANG
ANG
ANG
FIG. 3. Hormones of the renin-angiotensin system with effects on angiogenesis. Cleavage of angiotensinogen (AGT) by renin yields inactive
angiotensin I (ANG I), a short NH2-terminal decapeptide, and des[ANG I]AGT, which shares antiangiogenic properties with AGT. ANG I can be
further processed to angiogenic angiotensin II (ANG II) and antiangiogenic angiotensin-(1–7) [ANG-(1–7)], each of which can be cleaved to yield
peptides with no described effects on angiogenesis. The single-letter amino acid composition of each smaller peptide is indicated. ACE,
angiotensin-converting enzyme; ACE 2, angiotensin-converting-enzyme-related carboxypeptidase; PrCP, prolylcarboxypeptidase; ANG III, angiotensin III; ANG IV, angiotensin IV; ANG-(1–5), angiotensin (1–5); ANG-(1–9), angiotensin-(1–9). Molecules are color coded in green for their angiogenic
properties and in red for their antiangiogenic effects.
sensitive ANG II-generating enzyme, chymase, and tissue
plasminogen activator (Fig. 3) (311). Of importance, ACE
can cleave ANG-(1–9) to ANG-(1–7), and ANG-(1–7) to
ANG-(1–5), while neprilysin, chymase, and aminopeptidase A inactivate ANG II.
Increasing evidence indicates that members of RAS
exert both positive and negative effects on angiogenesis.
Because the main role of RAS is to maintain body fluid
homeostasis in response to a drop in perfusion pressure,
RAS hormones likely participate in controlling neovascularization during vasoconstriction-associated ischemia.
Intricate mechanisms govern their contrasting actions on
angiogenesis and involve the activation of different receptor subtypes with opposite outcomes depending on specific tissue and disease conditions as well as the proteolytic conversion of larger precursor molecules, which may
Physiol Rev • VOL
or may not have angiogenic actions, into smaller angiogenic or antiangiogenic peptides.
1. Angiotensin II
The most fully characterized component of the RAS
system, ANG II, is normally proangiogenic when administered in vivo or in vitro (for reviews, see Refs. 236, 276).
ANG II stimulates vessel proliferation in the chick embryo
chorioallantoic membrane (308), the rabbit cornea (158),
and the Matrigel model in mice (544). The two G proteincoupled receptors for ANG II, AT1 and AT2, have been
identified in endothelial cells (126), and AT1 is the main
mediator of the proangiogenic actions of ANG II. Inhibitors of AT1 block the proangiogenic effect of ANG II in
the mouse Matrigel model (544), the rat ischemic hindlimb (545), and the electrically stimulated rat skeletal
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NG
ANG
PEPTIDE HORMONES AND ANGIOGENESIS
Physiol Rev • VOL
growth, tissue repair, and apoptosis. Each receptor subtype activates multiple signaling pathways (reviewed in
Refs. 153, 276), and the opposing influence of the two
receptor subtypes is supported by signaling experiments
in vitro. For example, AT1 receptors upregulate the expression of VEGF and angiopoietin-2 in microvascular
endothelial cells by stimulating the release of heparinbinding EGF followed by the transactivation of the EGF
receptor, whereas AT2 attenuates these actions by blocking EGF receptor phosphorylation (186). Also, AT1 acts in
endothelial cells through the PI3-K/Akt pathway to upregulate survivin, suppress caspase-3 activity (412), and
induce focal adhesion kinase/paxillin phosphorylation
(372), which lead to endothelial cell survival and migration, respectively. In contrast, AT2 blocks VEGF-induced
phosphorylation of Akt, causing the inhibition of eNOS
activation, endothelial cell migration, and tube formation
(47). ANG II regulation of endothelium-derived NO is
complicated, as both positive and negative effects of AT1
and AT2 have been reported (42, 416, 645). AT2 signals
vasodilation directly by promoting eNOS activity and endothelial NO release (416), but also indirectly by stimulating the production of BK, which in turn stimulates the
eNOS/NO/cGMP pathway in the endothelium (564). These
AT2 actions counterbalance the vasoconstriction elicited
by AT1-induced inhibition of eNOS (416), G protein-mediated activation of phospholipase C (PLC), and inositol
trisphosphate-induced mobilization of intracellular Ca2⫹
in vascular smooth muscle cells (124). Other contrasting
mechanisms are the AT1 activation of tyrosine kinases
that phosphorylate and activate the Ras/Raf/MAPK cascade, resulting in cellular growth and survival, and the
AT2 activation of MAPK phosphatase-1 that inactivates
ERK1 and ERK2, leading to Bcl-2 dephosphorylation and
Bax upregulation (246).
Further complexity in the regulation of angiogenesis
by RAS hormones is illustrated by the fact that AGT,
des[ANG I]AGT, and ANG-(1–7) are antiangiogenic.
2. Angiotensinogen and des[ANG I]angiotensinogen
The human AGT protein contains 452 amino acids;
the first 10 correspond to ANG I and the remainder to
des[ANG I]AGT (Fig. 3). Circulating AGT is synthesized in
the liver, but AGT is also produced in tissues such as the
brain, large arteries, kidney, heart, and adipose tissue,
where it is hydrolyzed by extravascular renin or other
proteases to ANG I or directly to ANG II (Fig. 3) (111).
AGT shares structural homology with the serine protease
inhibitor (serpin) family of proteins, and the fact that
some serpin proteins regulate angiogenesis [angiogenin
(190), pigment epithelium-derived factor (PEDF) (123),
maspin (30), and cleaved antithrombin (406)] led to the
discovery of the antiangiogenic properties of AGT and
des[ANG I]AGT. Both proteins inhibit in vivo angiogene-
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muscle (18). Likewise, inhibitors of AT1, but not of AT2,
prevent the stimulatory effects of ANG II on the proliferation and tube formation of cultured endothelial cells
(421, 526) and bone marrow-derived endothelial progenitor cells (257). Also, AT1 antagonists inhibit the ANG
II-induced upregulation of VEGF, VEGFR2, angiopoietin-2, and Tie2 in endothelial cells (90, 421) and in vascular smooth muscle cells (462). However, in kidney, both
AT1 and AT2 inhibitors are effective (465). ANG II upregulates other proangiogenic mediators, including NO
(416, 544), bFGF (431, 518), PDGF (106, 386), IGF-I and its
receptor (63, 227, 581), EGF (186), hepatocyte growth
factor (HGF) (153), and TGF-␤ (198, 271, 286, 414). ANG
II can also directly signal endothelial cell proliferation via
c-Src-mediated increase of NADP oxidase activation
(563), phosphorylation of ERK1/2 (429), p38 MAP kinase
(571), and JNK (488), as well as reduced phosphorylation
of Src homology 2-containing inositol phosphatase 2
(SHP-2) (482).
On the other hand, ANG II is antiangiogenic under
certain conditions, as inhibition of endogenous ANG II
production or action by treatment with ACE inhibitors or
AT1 and AT2 blockers, respectively, stimulates angiogenesis in vivo (236, 593). ANG II may inhibit angiogenesis by
activating the AT2 receptor. AT2 expression is augmented
in the ischemic limb of wild-type mice, and vessel density
increases in the ischemic limb of AT2-knockout mice
(505). Furthermore, ANG II-induced neovascularization in
the cremasteric muscle is enhanced by AT2 blockers,
although it is inhibited by AT1 antagonists (384). However, the contribution of each receptor subtype to the
antiangiogenic effect of ANG II appears to depend on the
chosen angiogenesis model. In the alginate tumor model,
AT2-null mice show impaired angiogenesis, and treatment
with AT1 inhibitors promotes angiogenesis (593). Interestingly, evidence for the antiangiogenic effects of ANG II
via AT2 has also been provided in cultured endothelial
cells (47), where AT2 receptor stimulation inhibits VEGFinduced endothelial cell migration and tube formation.
Although much needs to be learned about the mechanisms controlling the dual effects on angiogenesis of AT1
and AT2, it is generally accepted that the two receptors
essentially mediate contrasting effects of ANG II (for
reviews, see Refs. 124, 276). AT1 receptors are ubiquitously expressed and responsible for most of the wellknown actions of ANG II, including vasoconstriction, aldosterone and vasopressin release, renal sodium and water reabsorption, sympathetic activation, augmented
cardiac contractility, smooth muscle cell proliferation,
vascular and cardiac hypertrophy, inflammation, and oxidative stress. In contrast, AT2 receptors are restricted to
organs like the brain, kidney, adrenals, uterus, ovary, and
the cardiovascular system, where their activation leads to
vasodilation, lower blood pressure, reduced cardiac and
vascular hypertrophy, anti-inflammation, and suppressed
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CLAPP ET AL.
2. Angiotensin-(1–7)
ANG-(1–7) is present in the circulation and in tissues,
where its concentration increases after any condition that
raises plasma or tissue levels of ANG I (161). For example, circulating levels of ANG-(1–7) increase 25- to 50-fold
during ACE inhibition (71, 294, 377) due to increased ANG
I conversion to ANG-(1–7) and inhibition of ANG-(1–7)
breakdown by ACE (83). Although ANG I is the primary
substrate for the generation of ANG-(1–7), the latter may
also be formed from ANG II (Fig. 3), and higher availability of ANG II after treatment with blockers of the AT1
receptor also elevates circulating ANG-(1–7) (71, 294,
377).
ANG-(1–7) was characterized as the first NH2-terminal angiotensin peptide opposing the vasopressor, proliferative, and angiogenic actions of ANG II, thereby endowing RAS with greater capability for regulating tissue perfusion (161, 341, 528). ANG-(1–7) acts as a vasodilator in
vascular beds of different species (161, 162, 299, 458, 486),
lowers blood pressure (48), reduces the proliferation of
smooth muscle vascular cells in vitro (176) and in vivo
(528), is cardioprotective (483), and inhibits angiogenesis
and fibrovascular tissue infiltration in the mouse sponge
model (341).
Although there is some evidence that ANG-(1–7) can
activate ANG II receptors (592), the G protein-coupled
Mas receptor has been identified as the functional receptor for ANG-(1–7) (12). Mas is expressed in endothelial
cells (119), and its targeted disruption in mice causes
increased blood pressure, endothelial dysfunction, imbalance between NO and reactive oxygen species, and a
major cardiovascular phenotype, all of which are consistent with lack of ANG-(1–7) signaling (625). ANG-(1–7)
induces endothelium-dependent vasodilation by stimulating NO release indirectly through BK-induced eNOS actiPhysiol Rev • VOL
vation (237, 299), but also directly by promoting Masmediated eNOS activation via Akt (482). In addition, ANG(1–7) inhibits ANG II-induced phosphorylation of MAPK
through prostacyclin-mediated production of cAMP and
activation of cAMP-dependent kinase (542), and it prevents ANG II-induced activation of Src and its downstream targets ERK1/2 and NADPH oxidase (482). ANG(1–7) induces as well the phosphorylation of SHP-2,
which could act as a negative regulator of ANG II-induced
MAPKK and Src signaling (482).
In summary, due to the dual effects of RAS hormones, local conditions affecting their synthesis and
clearance rate, the production and activity of the converting proteases, and their receptor-mediated signaling pathways would determine whether an antiangiogenic or an
angiogenic condition prevails. ACE inhibitors and AT1
receptor blockers, which are among the most widely prescribed drugs for blood pressure control, lower ANG II
generation and action and increase renin levels, accelerating AGT cleavage into antiangiogenic des[ANG I]AGT
and ANG-(1–7) (311). However, treatment with ACE inhibitors is frequently proangiogenic (for a review, see
Refs. 236, 504), primarily due to blockage of ACE-induced
degradation of the potent vasodilator and proangiogenic
hormone BK (236, 504). RAS/BK interactions are essential
for balancing blood pressure and illustrate the sophisticated local and systemic interactions influencing the final
angiogenic response.
C. The Plasma Kallikrein-Kinin System
The KKS in plasma comprises the serine proteases,
coagulation factor XII and plasma prekallikrein, and highmolecular-weight kininogen (HK). The plasma KKS is
known as the contact system, because originally the only
known mechanism for its activation was contact with
artificial, negatively charged surfaces. However, it is now
recognized that the contact system is activated physiologically at the cell membrane, leading to the generation of
small peptides and proteins with effects on blood coagulation, inflammation, pain, natriuresis, blood pressure,
vascular permeability, and angiogenesis (for reviews, see
Refs. 8, 481, 487).
HK is a 120-kDa, single-chain glycoprotein composed
of six domains (D1 to D6), originally identified as the
protein that, upon cleavage, yields the nonapeptide BK,
the main effector of the plasma KKS (266) (Fig. 4). Most
plasma prekallikrein circulates bound to HK, and on the
endothelial cell surface HK serves as its main binding site
(381). Upon binding to the endothelial cell surface via HK,
prekallikrein is converted to kallikrein by prolylcarboxypeptidase (PrCP) (495), the same serine protease
that generates ANG-(1–7) and ANG II (Fig. 3). Kallikrein
favors factor XII association with and activation by endo-
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sis in the chick embryo chorioallantoic membrane and the
in vitro proliferation, migration, and tube formation of
endothelial cells (20, 80). No specific AGT or des[ANG
I]AGT receptors have been detected, but both proteins
bind to AT1 and AT2 receptors at their micromolar
plasma concentrations (197). AGT does not affect the
expression of angiogenic growth factors in vivo; instead,
it directly suppresses proliferation of endothelial cells
and induces their apoptosis (62). AGT-deficient mice exposed to cold display an abnormal vascular brain barrier
phenotype (272) that may reflect blood vessels destabilized by the absence of AGT in glial cells surrounding
brain capillaries (527).
Local conditions may determine whether the antiangiogenic properties of AGT and des[ANG I]AGT prevail
over the proangiogenic effects of ANG II. For example,
circulating AGT could prevent angiogenesis at sites lacking renin.
PEPTIDE HORMONES AND ANGIOGENESIS
thelial cells, and activated factor XII (factor XIIa) feeds
back to cleave prekallikrein to kallikrein, accelerating its
formation (for a review, see Ref. 487). Kallikrein cleaves
D4 in HK to release BK and cleaved HK (HKa), a twochain structure (D1-D3 and D5-D6) linked through a single
disulfide bond (Fig. 4). HK is also converted to BK and
HKa by factor XIIa, albeit to a lesser extent than by
plasma kallikrein (102).
Various peptidases, including ACE, metabolize BK to
generate smaller peptides that have no known effect on
angiogenesis (70). Pharmacological inhibitors of ACE,
both by reducing ANG II levels and by blocking the degradation of BK, help control cardiovascular diseases, including hypertension and myocardial infarction (for reviews, see Refs. 236, 604). In fact, hypertension and cardiac failure have been functionally linked to impaired
angiogenesis (236, 284, 604), and the plasma KKS is another hormonal system in which a protein generates both
proangiogenic (BK) and antiangiogenic (HKa) fragments
after undergoing proteolytic cleavage (Fig. 4).
1. Bradykinin
Discovered half a century ago, BK has multiple biological activities (reviewed in Ref. 348) and is involved in
pathological states including hypertension (278) and inflammation (481). Besides being a well-known vasodilator
and vasopermeability factor, BK has clear proangiogenic
effects (236). It stimulates the proliferation, tube formaPhysiol Rev • VOL
tion, and survival of cultured endothelial cells (366, 376)
and promotes angiogenesis in the rabbit cornea (426), the
chick embryo chorioallantoic membrane (104), the nude
mouse xenograft assay (514), the rat subcutaneoussponge model (234, 251), and the mouse ischemic hindlimb (146, 147). Moreover, angiogenesis is suppressed in
HK-deficient rats and is restored by treatment with a BK
analog (234).
BK stimulates angiogenesis by activating two G
protein-coupled receptor subtypes, B1 and B2 (see
Refs. 8, 356). Both receptors are present in endothelial
cells (614), but while the B2 receptor is constitutively
expressed, the B1 receptor is upregulated following
tissue damage, ischemia, and inflammation (see review
in Ref. 8). Actually, activation of B1 receptors may be
seen as a mechanism to magnify BK actions, since this
receptor subtype is normally expressed in the same cell
types as the B2 receptor, uses similar signaling pathways but is less vulnerable to desensitization, and mediates the activity of other kinin metabolites (8). Inhibitors of receptors B1 (234, 321) and B2 (234, 262, 489)
reduce in vivo angiogenesis and inhibit BK-induced
endothelial cell proliferation (366, 376) and tube formation (366) in vitro. Notably, BK also stimulates endothelial cell growth and permeability by increasing B2
receptor-mediated VEGF expression in fibroblasts (255,
262) and smooth muscle cells (289), whereas the B1
receptor contributes to the proangiogenic action of BK
by increasing bFGF synthesis in endothelial cells (137,
376, 426).
The mechanisms mediating the vascular effects of BK
are not entirely understood, but it is clear that eNOSderived NO is a major effector of BK-induced vasodilation
(51, 209), vasopermeability (439), and angiogenesis (321,
426, 556). Although both B1 (426) and B2 receptors (366)
signal to promote eNOS activity, B2 receptors likely predominate in mediating this action. BK stimulation of B2
receptors on endothelial cells activates PLC and phospholipase A2, which in turn trigger the intracellular mobilization of Ca2⫹ and the activation of eNOS via calmodulin
binding. In addition, BK stimulates the activation of eNOS
by promoting PI3-K/Akt-induced eNOS phosphorylation
at Ser-617, Ser-635, and Ser-1179 and by stimulating calcineurin-mediated eNOS dephosphorylation at Thr-497,
modifications that serve to increase the Ca2⫹-calmodulin
sensitivity of the enzyme (for a review, see Ref. 579). BK
also induces the phosphorylation/activation of VEGFR2,
which can promote eNOS activation (366, 556).
Of importance, BK is rapidly inactivated in the intravascular compartment (half-life ⬃15 to 30 s; Ref. 378), and
it disappears completely after a single passage through
the pulmonary circulation. Its degradation is ensured by
three different kininases: ACE, aminopeptidase P, and
carboxypeptidase N, which cleave at positions 7– 8, 1–2,
and 8 –9 of BK, respectively. The stable metabolic end
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FIG. 4. Angiogenesis-related components of the kallikrein-kinin
system. Domain 4 (D4) of high-molecular-weight kininogen (HK) can be
cleaved by plasma kallikrein to produce the angiogenic nonapeptide
bradykinin (BK) and antiangiogenic cleaved high-molecular-weight
kininogen (HKa). BK can then be processed by angiotensin-converting
enzyme (ACE) to yield nonangiogenic BK-(1–5). The single-letter amino
acid composition of the BK peptides is indicated. S-S stands for disulfide
bonds. Molecules are color coded in green for their angiogenic properties and in red for their antiangiogenic effects.
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CLAPP ET AL.
2. Cleaved high-molecular-weight kininogen
HKa encompasses one heavy chain composed of D1
to D3 and a light chain corresponding to D5 and D6 linked
by a disulfide bond (Fig. 4). The conversion of HK to HKa
involves important conformational changes that expose a
major region of D5 (599), which mediates the acquired
ability of HKa to inhibit angiogenesis. HKa and recombinant D5 (also named kininostatin, Ref. 103) inhibit proliferation, migration, and survival of cultured endothelial
cells (103, 226, 277, 640). Inhibition of endothelial cell
proliferation is Zn2⫹ dependent and interferes with the
mitogenic effects of bFGF, VEGF, HGF, and PDGF (640)
by blocking the transition from G1 to S phase of the cell
cycle (226). HKa also inhibits bFGF-induced angiogenesis
in the Matrigel plug assay in mice and the cornea of rats
(640), and both HKa and recombinant D5 inhibit the
proangiogenic effects of bFGF and VEGF in the chick
embryo chorioallantoic membrane (103, 640). The antiangiogenic properties of HKa may be mediated by its interaction with urokinase receptors through the D5 region, an
interaction that would compete with the urokinase plasminogen activator receptor (uPAR) for the binding of
ECM proteins (vitronectin) (72). An alternative mechaPhysiol Rev • VOL
nism is the binding of HKa to the cytoskeletal protein
tropomyosin (641), which is involved in mediating the
antiangiogenic properties of endostatin, an antiangiogenic
fragment of collagen XVIII (338). The proposed signaling
pathways underlying the antiangiogenic effects of HKa
through its D5 region include the disruption of focal adhesions via vitronectin-uPAR-␣v␤3-caveolin-Src-FAK-paxillin (102) or by vitronectin-uPAR-PI3K/Akt-paxillin (277),
the reduction of cyclin D1 expression (226), the activation
of Cdc2 kinase/cyclin A (597), and the generation of reactive oxygen species dependent on ECM components
(531).
In summary, specific proteolytic cleavage of HK
yields both proangiogenic (BK) and antiangiogenic (HKa)
moieties. Because BK is hydrolyzed very rapidly and thus
is active only close to its site of formation, BK may
function as an initiator of angiogenesis, particularly in
inflammatory and ischemic conditions (356), when the
induction of B1 receptors can amplify its action. In contrast, HKa has a long in vivo half-life (9 h) and may
counteract the angiogenic response to BK with time, tipping the balance towards antiangiogenesis. Of note, the
outcome of the plasma KKS effect on angiogenesis depends not only on a repertoire of endothelial cell membrane proteins (i.e., HK-binding proteins, bound proteases, and receptors) but also on ECM proteins. HKa
only induces death of proliferating endothelial cells on
permissive surfaces like gelatin, fibronectin, vitronectin,
and laminin (640), and its effect on vessel regression
depends on the type of collagen (531). Furthermore, compensatory actions of RAS peptides may be integrated in
the regulation of angiogenesis by the KKS, since the same
enzyme (ACE) upregulates and downregulates the accumulation of proangiogenic ANG II and BK, respectively.
IV. HORMONAL REGULATION OF
PHYSIOLOGICAL ANGIOGENESIS
Angiogenesis is normally absent in most adult organs
except in female reproductive organs where intense vascular growth and regression occur physiologically, contributing to their growth, function, and involution. Members of the GH/PRL/PL family, the RAS, and the KKS
regulate the physiology of reproductive organs, and some
of their actions involve the control of blood vessel growth
and regression.
A. Female Reproductive Organs
The endocrine system orchestrates a series of cyclical events in the female reproductive organs, allowing the
ovum to mature and eventually become fertilized and the
resulting new individual to be nurtured during the intrauterine and neonatal periods. Gonadotropin hormones
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product of BK produced by ACE is a pentapeptide, known
as BK-(1–5) (Fig. 4), that inhibits thrombin-induced platelet aggregation (385) but has no known effect on angiogenesis. BK inactivation and ANG I to ANG II conversion
in the lungs are caused by the same ACE enzyme (397),
and because ACE has a higher affinity for BK than for
ANG I (269), the interplay between RAS and KKS must be
considered to fully understand the role of both systems in
angiogenesis.
Blockage of ACE stimulates angiogenesis in the heart
of stroke-prone, spontaneously hypertensive rats (205)
and in the rat limb muscle (69), promotes ischemia-induced angiogenesis in the rabbit hindlimb (155), and induces pseudocapillary formation and endothelial cell
growth in vitro (137). The effect of BK after ACE inhibition is illustrated by the fact that neovascularization is
greater in ischemic wild-type mice treated with ACE inhibitors than in the corresponding B2-receptor-null animals (504). The proangiogenic effect of ACE inhibition in
the ischemic hindlimb is suppressed in B2-receptor-deficient mice (143). Importantly, the RAS and KKS interaction can also regulate angiogenesis via ANG II-dependent
activation of B2 receptors (1, 383, 512, 564, 607), which
leads to proangiogenic and vasodilator effects. The impact of ACE activity on RAS and BK generation and how
it relates to angiogenesis regulation has been recently
reviewed (236).
Predicting the outcome of KKS hormone actions on
angiogenesis is complicated by the concomitant production of proangiogenic BK and antiangiogenic HKa.
PEPTIDE HORMONES AND ANGIOGENESIS
cells of follicles as they become dependent on gonadotropin stimulation (501), and inhibition of gonadotropin release using a gonadotropin releasing hormone (GnRH)
antagonist inhibits VEGF expression and angiogenesis in
ovulatory follicles (549). Other peptide hormones stimulate follicle VEGF expression and angiogenesis. For example, IGF-I and IGF-II promote VEGF expression in
granulosa cells (350), and the PRL present in follicular
fluid stimulates endothelial cell proliferation (78). Of interest, a functional angiotensin system exists in the endothelial cells of the early corpus luteum (292), and ANG II
induces VEGF synthesis in endothelial cells (90), promotes the expression of bFGF in bovine luteal cells (524),
and may contribute to LH-induced corpus luteum angiogenesis. Furthermore, LH upregulates ovarian ANG II production (see review, Ref. 632), and ANG II antagonists can
block LH-induced expression of bFGF in luteal cells
(524). In addition, bFGF and VEGF upregulate luteal ANG
II secretion, which supports the mechanism promoting
progesterone secretion in the early corpus luteum (292).
As the corpus luteum ages in a nonfertile cycle,
VEGF levels decline (422), and the angiopoietin-2/angiopoietin-1 ratio rises (203), leading to the endothelial cell
apoptosis and vascular breakdown characteristic of luteolysis. In contrast, in a fertile cycle, the corpus luteum is
rescued by chorionic gonadotropin, which promotes endothelial cell survival by upregulating VEGF, angiopoietin-2, and Tie-2 (621). Another important hormone regulating luteal function is PRL. In rodents, the proestrus
surge of circulating PRL in a nonfertile cycle induces
luteolysis, but after pseudopregnancy or pregnancy, the
increase in systemic PRL promotes the survival and function of the corpus luteum (194). The opposing actions of
PRL are perplexing and may involve several mechanisms
(525), including both proangiogenic and antiangiogenic
effects. Treatment with PRL induces endothelial cell proliferation in the corpus luteum of cycling rats, whereas
reducing circulating PRL levels with bromocriptine (195)
or deleting the PRL receptor gene (220) interferes with
corpus luteum angiogenesis. In addition, the levels of
PRL-derived vasoinhibins may rise at the end of a nonfertile cycle, because PRL increases MMP-2 activity during
PRL-induced luteal regression (150), and MMP-2 generates vasoinhibins from PRL (339). Moreover, at the onset
of luteal regression, corpus luteum-derived endothelial
and granulosa cells produce and release higher levels of
the vasoinhibin-generating protease cathepsin D (152).
2. Uterine endometrium and placenta
1. Ovary
The information regarding ovarian angiogenesis has
been extensively reviewed (172, 173, 175, 543), and accumulating evidence shows that ovarian VEGF is under
hormonal control. VEGF increases in granulosa and theca
Physiol Rev • VOL
Angiogenesis is required for the cyclic processes of
endometrial growth, breakdown, and repair during the
menstrual cycle, and it provides a richly vascularized
tissue receptive for implantation and placentation (reviewed in Refs. 84, 202, 265, 560, 619).
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from the pituitary gland drive ovarian function by stimulating estrogen and progesterone production, follicle
growth, ovulation, and corpus luteum development. After
fertilization, the maintenance of the corpus luteum is
dependent on chorionic gonadotropin and PRL, permitting the continued secretion of progesterone necessary to
maintain the endometrium in a state favorable for implantation and placentation (for reviews, see Refs. 27, 525). As
for the growth, differentiation, and secretory activity of
the mammary gland during pregnancy and lactation, the
relative contribution of PRL, GH, and PL varies among
species (44), but activation of the PRL receptor is crucial
(396).
In addition to these hormonal inputs, evidence indicates that GH, directly or via stimulation of IGF-I production, regulates follicular growth, sexual maturation, and
luteal function (28, 636) and that ANG II produced in
response to gonadotropins can stimulate follicular maturation, steroidogenesis, ovulation, and corpus luteum
growth and regression (see review, Ref. 632). Also, BK has
been implicated in ovulation (546, 633), and both the RAS
(400) and the KKS (99) participate in regulating implantation and placentation.
Reproductive events are also determined by cyclical
changes in blood vessel growth and regression within the
various reproductive organs, driven primarily by VEGF
and then by its blockage (for reviews, see Refs. 173, 174,
202). The transient interruption of VEGF signaling by
agents specifically designed to inhibit VEGF or block its
receptors suppresses follicular development, ovulation
(620, 623), corpus luteum formation, progesterone release
(622), and postmenstrual endometrial regeneration (156).
Homozygous and heterozygous knockouts of the VEGF
gene exhibit major defects in placental blood vessels (76,
159), and interference with placental VEGF compromises
normal angiogenesis and leads to a poorly perfused fetoplacental unit (355). In addition, inactivation of VEGF
severely limits the development and function of the mammary gland (472). The fact that female reproductive organs are under the control of hormones able to affect
angiogenesis, either directly or via the expression and
action of VEGF or other proangiogenic signals, strongly
argues in favor of angiogenesis regulation as an essential
hormonal function. We refer to recent reviews on the
action of gonadotropins and steroid hormones that are
considered to be important regulators of angiogenesis in
reproductive organs (11, 440, 457) and keep our focus on
certain proteolysis-derived peptide hormones.
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genesis and elevated blood flow (for a review, see Ref.
646). AT1 receptors are expressed predominantly in placental blood vessels and mediate ANG II-induced proliferation (55) and NO production by endothelial cells from
fetoplacental arteries (646). In addition to mediating
proangiogenic actions, ANG II-induced NO production
helps attenuate the vasopressive response to ANG II
(646). This effect is relevant, as vasodilation of maternal
systemic circulation and the increased blood flow within
the fetoplacental unit are major adaptations of mammalian pregnancy (509). The vasodilator response to ANG(1–7) is enhanced during gestation (395), and systemic
and renal ANG-(1–7) levels increase during late pregnancy (64, 361, 573). The different components of the KKS
have also been identified in the cycling (98) and early
pregnant uterus (15), suggesting that BK and its receptors
actively participate in increased uterine blood flow, vasopermeability, and angiogenesis.
In addition to proangiogenic mechanisms, antiangiogenic events operate to regulate the regional distribution
of placental neovascularization (reviewed in Ref. 254).
Antiangiogenic mechanisms maintain the avascular nature of the decidual layer immediately surrounding the
synciotrophoblastic mass of the invading embryo. Antiangiogenic events, such as endothelial cell apoptosis, also
occur during human spiral arterial remodeling, which
prevents maternal vessels from invading the embryonic
compartment and fetal vessels from growing into the
uterus. Notably, placental trophoblasts produce the secreted form of the VEGF receptor 1 (sVEGFR1), also
known as soluble fms-like tyrosine kinase-1 (sFlt-1),
which functions as an endogenous trap for VEGF (38,
280) and is a major contributor to decidual avascularity
(254). Proteolytically modified hormones may participate
in inhibiting placental angiogenesis as well. Cathepsin D
is produced at the deciduo-placental interface (142, 379)
and may generate vasoinhibins from decidual PRL. Indeed, amniotic fluid accumulates decidual PRL (46) and
contains PRL-derived vasoinhibins, and cathepsin D from
placental trophoblasts cleaves PRL to vasoinhibins (210).
Likewise, the antiangiogenic vasodilator ANG-(1–7) and
its generating enzyme, ACE2, are present in the decidua
during early placentation when the ANG II/ANG-(1–7)
ratio decreases at the implantation and interimplantation
sites (395) and in various cell types of the placenta at term
(574).
3. Mammary gland
The mammary gland undergoes dramatic changes in
growth, differentiation, function, and involution during
the reproductive cycle (see reviews in Refs. 240, 503).
Pituitary gland hormones and ovarian steroids orchestrate these changes starting at puberty, when gonadotropins promote the ovarian release of estrogen and proges-
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Uterine angiogenesis is regulated by multiple hormones, among which estrogen and progesterone predominate in regulating endometrial growth and differentiation. There is good evidence that estrogen drives VEGF
production and angiogenesis during the proliferative
phase of the cycle, whereas the presence and the absence
of progesterone have been implicated in endometrial angiogenesis during the secretory and postmenstrual phases
of the cycle, respectively (see reviews in Refs. 11, 202,
265). Other hormones involved in endometrial angiogenesis include chorionic gonadotropin (457), adrenomedullin (401), relaxin (208), and two subjects of this review,
PRL (264) and ANG II (646).
Systemic PRL derived from the anterior pituitary
gland increases during proestrus and early pregnancy in
rodents, whereas in humans, circulating PRL remains low
during the menstrual cycle and gradually increases during
gestation, reaching its maximum level at term (reviewed
in Ref. 44). PRL is also produced by the decidua (264,
447), a specialized endometrial stromal tissue that differentiates in the luteal phase of the menstrual cycle and
throughout pregnancy. The location and temporal presence
of PRL suggest its influence on endometrial angiogenesis
during the secretory phase of the cycle and at the time of
implantation and early placental development (264). Consistent with this, pharmacologically induced hyperprolactinemia enhances endometrial thickness (471) and uterine gland
hyperplasia (281). PRL receptors are localized in the decidua, cytotrophoblasts, synciotriotrophoblasts (337), differentiated stromal, and uterine natural killer cells (224), which
are important cellular sources of proangiogenic factors like
VEGF, placental growth factor, bFGF, and angiopoietins (84,
130, 322), and PRL stimulates the expression of bFGF by
decidual cells (517). Also, the placenta produces GH and PL,
both of which promote endometrial gland proliferation (403,
516) and can activate PRL receptors.
On the other hand, cyclic changes in the activity of
the RAS also occur during the reproductive cycle and are
reflected in the circulation and in the expression of all of
its components in the uteroplacental unit (reviewed in
Ref. 400). During the luteal phase, ANG II increases in
stromal cells near endometrial spiral arterioles, and ANG
II receptor expression is increased in endometrial glands
and blood vessels (9). Because ANG II stimulates the
contraction of uterine blood vessels (444), ANG II may
contribute to the vasopressor mechanism that initiates menstruation, causing hypoxia-induced regression and degradation of upper endometrial tissue in response to the withdrawal of progesterone (115). Also, a role for ANG II in
endometrium regeneration is suggested by the presence of
ANG II and ANG II receptors in endometrial glandular and
stromal cells during the proliferative phase (9).
During pregnancy, all the components of RAS are
active in the placenta, and increased ANG II levels in the
maternal circulation are associated with placental angio-
PEPTIDE HORMONES AND ANGIOGENESIS
Physiol Rev • VOL
strictive effects (see review in Ref. 96). These vasomotor
actions also occur in response to human GH (572) and PL
(221).
Likewise, members of the RAS and KKS can affect
mammary gland function. BK regulates mammary gland
blood flow (448, 637), and both BK and ANG II act as
growth factors for normal mammary gland epithelial cells
(214, 215). ANG II present in mammary gland is not
necessarily derived from the circulation, as RAS components have been localized in normal mammary gland tissue, particularly in epithelial cells (538). Also, milk contains BK (613), and the isolated lactating bovine udder
releases BK into the vascular perfusate (637). To our
knowledge, the role of the RAS and KKS in normal mammary gland angiogenesis has not yet been investigated.
B. Nonreproductive Organs
With the exception of the female reproductive system, the vasculature of most healthy tissues is quiescent
during adult life, reflecting the predominance of naturally
occurring inhibitors able to counterbalance the effects of
relatively abundant proangiogenic mediators. The study
of this tight control of angiogenesis is particularly attractive in tissues like retina and cartilage, which are partially
or totally devoid of blood vessels, respectively, and where
damage to the mechanisms regulating angiogenesis contributes to the development of vasoproliferative retinopathies and arthritis.
1. Retina
In the normal adult retina, the vascularized compartment is confined to the inner organ, whereas the outer
retina never becomes vascularized. Failure to inhibit
blood vessel growth can result in reduced visual acuity
and underlies retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, the leading causes of blindness worldwide (642). Among the multiple regulators of retinal angiogenesis (122, 138) evidence
suggests that vasoinhibins derived from PRL are crucial (see
review in Ref. 95). PRL and vasoinhibins are present in
ocular fluids and in the retina of rats (22, 464) and humans
(140, 441) and may originate from systemic PRL (407) or
from PRL synthesized locally, as PRL mRNA and protein are
localized in cells throughout the retina (22, 464), including
endothelial cells (410). Notably, the intravitreal injection of
antibodies able to inactivate vasoinhibins promotes vessel
growth in the retina, and the intraocular transfection of
siRNA to block PRL expression stimulates retinal angiogenesis and vasodilation (22). Endogenous vasoinhibins
may also participate in the control of vessel remodeling
during development. Immunosequestering vasoinhibins in
neonatal rats reduced the apoptosis-mediated regression
of hyaloid vessels, a transiently existing intraocular sys-
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terone that stimulate the elongation and branching of the
mammary gland ductal system. In addition, adrenocorticotropin hormone stimulates ductal growth in cycling
females through glucocorticoid and GH release (see reviews in Refs. 250, 282). During pregnancy, progesterone,
PRL, and PL promote the proliferation, differentiation,
and maturation of the alveolar system responsible for
milk secretion (240, 409), and while PRL appears essential
for the initiation and maintenance of lactation in most
species, milk production is controlled predominantly by
GH in ruminants (44, 169). After weaning, involution returns the mammary gland to a virgin state, and both PRL
and GH help regulate mammary gland survival by protecting it against epithelial cell apoptosis and ECM degradation (31, 168, 169).
The growth and function of the mammary gland depends on an increasing supply of oxygen, nutrients, and
fluid and is therefore accompanied by the expansion of
the mammary gland vasculature during pregnancy and
enhanced vasodilation and vasopermeability during lactation (136, 352, 432), whereas this new vascular bed progressively disappears during the involution phase (432,
587). The importance of angiogenesis and specifically of
VEGF in the mammary gland is illustrated by the fact that
inactivation of the VEGF gene in the mammary gland
epithelium impairs angiogenesis and blood vessel function during lactation and leads to reduced milk production and stunted growth of the offspring (472). The fact
that hormones with effects on angiogenesis control the
growth and function of the mammary gland makes it an
attractive model for the study of the hormonal regulation
of angiogenesis.
VEGF and VEGFR2 increase in the mammary gland
during pregnancy and even more during lactation (432),
when the influence of PRL appears to be greatest (44).
PRL promotes the expression of VEGF in HC11 mouse
mammary epithelial cells (207) and in immune cells associated with mammary gland involution (207, 344). Furthermore, both PRL (301, 520) and GH (450) are expressed in mammary gland epithelial cells and may regulate VEGF levels in an autocrine manner. Consistent with
these findings, human MCF-7 mammary carcinoma cells
overexpressing human GH produce higher levels of VEGF
that promote angiogenesis in vivo and in vitro (67). The
proangiogenic actions of these hormones may be counterbalanced by their conversion to vasoinhibins, since
cathepsin D-mediated generation of vasoinhibins from
PRL increases in the lactating mammary gland (91, 325),
and the expression of various vasoinhibin-generating
MMPs is upregulated during mammary gland development and involution (216). PRL, GH, PL, and vasoinhibins
can also regulate mammary gland growth and function by
controlling peripheral vascular resistance and blood flow
to the gland. PRL can stimulate either vasodilation or
vasoconstriction, and vasoinhibins have clear vasocon-
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2. Cartilage
Cartilage is resistant to vascular invasion except during endochondral bone formation (120, 228) or in degenerative joint diseases such as rheumatoid arthritis (293).
Avascularity helps provide the elasticity, flexibility, and
strength of cartilage and results from the action of a
Physiol Rev • VOL
variety of locally produced antiangiogenic factors that
overcome the effect of multiple proangiogenic mediators
(228, 500). Vasoinhibins are among the antiangiogenic
factors produced in cartilage, since PRL is a component
of synovial fluid (411), chondrocytes are enriched in the
MMPs that convert PRL to vasoinhibins, and PRL mRNA,
PRL, and vasoinhibins have been detected in articular
chondrocytes (339). Articular chondrocytes also express
PRL receptors, and PRL promotes chondrocyte survival
(638), suggesting that both PRL and vasoinhibins act to
maintain the functional integrity of cartilage.
During endochondral ossification, hypertrophic chondrocytes of the growth plate switch their phenotype from
antiangiogenic to proangiogenic, producing factors including VEGF that attract blood vessels (120). The invading
blood vessels bring progenitor mesenchymal cells that will
later differentiate into osteoblasts and chondroclasts/osteoclasts to remodel the newly formed cartilage into bone
(120). Endochondral ossification leads to longitudinal
bone formation, a process governed by an intricate system of endocrine signals, including the GH/IGF-I axis (see
review in Ref. 402). GH promotes longitudinal bone
growth by IGF-I-independent and -dependent effects on
growth plate chondrocyte proliferation and hypertrophy,
respectively (595). It remains to be determined whether
proangiogenic effects of the GH/IGF-I axis contribute to
their actions on endochondral ossification.
V. HORMONAL CONTRIBUTION TO
ANGIOGENESIS-DEPENDENT DISEASES
As previously noted, tight regulation of angiogenesis
is required to prevent either excessive vascular growth or
aberrant vessel regression, each of which can lead to
various diseases. Consequently, the angiogenic and antiangiogenic actions of members of the GH/PRL/PL family,
the RAS, and the KKS have been linked to both the
etiology and treatment of angiogenesis-related pathologies.
A. Preeclampsia
Preeclampsia is defined as the onset of hypertension
and proteinuria after 20 wk of gestation that, if left untreated, can progress to eclampsia, a state of generalized
seizures that may harm or kill the mother or the unborn
child. This disease affects 5% of all pregnancies and is a
major cause of maternal, fetal, and neonatal morbidity
and mortality (502). Although the etiology of preeclampsia remains undefined, it is clear that the disease depends
on the placenta, as all symptoms disappear after its delivery.
Studies carried out during the last decade have
shown that antiangiogenic factors produced by the pla-
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tem of blood vessels that nourishes eye tissues during the
embryonic period (140).
An important aspect of the retinal vasculature in
mice is that its development begins during the first week
after birth, making the murine retina a valuable model in
which to study the mechanisms governing the whole angiogenesis process under physiological conditions (569).
Vascularization originates at the optic nerve in the superficial layer of the inner retina and radiates towards the
periphery, using a mesh of migrating astrocytes as a template and proangiogenic factors released by ganglion
cells, astrocytes, and endothelial cells themselves as a
guide (193, 569). GH may be among the proangiogenic
factors promoting vascular development in the retina,
since GH and the GH receptor are expressed in the ganglion cell layer and inner nuclear layer of the newborn
mouse retina at the time when retinal vascularization
occurs, and GH receptor-deficient mice show a reduction
in the width of the retina and altered levels of proteins
involved in retinal vascularization, i.e., protein kinase C
inhibitor 1, cyclophilin A, and Sam68-like mammalian protein-2 (41). Furthermore, patients with defects in the GH/
IGF-I axis exhibit reduced retinal vascularization (238,
239). The GH affecting retinal vascular development may
also be derived from the circulation, since GH levels in
the vitreous correlate with those in the systemic circulation in neonatal rats (43, 369). In addition, the RAS may
promote retinal angiogenesis in the retina during development, when AGT, prorenin, ANG II, and the AT1 and
AT2 receptors are localized in cells and blood vessels of
the ganglion cell layer of the inner retina (485). The
hypertensive transgenic m(Ren-2)27 rat model, in which
renin and ANG II are elevated in various tissues including
the retina (375), shows a more extensive development of
the peripheral retinal vasculature and a reduction in vascular density in the immature retina after ACE inhibition
(485).
Members of RAS are also expressed in the adult
retina of mammals, including humans and rats (295, 584,
605), and there is evidence for the local production of the
antiangiogenic ANG-(1–7) metabolite in the human retina
(490). Furthermore, some components of the tissue KKS
are expressed in neuronal cells of the outer nuclear layer,
inner nuclear layer, and ganglion cell layer of the adult
retina of humans (336) and rats (540), but the possible
effects of counterbalancing RAS and KKS upon physiological angiogenesis in the retina remain undefined.
PEPTIDE HORMONES AND ANGIOGENESIS
Physiol Rev • VOL
cular peripheral resistance in preeclampsia may reflect
reduced responsiveness to BK, since BK-induced vasodilation of small peripheral arteries is enhanced in normal
pregnancy and impaired in preeclampsia (288). However,
the influences of ANG-(1–7) and BK in preeclampsia remain poorly understood.
A role for PRL in the pathogenesis of preeclampsia
was suggested 30 years ago based on its osmoregulatory
and hypertensive properties (248), and interest in this
hypothesis was renewed with the discovery of the antiangiogenic and vasoconstrictive effects of vasoinhibins
(428). Although the maternal, fetal, or amniotic fluid levels of PRL do not change in preeclampsia (333, 453), a
recent study showed that urinary PRL increases in preeclamptic women in relation to the severity of the disease
(310). The association between PRL levels and adverse
outcomes in preeclampsia may reflect its conversion to
vasoinhibins. Vasoinhibins are enhanced in the amniotic
fluid, serum, and urine of preeclamptic women and may
derive from the cathepsin D-mediated cleavage of PRL in
the preeclamptic placenta (210, 310). Notably, the concentrations of PRL and vasoinhibins in the amniotic fluid
follow an inverse correlation with birth weight in preeclampsia (210), indicating the association of these proteins with the clinical manifestation of the disease. Moreover, although much needs to be learned in this regard,
there is compelling evidence that overproduction of vasoinhibins can lead to postpartum cardiomyopathy, another antiangiogenesis-dependent disease in reproduction
similar to preeclampsia in that oxidative stress is a key
factor for its etiology (243). In postpartum cardiomyopathy, cardiomyocyte-specific deletion of STAT-3 promotes
oxidative stress, thereby enhancing cathepsin D-mediated
generation of vasoinhibins, which in turn interfere with
the coronary microvasculature growth and function required for adequate performance of the maternal heart
during pregnancy and lactation (243).
B. Diabetic Retinopathy
Diabetic retinopathy is the leading cause of blindness
in working-age individuals throughout the world. After 20
years, more than 60% of patients with type 2 diabetes and
nearly all patients with type 1 diabetes develop retinopathy (171). The major risk factor is chronic hyperglycemia,
which causes the apoptosis of pericytes and endothelial
cells, the thickening of capillary basement membranes,
and enhanced vasopermeability. Hyperpermeability leads
to abnormal retinal hemodynamics and to the accumulation of extracellular fluid and hard exudates that impair
vision when the macula is affected (290). Over time, intraretinal hemorrhages and capillary occlusion create areas of ischemia; the resulting retinal hypoxia leads to the
production of local proangiogenic factors. In the more
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centa are central to the pathophysiology of preeclampsia
(for reviews, see Refs. 128, 199, 456). The syndrome is
thought to arise at an early stage of pregnancy due to
placental ischemia/hypoxia produced by defective trophoblast remodeling of the uterine spiral arteries. Hypoxia, in
association with oxidative stress and other placental abnormalities (259, 456), stimulates the release of antiangiogenic
molecules such as sVEGFR1 (247, 316, 355), soluble endoglin (sEng) (315, 318, 580), and possibly autoantibodies
against AT1 receptors (AT1-AA) (259, 594). sVEGFR1 decreases free VEGF and placental growth factor levels in
preeclampsia, leading to endothelial cell dysfunction and
inhibition of vasodilation (331, 355). Eng is part of the
TGF-␤ receptor complex, and sEng is antiangiogenic and
inhibits eNOS-mediated vasodilation (580). Furthermore,
the adenoviral expression of sVEGFR1 in pregnant rats
induces the clinical signs of preeclampsia, i.e., hypertension, proteinuria, and glomerular endotheliosis (355), and
the coexpression of both sVEGFR and sEng exacerbates
endothelial cell dysfunction leading to severe preeclampsia, including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal
growth (580). In addition, AT1-AA with agonistic properties (57, 624) increases in the circulation of women with
preeclampsia (594), and ANG II can stimulate sVEGFR1
expression in trophoblasts via AT1 receptors (647).
The influence of RAS on the pathophysiology of preeclampsia is indicated by the development of a preeclampsia-like syndrome in transgenic mice overexpressing placental renin and maternal AGT (541) and involves
multiple mechanisms (see reviews in Refs. 259, 493). Although RAS components exist in the maternal and fetal
placenta (108, 317) and at high levels in the circulation
(33, 241), vascular responsiveness to ANG II is reduced
during pregnancy (188). In contrast, components of RAS
are lower in plasma (66, 305), and vascular responsiveness to ANG II is enhanced in patients with preeclampsia
(417). Increased sensitivity to ANG II can contribute to
preeclamptic characteristics, including abnormal trophoblast invasion and spiral artery remodeling, reduced
uteroplacental blood flow, systemic vasoconstriction, and
hypertension (259). Increased ANG II sensitivity may involve elevated AT1 receptor expression, which is reported to occur in the decidua of preeclamptic women
(241), but, more importantly, heterodimers between AT1
receptors and BK B2 receptors are more abundant in
blood vessels during preeclampsia (3). AT1-B2 heterodimers induce increased ANG II-mediated signaling in
blood vessels (3) and are resistant to inactivation by
oxidative stress (2, 3, 24). On the other hand, an altered
production of the antiangiogenic, vasodilating ANG-(1–7)
metabolite may also counterbalance the actions of ANG II
in preeclampsia, since its levels increase and decrease in
the circulation during normal pregnancy and preeclampsia, respectively (64, 578). Moreover, the increased vas-
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ACE inhibition also prevents retinal neovascularization
and decreases VEGF, VEGFR2, and angiopoietin-2 expression in murine ischemia-driven retinopathy (327,
374, 388, 484) in diabetic, transgenic rats overexpressing renin and AGT in the eye (375), and in the vitreous
of patients with diabetic retinopathy (244).
In spite of the above experimental evidence, blockage of RAS has shown little or no effect on retinal blood
vessel abnormalities in clinical trials. Improvement of
diabetic retinopathy was reported after RAS blockage in
patients with normotensive type 1 diabetes (85, 86, 306),
but no beneficial effect was reported in patients with
hypertensive type 1 diabetes (151), nor in most studies of
patients with type 2 diabetes (609). The reasons for this
are unclear and may involve interaction with other members of RAS and the KKS (127, 436). For example, activation of ACE2 can counterbalance the effects of ACE and
ANG II by causing ANG II degradation and the production
of ANG-(1–7) (Fig. 3). ACE2 expression is reduced in the
diabetic retina (557), suggesting that the deleterious effect of ANG II may be exacerbated by local ACE2 deficiency. On the other hand, ACE catalyzes not only ANG II
formation, but also the degradation of the vasodilator and
proangiogenic peptide, BK. Recent evidence shows that
BK increases vasopermeability in the healthy retina, that
B1 receptors are upregulated in the retina of diabetic rats
in response to oxidative stress, and that the blockage of
both B1 and B2 receptors prevents the breakdown of the
blood-retinal barrier associated with experimental diabetes (4). Furthermore, treatment with ACE inhibitors
blocks oxidative stress and the induction of B1 receptors
in diabetic rats (114), suggesting that these actions prevent the deleterious effects of BK accumulated in response to ACE inhibitors. Importantly, members of the
KKS (prekallikrein, kallikrein, FXII, FXIIa, and HK) are
present in the vitreous of individuals with advanced diabetic retinopathy and are activated in response to and
mediate hemorrhage-induced retinal edema (189).
The contribution of the GH/IGF-I axis to the pathophysiology of diabetic retinopathy (180, 612) was described nearly four decades ago based on the elevated
circulating GH levels found in diabetic subjects (275, 445,
497), the halted progression of diabetic retinopathy after
anterior pituitary ablation (335) or radiation (496), and
the reduced incidence of the disease in GH-deficient diabetic patients (14). Moreover, evidence that IGF-I reverses protection by a GH antagonist against ischemiainduced retinopathy (510), promotes VEGF-mediated retinal angiogenesis (443, 511), and induces most of the
alterations seen in diabetic retinopathy (475) substantiates the causative role of the GH/IGF-I axis in the development of the disease.
Although IGF-I circulating levels increase as a function of the progression of diabetic retinopathy in type 1
diabetic women during pregnancy (307), most studies in
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advanced stages, the new blood vessels invade and bleed
into the vitreous, producing a fibrovascular tissue that
may result in tractional retinal detachment and blindness.
The main therapy for diabetic retinopathy is laser photocoagulation, which limits vascular leakage in the retina
and blocks the induction of proangiogenic factors by
ablating retinal ischemic areas (628). Although laser photocoagulation is effective in preventing visual loss in
many cases, it rarely improves visual acuity, may damage
peripheral and night vision, and often does not quell
progression of the disease (56). Thus new pharmacological therapies are being developed to target microvascular
abnormalities, including anti-VEGF agents, ACE blockers,
and GH inhibitors.
VEGF is a major factor enhancing vasopermeability
and inducing angiogenesis in diabetic retinopathy (68). It
is upregulated in the retina of animals with experimental
retinopathies (363, 437), and its levels increase in the
ocular fluids of patients with diabetic retinopathy (10,
507). Elevation of intraocular VEGF results in vasodilation, retinal hemorrhages, vascular leakage, and neovascularization in nondiabetic animals (100, 192, 368, 413,
558), and therapies based on the inhibition of VEGF expression and action have shown promising results as
effective and safe options for the treatment of vasoproliferative retinopathies (149, 506, 628). Although anti-VEGF
therapies still need to be evaluated in phase III clinical
trials, their use has been authorized for age-related macular degeneration, and they are currently employed by
many ophthalmologists to treat advanced diabetic retinopathy and diabetic macular edema (506).
Evidence for the role of RAS in the pathogenesis of
diabetic retinopathy has been the subject of comprehensive reviews (187, 608, 609) and stems from observations
showing that hypertension is a risk factor for the development and progression of diabetic retinopathy (287),
that chronic hyperglycemia activates RAS (19), that RAS
components are elevated in the plasma and ocular fluids
of patients with diabetic retinopathy (143, 187, 608) and,
importantly, that ACE inhibitors interfere with experimental retinopathy and reduce the onset and progression
of the disease in humans (608). ANG II promotes diabetic
retinopathy by stimulating systemic hypertension and retinal hyperperfusion and pressure, leading to shear stressmediated release of VEGF from retinal vessels (532).
However, the recent observation that an AT1 antagonist,
but not antihypertensive therapy, ameliorates vascular
pathology in the retina of certain diabetic rats implicates
actions of RAS that are independent of high blood pressure (611). Indeed, ANG II directly stimulates the expression of VEGF and VEGFR2 in retinal cells (420, 643) and
potentiates VEGF-induced proliferation of retinal capillary vessels in vitro (421). ACE inhibition reduces retinal
VEGF expression and hyperpermeability (143, 200, 643)
and restores retinal blood flow (245) in diabetic rats.
PEPTIDE HORMONES AND ANGIOGENESIS
C. Rheumatoid Arthritis
Rheumatoid arthritis is a chronic inflammatory autoimmune disorder of unknown etiology that targets the
synovial membrane, cartilage, and bone and affects 1% of
the world population (165). Autoimmunity followed by
the articular infiltration of leukocytes and the hyperplasia
of synovial cells lead to the development of an invasive,
inflammatory front, or “pannus” that destroys the adjacent cartilage and bone. The hypoxic environment of the
arthritic synovium and the action of a variety of cytokines, chemokines, and regulatory factors promote the
expression of proangiogenic substances, including VEGF
Physiol Rev • VOL
(113, 534). Subsequent angiogenesis facilitates the progression of the disease by enabling the continued accumulation of immune cells, expansion of the inflamed tissue, and swelling of the joints (32, 113). Indeed, blockage
of VEGF action (6, 332, 365, 513) ameliorates experimental arthritis, and various antirheumatic drugs have antiangiogenic properties (576). However, no clinical approval
has been obtained to use anti-VEGF therapies or other
antiangiogenic therapies in patients with rheumatoid arthritis.
Epidemiological, experimental, and clinical data
have linked GH and PRL to the pathophysiology of rheumatoid arthritis (reviewed in Refs. 347, 393). Interest in
GH is raised by the observation that growth retardation is
a major problem in juvenile rheumatoid arthritis (52),
whereas emphasis on PRL derives from rheumatoid arthritis being three times more frequent in women than in
men and the disease becoming exacerbated in the postpartum period in association with breast-feeding (229).
Notably, both GH and PRL have immunoenhancing properties (357, 635) and restore experimental arthritis in
hypophysectomized rats (50, 392); treatments with somatostatin and bromocriptine, which suppress pituitary secretion of GH and PRL, respectively, are beneficial in
experimental (353, 354) and clinical (163, 164) arthritis.
Levels of GH and PRL have been shown to increase in the
serum (492, 562, 650) and synovial fluid (131, 387) of
patients with rheumatoid arthritis. However, this issue is
controversial (452, 473, 474), and no experimental evidence has demonstrated the proangiogenic actions of GH
and PRL in the development of rheumatoid arthritis. Of
note, the finding that MMPs capable of generating vasoinhibins are upregulated in the arthritic joint (339, 539) and
that some of them are activated by locally produced PRL
(387) raises the possibility that vasoinhibins generated in
rheumatoid arthritis could help counterbalance the immunoenhancing and proangiogenic properties of the fulllength hormones.
The contribution of RAS to the pathology of rheumatoid arthritis is suggested by the observations that ANG II
has proinflammatory effects (476), that ACE, ANG II, and
AT1 receptors are upregulated in synovial tissue from
experimental arthritis (446) or from patients with rheumatoid arthritis (589, 590), and that targeting the angiotensin pathway with ACE blockers and AT1 inhibitors
attenuates experimental arthritis (121, 479) and human
inflammatory synovitis (446). Blockers of ACE activity
may exacerbate inflammation by preventing the breakdown of BK. All components of the KKS have been detected in the synovial fluid of patients with rheumatoid
arthritis (see review in Ref. 77) and are elevated in the
peptidoglycan polysaccharide-induced rat model of arthritis and systemic inflammation (154). In this model, a
BK inhibitor (105) or blockage of BK generation by an
anti-HK monoclonal antibody (154) prevents joint swell-
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nonpregnant, diabetic patients have failed to show a relationship between circulating hormones and diabetic retinopathy. Various studies have demonstrated an increase
(135, 268), decrease (157), or lack of change (181, 596) in
circulating IGF-I in association with the presence or progression of the disease. Clinical trials with the GH antagonist pegvisomant yielded negative results (222), and the
use of somatostatin analogs to block anterior pituitary GH
secretion and to promote local somatostatin antiangiogenic actions on endothelial cells generated varying outcomes (see review in Refs. 213, 424). The reasons for
these discrepancies are unclear and are likely influenced
by small patient cohorts confounded not only by systemic
factors such as glucose control, aggressive insulin treatment, and differential renal function, but also by ocular
factors that modify the systemic incorporation or the
local synthesis of GH, IGF-I, and IGF-I binding proteins
(180, 612).
Little is known regarding the involvement of PRL in
diabetic retinopathy (95). PRL may protect against diabetes, as suggested by the facts that PRL and PL promote
the function, proliferation, and survival of ␤-cells (166,
177, 183), and circulating PRL levels are often decreased
in poorly controlled diabetic patients (260) and rats (60).
However, studies measuring circulating PRL in association with diabetic retinopathy have reported increased
(373), decreased (253), or normal (81) levels. These contradictory observations may be due in part to the intraocular generation of vasoinhibins. Systemic PRL increases
and gets processed to vasoinhibins in ocular fluids and in
retrolental fibrovascular membranes of patients with retinopathy of prematurity (140), a neovascular eye disease
caused by elevated oxygen used to improve the survival of
premature neonates. Notably, vasoinhibins prevent retinal angiogenesis in ischemia-induced retinopathy (425)
and inhibit the retinal vasopermeability associated with
diabetic retinopathy (192). Nevertheless, studies addressing the endogenous levels of vasoinhibins and their proteolytic generation from PRL, GH, or PL in diabetic retinopathy are still needed.
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CLAPP ET AL.
ing and inflammation. BK inhibitors also suppress synovitis and joint erosion in collagen-induced arthritis in
mice (182). The B2 receptor is present in the normal
synovia, and the B1 receptor is upregulated in arthritic
tissue (40, 489); the B2 receptor has been proposed to
promote angiogenesis in the early stages of synovitis,
whereas the B1 receptor mediates endothelial cell proliferation in the established disease (489).
D. Cancer
Physiol Rev • VOL
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As in normal tissues, tumors depend on the blood
supply for oxygen, nutrients, and waste removal so that in
the absence of angiogenesis, tumor growth is limited to
1–2 mm in diameter (639). A key mechanism for tumor
angiogenesis is local hypoxia resulting from the persistent
and uncontrolled proliferation of tumor cells (231). Hypoxia triggers the expression of proangiogenic factors such
as VEGF, placental growth factor, and bFGF that, when
combined with oncogene-driven expression of proangiogenic peptides and inhibition of antiangiogenic agents, tilt
the angiogenic balance in favor of new vessel growth
(170, 498).
VEGF is overexpressed in 60% of all human cancers
and is the target of antiangiogenic drugs currently used
for cancer therapy that include a monoclonal anti-VEGF
antibody adapted for human use (bevacizumab) and tyrosine kinase inhibitors selective for VEGF receptors
(170). The survival benefits of anti-VEGF therapy are
small, transitory, and accompanied by some toxic side
effects (145, 283, 328). The benefits may be limited by the
fact that the tumor microenvironment contains a variety
of angiogenesis regulators besides VEGF (170). Insights
into the role of hormones may help clarify the mechanisms mediating tumor angiogenesis and contribute to
improving antiangiogenic therapies so that they continue
to be effective when resistance to VEGF inhibition develops.
The contribution of pituitary gland hormones to
mammary gland tumorigenesis was revealed more than 50
years ago when breast cancer was treated by hypophysectomy (334, 454). The regression of breast cancers resistant to anti-estrogen therapy following hypophysectomy (430) and the fact that PRL restored vulnerability to
mammary tumorigenesis in hypophysectomized rats (21)
pointed to PRL as the putative pituitary hormone essential
for mammary tumor development. The participation of
PRL in mammary cancer has been established in rodents,
where hyperprolactinemia or PRL treatment increases the
number of spontaneous mammary tumors and susceptibility to mammary carcinogens, while decreasing systemic PRL inhibits mammary tumor growth (see reviews,
in Refs. 232, 583, 600). Furthermore, immunoneutralization of PRL inhibits the development of carcinogen-in-
duced mammary tumors (362), transgenic mice overexpressing PRL develop mammary carcinomas (470, 601),
and lack of PRL receptors reduces the size of mammary
neoplastic growths (408).
PRL was initially considered irrelevant due to contrasting data provided by multiple clinical studies (reviewed in Ref. 101). Such variability was recently overcome by large, well-controlled studies showing that
higher plasma PRL levels significantly increase the relative risk of developing breast cancer in premenopausal
and postmenopausal women (230, 565, 566). In addition,
epidemiological studies support the association of both
dopamine antagonists and hyperprolactinemia with increased breast cancer risk (reviewed in Ref. 232). Of
importance, however, neoplastic breast tissue synthesizes
PRL, which is unaffected by dopamine, and it is recognized that PRL acts partly as an autocrine/paracrine promoter of mammary tumor growth (for review, see Refs.
45, 101, 583). Up to 98% of breast tumors express PRL
receptors, and receptor levels are higher in neoplastic
tissue than in adjacent normal tissue (201, 561). PRL
stimulates the growth and survival of breast cancer cells
(101, 433), and it promotes the expression of VEGF in
mammary gland cell lines (207); thus increased angiogenesis may contribute to the stimulatory action of PRL on
breast cancer. Mammary carcinomas in organ culture
have diminished ability to generate vasoinhibins from
PRL (34), and hypoxic conditions, mimicking the tumor
microenvironment, are associated with reduced secretion
of cathepsin D by a cultured pituitary adenoma cell line
(112). These findings are in contrast to the reported
greater ability of tumor cells to express and secrete cathepsin D and MMPs (423, 467), but imply that levels of
vasoinhibins could be reduced in the microenvironment
of tumors, thus creating a more favorable angiogenic
condition for tumor progression. Notably, colon (49) and
prostate (285) cancer cells overexpressing vasoinhibins
generate smaller and less vascularized tumors in mice.
In addition to PRL, the GH/IGF-I axis has been shown
in recent studies to play a key role in mammary cancer,
particularly in animal models (see reviews in Refs. 434,
598, 627). GH restores vulnerability to mammary carcinogens in hypophysectomized rats (634) and in GH-deficient rats and mice (499, 533, 552). Disruption of the GH
receptor gene inhibits oncogene-driven mammary tumorigenesis (644), and transgenic mice overexpressing a GH
antagonist (442) and mice with a liver-specific IGF-I gene
deletion (618) exhibit low incidence of chemically induced mammary tumors. Along this line, clinical studies
have reported an association between height at various
stages of development and breast cancer risk (225). High
levels of both GH (148) and IGF-I (435) have been reported in the serum of breast cancer patients, and a
correlation has been noted between elevated circulating
IGF-I and increased risk of breast cancer development in
PEPTIDE HORMONES AND ANGIOGENESIS
Physiol Rev • VOL
moted by ANG II-induced activation of AT1 receptors
(236). Studies comparing the growth and neovascularization of syngeneic tumors growing in wild-type and AT1
receptor null-mice have shown that AT1 receptors in host
cells contribute to tumor growth and angiogenesis via
VEGF synthesis (184, 256). In addition, long-term blockage of AT1 receptors leaves the AT2 receptor fully activated (606) and, because there is evidence that AT2 receptors mediate ANG II-induced inhibition of angiogenesis (47), the selective activation of only AT2 receptors
may contribute to the antiangiogenic effect of AT1 blockers. However, AT2 receptors may also be proangiogenic
(465), and an alternative pathway by which AT1 blockers
may prevent angiogenesis is by increasing the concentration of ANG II and thus its conversion to antiangiogenic
ANG-(1–7) (71, 294, 377). ACE inhibitors can also increase
circulating ANG-(1–7) by enhancing ANG I levels and
preventing ACE-mediated degradation of ANG-(1–7) (71,
83). On the other hand, inhibition of renin, leading to the
accumulation of antiangiogenic AGT, may help inhibit
tumor angiogenesis. Adenovirus-mediated gene transfer
of AGT inhibits the growth, neovascularization, and metastasis of mammary carcinomas and melanomas in mice
(61). Therefore, the outcome of RAS effects on tumor
angiogenesis depends on the balance between its various
metabolites with opposite effects on blood vessel growth.
It is noteworthy that a common side effect of anti-VEGF
cancer therapies is hypertension (328), and ACE inhibitors are frequently used in clinical trials of anti-VEGF
therapies with no reference to whether these treatments
also influence tumor angiogenesis (7).
In addition to interfering with the RAS system, ACE
inhibitors can affect tumor growth and angiogenesis by
inhibiting ACE-mediated BK degradation. Indeed, sarcoma neovascularization and growth is enhanced by the
ACE inhibitor captopril, and these effects are attenuated
by blocking the KKS with plasma kallikrein inhibitors or
B2-receptor antagonists (261). BK is increased in plasma
and ascitic fluid of some cancer patients (342, 343). Experimental data support the contribution of the KKS to
tumor angiogenesis. In mice, BK enhances vascular permeability and VEGF expression in solid and ascitic tumors (262, 617), and immunoneutralization of HK to block
its cleavage to BK inhibits the growth and neovascularization of human colon carcinoma cells (514) and murine
multiple myeloma cells (480). Also, inoculation of Walker
256 carcinoma cells into kininogen-deficient rats that cannot generate BK results in smaller and less-vascularized
tumors with a reduced VEGF content, characteristics that
are mimicked by the treatment of carcinoma-bearing, normal rats with a B2-receptor antagonist (255). B2 receptors
are highly upregulated in human and rodent cancer tissues (54, 616), and tumor angiogenesis and growth are
markedly reduced in B2 receptor-knockout mice bearing
sarcomas compared with their wild-type littermates (255).
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women (reviewed in Ref. 585). GH may act as an oncogene, since its expression in the normal human mammary
gland increases with the acquisition of proliferative lesions, and the experimental overexpression of GH transforms a human, nontumorigenic mammary epithelial cell
line into a tumorigenic, invasive phenotype (382, 434,
648).
In support of angiogenesis being among the tumorigenic effects of GH, receptors for GH are found in endothelial cells of newly formed tumor capillaries (550), and
the overexpression of GH in human mammary carcinoma
cells stimulates endothelial cell migration and tube formation in vivo dependent of VEGF (67). Also, autocrine
GH downregulates the production of the antiangiogenic
factor thrombospondin (626). The direct actions of GH in
promoting tumor growth may involve cross-talk with the
PRL receptor, which binds human GH. By overexpressing
receptor-specific ligands it was shown that the PRL receptor, but not the GH receptor, mediates the high incidence of chemically induced mammary tumors in mice
(601).
In contrast to PRL and GH, for which little is known
in malignancies other than breast cancer (for reviews see
Refs. 37, 45, 232, 627), substantial information relates RAS
members to a wide variety of cancers. The extensive use
of ACE inhibitors and AT1-receptor blockers to treat hypertension and congestive heart failure allowed the accumulation of clinical data that, nonetheless, is inconclusive
(see reviews in Refs. 7, 323). While some studies showed
that ACE inhibitors or AT1 receptor blockers reduce the
incidence of cancer of the breast, female reproductive
tract, lung (314), esophagus (508), and prostate (469),
other studies have failed to establish such an association
(179, 324, 358). Variability may relate to differences in
population profiles, type of inhibitors, pharmacological
parameters, and follow-up times. Also, the type of neoplasia appears relevant since the levels and activity of
RAS members increase in concert with the progression of
some cancers but not with others (7, 133, 153, 258, 329,
466). A naturally occurring deletion in the ACE gene
leading to its elevated expression correlates with increased susceptibility to prostate (630) and breast cancer
(575), but not to colorectal and lung cancer.
Experimental studies have provided stronger support
for the role of RAS blockers as anticancer agents. ACE
inhibitors and/or AT1 receptor antagonists inhibit tumor
growth and angiogenesis in murine models of fibrosarcoma (582), renal carcinoma (242, 367), glioblastoma
(463), hepatocellular carcinoma (631), head and neck
squamous cell carcinoma (629), Lewis lung cancer (185),
colorectal cancer metastasis to the liver (394), melanoma
(125, 144), prostate cancer (298, 570), ovarian cancer
(530), and gastric tumors (252). Blockage of RAS is frequently associated with reduced levels of VEGF (144, 298,
582), and both VEGF expression and action can be pro-
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CLAPP ET AL.
ANG II
ANG
ANG I
VI. CONCLUSIONS AND FUTURE DIRECTIONS
Members of the GH/PRL/PL family, the RAS, and the
KKS regulate a wide spectrum of biological effects that
depend on blood vessel number and function, including
organ growth and involution, vascular permeability, and inflammation. In recent years it has become evident that these
hormonal systems regulate angiogenesis by exerting both
stimulatory and inhibitory influences, but the mechanisms of
these actions are not well understood. The complexity of
hormonal involvement is evidenced by the fact that regulation of angiogenesis depends on diverse ligands, their receptors, and their multiple signaling pathways. Also, the overlapping functions of members within and among these hormonal families influence the outcome of the angiogenic
response.
Proteolytic cleavage is a mechanism shared by the PRL/
GH/PL family, the RAS, and the KKS for the release of both
positive and negative regulators of angiogenesis. Such cleavage can efficiently balance blood vessel growth and regression under physiological conditions, particularly in the female reproductive system, where members of these hormonal systems influence the growth and involution of the
various organ structures. In addition, high circulating levels
of the antiangiogenic hormonal derivatives help to maintain
the quiescent state of blood vessels in adult life, while their
downregulation in favor of proangiogenic metabolites contributes to angiogenesis-dependent diseases (Fig. 5).
Substantial evidence supports the action of PRL/GH/
PL/vasoinhibins, RAS, and KKS in controlling angiogenesis
in the reproductive organs and retina, although their putative effects in cartilage require further study. In addition,
various experimental approaches including the use of powerful genetic models have highlighted the contribution of
RAS in preeclampsia, of vasoinhibins in postpartum cardioPhysiol Rev • VOL
FIG. 5. Angiogenic balance as determined by protease action. The
transition between quiescent and active states of angiogenesis involves
the summed contribution of angiogenic and antiangiogenic factors.
Within the growth hormone/prolactin/placental lactogen (GH/PRL/PL)
family, the renin-angiotensin system, and the kallikrein-kinin system, the
actions of proteases determine whether the net action exerted on neovascularization will be inhibitory or stimulatory. Vi, vasoinhibins; AGT,
angiotensinogen; ANG II, angiotensin II; ANG-(1–7), angiotensin-(1–7);
HKa, cleaved high-molecular-weight kininogen; BK, bradykinin.
myopathy, of GH/IGF-I and RAS in diabetic retinopathy, and
of PRL/GH, RAS, and KKS in cancer. The use of selective
enzyme inhibitors and receptor blockers for RAS, dysfunctional mutations of the genes along the GH/IGF-I axis, and
treatment with agents that target this axis at various levels
have provided clinical data supporting the role of these
hormones in the control of angiogenesis-related diseases.
Nonetheless, insufficient information concerning the
regulation of angiogenesis by these hormonal families is
available, few physiological and disease conditions have
been examined in depth, many exceptions have been reported, and contrasting data are frequently encountered
due, at least in part, to differences in animal models, tissue
types, disease states, pharmacological parameters, and follow-up times. Tissue specificity is influenced by the relative
proportion of stromal cells and immune cells releasing
proangiogenic substances in response to hormone treatment. These effects also depend on the relative contribution
of circulating versus locally produced hormones, the hor-
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B1 receptors are found only in malignant tumors (548),
and evidence of their contribution to cancer comes from
studies in mice showing that both B1 and B2 receptors are
required for the growth of androgen-insensitive prostate
cancer cells (39, 522) and that a BK antagonist able to
block both B1 and B2 receptors inhibits lung cancer more
potently than does a VEGF-receptor inhibitor (82).
Blockage of BK synthesis may also prevent generation of the other product of HK cleavage, the antiangiogenic protein HKa. Experimental work shows that the
antiangiogenic domain 5 of HKa suppresses lung metastasis experimentally induced by a malignant melanoma
cell line (279). There is limited experience with BK antagonists in the clinic (reviewed in Ref. 521) and none in
relation to cancer. Both peptide and nonpeptide antagonists of BK are being developed that are more efficient
and less toxic than many of the current anticancer drugs
(523).
PEPTIDE HORMONES AND ANGIOGENESIS
NOTE ADDED IN PROOF
During the review process of the manuscript, the work showing
that cathepsin D is a primary protease for the generation of adenohypophysial vasoinhibins that was cited as unpublished observations (p.
1183) was accepted for publication (115a). Also, two seminal papers
were published showing that VEGF inhibitors, while reducing primary tumor growth, promoted tumor invasiveness and metastasis
(142a, 423a). These findings have raised significant concerns regarding the use of antiangiogenic therapies for cancer patients and highlight the need for a better understanding of local and systemic influences in the tumor and the blood vessel microenvironments that are
altered by proangiogenic factor removal.
ACKNOWLEDGMENTS
We thank Guadalupe Calderón for artistic contributions,
Gabriel Nava and Fernando López-Barrera for technical assistance, and Dorothy D. Pless for critically editing the manuscript.
Physiol Rev • VOL
Address for reprint requests and other correspondence: C.
Clapp, Instituto de Neurobiologı́a, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Queretaro, Qro. 76230, Mexico (e-mail: [email protected]).
GRANTS
This work was supported by National Council of Science
and Technology of Mexico Grants 87015, 44387, and 49292 and
by UNAM Grant 200509.
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monal clearance rate, and the production and activity of the
converting proteases. Data are surprisingly limited on the
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effects of these hormones may be used to increase the levels
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studies are needed to address the consequences of depleting
or overproducing the various hormonal metabolites and
their overlapping actions.
This review brings into focus the actions of the GH/
PRL/PL family, the RAS, and the KKS on angiogenesis.
Clearly, these hormonal systems are important in regulating the number and function of blood vessels, and numerous avenues of pharmacological intervention can be anticipated based on this research.
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