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Urotensin-II as an angiogenic factor
Peptides 31 (2010) 1219–1224
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Review
Urotensin-II as an angiogenic factor Diego Guidolin a,∗ , Giovanna Albertin a , Domenico Ribatti b a b
Department of Human, Anatomy and Physiology (Section of Anatomy), University of Padova Medical School, Via Gabelli, 65, I-35121 Padova, Italy Department of Human, Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11, I-79124 Bari, Italy
a r t i c l e
i n f o
Article history: Received 18 February 2010 Received in revised form 17 March 2010 Accepted 17 March 2010 Available online 24 March 2010 Keywords: Angiogenesis Antiangiogenesis Urotensin
a b s t r a c t Angiogenesis, the process through which new blood vessels arise from pre-existing ones, is regulated by numerous “classic” factors and other “nonclassic” regulators of angiogenesis. Among these latter urotensin-II is a cyclic 11-amino acid (human) or 15-amino acid (rodent) peptide, originally isolated from the fish urophysis, which exerts a potent systemic vasoconstrictor and hypertensive effect. This review article summarizes the literature data concerning the involvement of urotensin-II in angiogenesis. © 2010 Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . U-II/UT expression in vascular tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . U-II modulation of the angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . U-II and arterial remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signaling pathways mediating the structure modifying activity of U-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Angiogenesis, the process through which new blood vessels arise from pre-existing ones, is regulated by numerous “classic” factors, among which vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), transforming growth factors (TGFs), angiopoietins (Angs), platelet derived growth factor (PDGF), and other “nonclassic” regulators of angiogenesis. These latter include numerous endogenous peptides, among which erythropoietin (Epo), angiotensin II (Ang II), endothelins (ETs), adrenomedullin (AM), proadrenomedullin N-terminal 20 peptide (PAMP), urotensin-II (U-II), leptin, adiponectin, resistin, neuropeptide-Y, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), and substance P [55]. Findings also indicated that the pro-angiogenic action of many of these peptides could be at least partly mediated by the stimulation of VEGF and FGF-2 [55].
∗ Corresponding author. Tel.: +39 049 8272316; fax: +39 049 8272319. E-mail address: [email protected] (D. Guidolin). 0196-9781/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2010.03.022
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U-II is a cyclic 11-amino acid (human) or 15-amino acid (rodent) peptide, originally isolated from the fish urophysis, which exerts a potent systemic vasoconstrictor and hypertensive effect. U-II has been identified as an endogenous ligand of the orphan GPR-14, which has been renamed urotensin receptor (UT) [2,15]. This review article summarizes the literature data concerning the involvement of U-II in angiogenesis. 2. U-II/UT expression in vascular tissues Table 1 summarizes U-II and UT expression in vascular tissues of rats and humans. In the early studies using hybridization methods, U-II messenger RNA (mRNA) was thought to be expressed in very restricted organs such as spinal cord and medulla oblongata [2]. More sensitive real time-PCR methods, however, have revealed that mRNA encoding U-II and UT was well expressed in the heart and blood vessels, including internal thoracic artery, pulmonary artery and great saphenous vein [14,18,34,45,57,79]. Accordingly, immunohistochemical studies detected U-II-like immunoreactivity in the endothelial cells (EC) of human vascu-
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Table 1 Distribution of urotensin-II (U-II) and urotensin-II receptor (UT) in cardiovascular tissues and cells (selected references in square brackets). U-II mRNA Human
Heart
[18,45]
Aorta
[45]
Coronary arteries
Rat
Protein [18] [40] (small vessels) [7] [40] (EC) [40] (EC)
Peripheral arteries
[46]
Saphenous vein Cultured umbilical vein EC Cultured aorta EC Cultured saphenous vein EC Cultured jugular vein EC Inflammatory cells
[45] [1] [1]
[40] (EC) [60] [40] (EC) [1] [1]
[7]
[7]
Heart
[14]
Aorta Pulmonary artery Mesenteric artery Cultured cardiomyocytes Cultured neuromicrovascular EC
UT mRNA [2,18,45]
[2,45] [2]
Protein [2,18] [41] (SMC and cardiomyocytes) [41]
[45]
[38] [41] (SMC and EC) [41] (SMC)
[45] [1] [1] [1] [1] [7]
[1,41] [1] [1] [1] [7]
[34]
[79]
[79]
[79]
[67]
[67]
[67]
[24] [41] (cardiomyocytes) [32,38] [79] [32] [24] [67]
EC = endothelial cells; SMC = smooth muscle cells.
lature. Positive staining localized to the EC of large conductance arteries (including aorta, epicardial coronary, internal mammary and umbilical arteries) and capacitance vessels such as saphenous and umbilical veins with almost no detectable staining in the underlying smooth muscle or in the adventitial layer [40]. In addition, expression was detected in small resistance vessels within heart, kidney, lung, placenta, adrenal gland and in vasa vasorum of epicardial coronary arteries. Among blood vessels, U-II levels are highest in aorta > femoral artery > pulmonary artery, suggesting production in the pulmonary vasculature or the aorta with clearance of U-II in the systemic microcirculation [11,60,79]. As far as UT is concerned, the receptor appeared to be ubiquitously expressed in the cardiovascular system [57]. By using radioligand binding it was identified in human myocardium and in blood vessels of both rats and humans [24,32,38], and immunohistochemical and autoradiographical analyses confirmed the widespread localization of UT receptor protein to vascular smooth muscle cells (SMC) and EC of human arteries and veins [41]. A similar pattern of UT expression was also observed in rat vascular tissues, with the exception of rat vascular EC which exhibited levels of UT immunoreactivity generally lower than human EC or undetectable [41]. Data from studies on cultured cells are in general agreement with the expression pattern observed in tissue studies. As revealed by PCR and immunocytochemistry, rat neuromicrovascular EC were found to express U-II and UT mRNA and proteins [67] and a recent in vitro study [1] involving four populations of human EC of venous (saphenous, jugular, umbilical) and arterial (aorta) origin indicated that UT was expressed (at both mRNA and protein level) by all the EC examined, while the expression of U-II resulted more heterogeneous when compared to tissue studies. It has to be observed, however, that the expression of the peptide could be under control of paracrine regulatory processes, as demonstrated in some cell types, such as renal epithelium [69], suggesting (see [1]) the need of an intact tissue environment (lacking in the in vitro setup) for a physiological U-II expression. In particular, it was shown that U-II and UT expressions are regulated by inflammatory mediators and neurohumoral peptides. More specifically, interleukin-6, interleukin-1 and interferon-␥ increase U-II levels and UT expression [5].
Interestingly, other types of cells (such as monocytes, macrophages and lymphocytes), which do not belong to vascular tissues but interact with them, significantly express the urotensin system. In particular, monocytes and macrophages are the major cell types expressing UT receptors; lymphocytes express relatively little concentrations, although they are undoubtedly the largest producers of U-II [7]. Altogether these data strongly support the idea that, physiologically, U-II is a locally acting mediator of hemodynamic actions [40] and increasing evidence indicate that it may also play a significant part in the remodeling of vascular tissues (see [50] for a review). 3. U-II modulation of the angiogenesis The changes in function of EC play important roles in the development of the angiogenic process and a number of studies have shown that U-II can significantly modulate several EC activities. Gendron et al. [21] demonstrated a role for U-II in EC hyperpermeability, leading to an enhancement of plasma extravasations in specific vascular districts. The action of U-II appeared specific, since it was independent of the ET-1 and platelet activating factor pathways. A study by Wang et al. [72] showed that U-II up regulates the expression of collagen-I and decreases the expression and activity of matrix metalloproteinase-1 (MMP1) in human umbilical vein EC (HUVEC). In this EC type U-II was also shown to inhibit apoptosis induced by serum withdrawal [66], and in human coronary EC the peptide stimulated the expression of adhesion molecules, such as VCAM-1/ICAM-1 [12]. Furthermore, U-II has also been shown to exert a marked mitogenic action on many cell phenotypes [78]. Since EC destabilization, proliferation and migration through a remodeled extra cellular matrix are key events during the angiogenic process [58], these data strongly suggest a possible role for U-II in the regulation of angiogenesis. This point was specifically addressed by recent studies, based on in vitro and in vivo angiogenesis models (see [68]). In a study by Spinazzi et al. [67] U-II markedly stimulated the formation of capillary-like tubes by rat neuromicrovascular EC cultured on Matrigel, and image analysis showed that the effect of the peptide was of the same order of magnitude as that of FGF-2. Accordingly, U-II added to chick embryo chorioallantoic membrane (CAM),
D. Guidolin et al. / Peptides 31 (2010) 1219–1224
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Table 2 U-II-induced effects potentially relevant for angiogenesis and artery remodeling (selected references in square brackets). Endothelial cells
Hyper-permeability Inhibition of apoptosis Stimulation of cell proliferation Stimulation of the expression of adhesion molecules Stimulation of cell migration Stimulation of the capillary-like structures formation Stimulation of an angiogenic response in the CAM assay Stimulation of adrenomedullin secretion
[21] [66] [1,66] [12] [26,77] [1,67] [67] [65]
Smooth muscle cells
Stimulation of cell proliferation Induction of endothelin-1 expression Transactivation of EGFR Reduction of myointimal thickening in atherosclerotic arteries following U-II antagonism
[62,73] [70] [70] [51,54]
Monocytes/macrophages
Chemo attraction of monocytes Acceleration of foam cells formation
Cardiomyocytes
Induction of hypertrophic growth Transactivation of EGFR
[36, 64] [74] [49] [49]
CAM = chorioallantoic membrane; EGFR = epidermal growth factor receptor.
induced a strong angiogenic response. Both in vitro and in vivo pro-angiogenic effects of U-II were counteracted by Palosuran, a specific antagonist of UT (see [13]), indicating that they were mediated by the binding of U-II to its receptor. In this study FGF-2 also raised the EC proliferation rate, whereas U-II did not. Consistent with the above-mentioned data obtained on animal EC are the result of a recent study focused on different human vascular EC populations of both venous and arterial origin [1]. When tested in the Matrigel assay (see [3]) all the investigated EC exhibited a strong angiogenic response to the peptide, with the formation of a meshwork of capillary-like structures of increased density and complexity when compared to the unstimulated condition. The effect was comparable to that of FGF-2 and was counteracted by Palosuran. Interestingly, in this study U-II did not affect the proliferation rate of EC derived from adult vessels. On the contrary, U-II induced a moderate but significant increase of cell proliferation in HUVEC, a result probably linked to the peculiar profile of the fetal venous EC (see [33,80]). A U-II-stimulated increase of proliferation in HUVEC was also observed by Shi et al. [66], and U-II was also shown to promote the migration of this type of EC [26]. As reported by Xu et al. [77] UT is also expressed in endothelial progenitor cells and U-II is able to stimulate their migration. A summary of the pro-angiogenic activities of U-II is provided in Table 2. Taken together, the available data confirm that the peptide may be included in the group of “nonclassic” pro-angiogenic cytokines expressed in EC [55]. 4. U-II and arterial remodeling Angiogenesis is defined [58] as sprouting of new capillaries (intussusception is described as an alternative mechanism, see [16]) from pre-existing vessels resulting in new capillary networks. In contrast arteriogenesis describes the growth of functional collateral arteries from pre-existing arterio-arteriolar anastomoses [29]. Angiogenesis and arteriogenesis are initiated by distinct initial triggers [30]. In fact, while angiogenesis is mainly a reaction to hypoxia, initial triggers of arteriogenesis are physical forces, such as pressure changes [63] and altered shear forces [30], which induce structural adaptations including vascular wall cell proliferation and migration, and reorganization of the fibrillar or non-fibrillar extra cellular matrix of the vessel wall. In this respect it has to be observed that U-II is the most potent mammalian vasoconstrictor identified to date (see [17]). In human blood vessels studied in vitro, U-II has been shown to induce a potent vasoconstrictive effect in almost all types of arteries and veins tested [4], with approximately 10-fold, 100-fold, and 300-
fold greater potency than ET-1, serotonin, and nor-adrenaline, respectively, as evaluated in human right atrial muscles [59]. This response is attributed to direct activation of UT receptors [2,4]. However, vasoconstrictor response to U-II may be modified by the presence of an intact endothelium [39], because U-II also acts as an endothelium-dependent vasodilator [6,25,38]. Thus, the hemodynamic properties of U-II in conjunction with its significant mitogenic action [78] strongly suggest it may play a significant part in the remodeling of arteries. In this context of particular relevance data are available on U-II in pathological conditions (see [76] for a review), such as atherosclerosis and coronary artery disease (CAD). Patients with CAD were found to have significantly higher U-II plasma levels than normal patients and the severity of the disease increased proportionally to the U-II plasma levels [31]. Interestingly, U-II (both protein and mRNA) was abundantly expressed in endothelial cells, myointimal and medial smooth muscle cells of atherosclerotic human coronary arteries [18,28] in comparison to healthy arteries. As indicated by some studies, however, in atherosclerotic lesions of the human coronary arteries, U-II was mainly detected within the region of infiltrating macrophages, but not contractile SMC of tunica media or proliferated SMC of the thickened intima [39,40]. Macrophages represent important contributors in the atherosclerotic remodeling of coronary arteries. Via scavenger receptors, they take up low-density lipoprotein (LDL) and oxidizedLDL. Eventually, they become foam cells which accumulate with time, forming progressively the necrotic fibro fatty core of the lesion [50]. These cells express quite high levels of UT and it has been shown that U-II accelerates the human macrophage-derived foam cell formation [74] and acts as a chemo attractant for UT-expressing monocytes [36,64]. Another atherosclerotic remodeling process occurring in the early stages of plaque formation is intimal thickening, which involves proliferation of EC and SMC, in concert with fibroblastmediated collagen deposition. U-II was shown to positively modulate some of these cell changes: it suppresses cellular apoptosis [66] and stimulates smooth muscle cell proliferation [62,73]. Interestingly, in a rat model of carotid artery stenosis the use of UT antagonists reduced myointimal thickening and increased lumen size [54]. UT antagonism was also shown to induce a significant reduction of vessel remodeling in a mouse model of atherosclerosis [51]. Thus, several lines of evidence suggest that U-II has a functional part in the arterial remodeling processes that occur during cardiovascular disease. Table 2 reports a summary of the available data on the U-II-induced cellular events of potential relevance in this context.
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Fig. 1. Mechanisms of urotensin II-induced trophic actions in macrophages (see [74]), endothelial cells (see [26]), vascular smooth muscle cells (see [73]) and cardiomyocytes (see [49]). PLC, phospholipase-C; PKC, protein kinase C; ROCK, Rho kinase; ACAT-1, acyl-coenzyme A:cholesterol acyltransferase-1; PI3K, phosphoinositide 3-kinase; JNK, Jun N-terminal kinase; p38-MAPK, p38 mitogen-activated protein kinase; SR, scavenger receptor class A; EGFR, epidermal growth factor receptor.
5. Signaling pathways mediating the structure modifying activity of U-II At both recombinant and natively expressed UT receptors, the dissociation of U-II is essentially irreversible [76]: after 90 min only approximately 15% of [125 I] U-II was dissociated by the addition of an excess of unlabeled U-II in human SJRH30 rhabdomyosarcoma cells [19]. Furthermore, Giebing et al. [22] have demonstrated that the U-II/UT complex is internalized in a dynamin-dependent but arrestin-independent manner. After dissociation from U-II, the receptor recycles back to the plasma membrane. Thus, on removal of the agonist, the level of UT expressed at the cell surface recovers to that before U-II stimulation, indicating quantitative recycling. Both these characteristics of the U-II binding to UT are important determinants of UT functionality and may provide the molecular basis for long-lasting U-II-mediated responses. UT belongs to the class A family of G protein-coupled receptors (GPCR), which are homologous with the rhodopsin receptor and many structural features of this family can be found in UT ([48], see [53] for a review). The main transduction mechanism associated with UT is the coupling and activation of the G␣q/11 subtype of heterotrimeric G proteins [71], leading to the activation of phospholipase-C and to an increase in inositol triphosphates [61] with mobilization of intracellular Ca2+ [2]. In addition, UT may also couple to G␣i/0 proteins [81]. An increase of intracellular Ca2+ following UT stimulation by UII was reported to occur in endothelial cells from human aorta [8] and recently presented data provided evidence that in HUVEC the phospholipase-C/IP3 pathway was involved, since the cytoplasmic Ca2+ increase induced by the binding of U-II to UT is inhibited by the phospholipase-C inhibitor U73122 [26]. A significant increase of cytosolic free calcium concentration following U-II administration to cultured smooth muscle cells was observed by Chen et al. [10]. In SMC UT activation was also reported to enable a RhoA-dependent increase of cell contraction, cytoskeleton organization and proliferation [62]. Since Rho activation is usually associated with G␣12/13 coupling in GPCR, this result would suggest that UT may couple
to G␣12/13 in addition to G␣q/11 and G␣i/0 . On the other hand some controversy exists as to the role of G␣q/11 in Rho activation (see for instance [20,23]). Thus, the possibility that UT couples to G␣12/13 remains to be demonstrated. As far as the downstream signaling pathways are concerned, the involvement of extra cellular signal-regulated kinase (ERK1/2) as a result of UT stimulation is a common finding in the available literature, suggesting that this pathway plays a key role in the structure modifying effects mediated by U-II. It appeared to be activated in concert with other signaling cascades and it is noteworthy that the observed pattern of U-II-induced intracellular events exhibits differences depending on the cell type. This is not surprising, because after signal initiation from a GPCR, cell growth and differentiation are regulated by a network of interrelated signaling pathways, the relative contribution of each differs not only between receptors but also between cell types (see [43] for a review). Ziltener et al. [81] showed that U-II induced signal transduction pathways leading to the long-lasting activation ERK1/2 and PI3K-dependent cascade, with increase in cell proliferation of recombinant Chinese hamster ovary (CHO) cells expressing UT. In vascular SMC the ERK pathway was associated with the suppression of cellular apoptosis by U-II [66] and with cell migration [44] and Watanabe et al. [73] showed that U-II acts in synergy with mildly oxidized-LDL (ox-LDL) to induce vascular smooth muscle cells proliferation. The intracellular signaling mechanisms underlying this synergistic interaction were found to be through the activation of protein kinase C (PKC)/ERK and RhoA/Rho kinaserelated pathways by U-II along with simultaneous activation of the JNK pathway by ox-LDL [52,62,75]. The U-II-accelerated formation of foam cells from human macrophages was associated with an up-regulation of acylcoenzyme A:cholesterol acyltransferase-1 [74]. The intracellular mechanistic pathways involved are UT/Gq protein/c-Src/PKC/ERK and RhoA/Rho kinase in human monocyte-derived macrophages [74]. In cardiac myocytes [49] U-II was shown to potently activate both ERK1/2 and p38-MAPK (but not PI3K). Blocking these kinases
D. Guidolin et al. / Peptides 31 (2010) 1219–1224
with PD098059 and SB230580, respectively, significantly inhibited U-II-mediated hypertrophic growth and phenotipic changes (including cell enlargement and sarcomere reorganization) in these cells. Similarly using specific inhibitors of various steps of the signaling cascade the U-II-induced self-organization of HUVEC into capillary-like structures in vitro was associated with the activation of ERK1/2 and PI3K, but not p38-MAPK [26], and evidence of the involvement of ERK1/2 activation in U-II-mediated EC proliferation and inhibition of EC apoptosis was provided by Shi et al. [66]. Recently, the U-II-stimulated migration of endothelial progenitor cells was shown to involve the RhoA/Rho kinase pathway [77]. Consistent with the above mentioned patterns of downstream signaling is a study by Matsushita et al. [46] showing that in an epithelial cell line U-II can potently induce protooncogene cMyc, an immediate early response gene related to cell growth and differentiation. Thus, it could represent the end step of the abovementioned signaling cascades mediating the trophic effects of U-II. Fig. 1 summarizes the principal transduction pathways associated with U-II. It has also to be observed that some of the signaling pathways activated as a consequence of the binding of U-II to UT can, in principle, be started in several ways. Following UT stimulation, ERK1/2 can be directly activated through a cascade involving PLC and PKC (see [9,46,47,73,81]). In addition, the recently reported mechanism of ERK1/2 autophosphorilation triggered by the ␥ subunits released from activated Gq proteins [27,37] could contribute as well to the U-II-stimulated ERK1/2 activation. As far as PI3K-dependent pathways are concerned, they could be simply initiated by the elevation of intracellular calcium concentration induced by the binding between U-II and UT, as demonstrated by Liu et al. [35]. Alternative hypotheses, however, have to be considered. In fact GPCR can also indirectly activate these pathways by inducing the synthesis and release of growth factors and/or via receptor tyrosyne kinase transactivation [47]. In this respect, Shi et al. [65] showed that U-II stimulates adrenomedullin secretion in human vascular endothelial cells and Tsai et al. [70] demonstrated that in aortic smooth muscle cells the peptide induced ET-1 expression. Both these factors are characterized by well known pro-angiogenic properties (see [55]). The activation of receptors other than UT, however, also seems to play critical roles in U-II signal transduction. U-II-induced transactivation of epidermal growth factor receptor was demonstrated in SMC [70] and in cardiac myocytes [49], and Malagon et al. [42] showed a direct activation of somatostatin receptor subtypes 2 and 5 by U-II in transfected CHOK1 cells. Although further investigation is required, altogether the available data suggest that all these mechanisms could be involved in mediating the trophic and tissue remodeling activity of U-II.
6. Concluding remarks Angiogenesis is controlled by the balance between molecules that have a positive and negative regulatory activity. This concept led to the notion of the “angiogenic switch”, which depends on an increased production of one or more positive regulators of angiogenesis [56]. The contribution of each “classic” and/or “nonclassic” angiogenic factor play a different role in the definition of the angiogenic phenotype. Increased production of angiogenic stimuli and/or reduced production of “classic” and/or “nonclassic” angiogenic inhibitors may lead to abnormal neovascularization, such as that occurring in cancer, chronic inflammation, diabetic retinopathy, macular degeneration and cardiovascular disorders. Detailed knowledge of the mechanism of action and expression as well as the interaction of the “nonclassic” regulators of angiogenesis with their receptors, such as U-II, will provide new insight
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that are essential for the development of new compounds that could act as antiangiogenic molecules, useful in the treatment of angiogenesis-dependent diseases. References [1] Albertin G, Guidolin D, Sorato E, Spinazzi R, Mascarin A, Oselladore B, et al. Proangiogenic activity of Urotensin-II on different human vascular endothelial cell populations. Regul Pept 2009;157:64–71. [2] Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999;401:282–6. [3] Arnaoutova I, George J, Kleinman HK, Benton G. The endothelial cell tube formation assay on basement membrane turns 20: state of the science and the art. Angiogenesis 2009;12:267–74. [4] Behm DJ, Harrison SM, Ao Z, Maniscalco K, Pickering SJ, Grau EV, et al. Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout mice. Br J Pharmacol 2003;139:464–72. [5] Birker-Robaczewska M, Boukhandra C, Studer R, Mueller C, Binkert C, Nayler O. The expression of urotensin II receptor (U2R) is up regulated by interferon-␥. J Recept Signal Transduct Res 2003;23:289–305. [6] Bottrill FE, Douglas SA, Hiley CR, White R. Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries. Br J Pharmacol 2000;130:1865–70. [7] Bousette N, Patel L, Douglas SA, Ohlstein EH, Giaid A. Increased expression of urotensin-II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta. Atherosclerosis 2004;176:117–23. [8] Brailoiu E, Jiang X, Brailoiu GC, Yang J, Chang JK, Wang H, et al. State-dependent calcium mobilization by urotensin-II in cultured human endothelial cells. Peptides 2008;29:721–6. [9] Chen Y, Zhao M, Liu X, Yao W, Yang J, Zhang Z, et al. Urotensin II receptor in the rat airway smooth muscle and its effect on the rat airway smooth muscle cells proliferation. Chin Med Sci J 2001;16:231–5. [10] Chen YH, Zhao MW, Yao WZ, Pang YZ, Tang CS. The signal transduction pathway in the proliferation of airway smooth muscle cells induced by urotensin II. Chin Med J (Engl) 2004;117:37–41. [11] Chen YH, Yandle TG, Richards AM, Palmer SC. Urotensin II immunoreactivity in the human circulation: evidence for widespread tissue release. Clin Chem 2009;55:2040–8. [12] Cirillo P, De Rosa S, Pacileo M, Gargiulo A, Angri V, Fiorentino I, et al. Human urotensin II induces tissue factor and cellular adhesion molecules expression in human coronary endothelial cells: an emerging role for urotensin II in cardiovascular disease. J Thromb Haemost 2008;6:726–36. [13] Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, et al. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methylquinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther 2004;311:204–12. [14] Coulouarn Y, Jegou S, Tostivint H, Vaudry H, Lihrmann I. Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett 1999;457:28–32. [15] Davenport AP, Maguire JJ. Urotensin II: fish neuropeptide catches orphan receptor. Trends Pharmacol Sci 2000;21:80–92. [16] Djonov V, Makanya AN. New insights into intussusceptive angiogenesis. In: Clauss M, Breier G, editors. Mechanisms of angiogenesis. Bern: Birkhäuser Verlag; 2005. p. 17–33. [17] Douglas SA, Ohlstein EH. Urotensin receptors. In: Girdlestone D, editor. The IUPHAR compendium of receptor characterization and classification. London: IUPHAR Media; 2000. p. 365–72. [18] Douglas SA, Tayara L, Ohlstein EH, Halawa N, Giaid A. Congestive heart failure and expression of myocardial urotensin II. Lancet 2002;359:1990–7. [19] Douglas SA, Naselsky D, Ao Z, Disa J, Herold CL, Lynch F, et al. Identification and pharmacological characterization of native, functional human urotensin-II receptors in rhabdomyosarcoma cell lines. Br J Pharmacol 2004;142:921–32. [20] Dutt P, Kjoller L, Giel M, Hall A, Toksoz D. Activated Galphaq family members induce Rho GTPase activation and Rho-dependent actin filament assembly. FEBS Lett 2002;531:565–9. [21] Gendron G, Simard B, Gobeil F, Sirois P, D’Orleans-Juste P, Regoli D. Human urotensin-II enhance extravasation in specific vascular districts in Wistar rats. Can J Physiol Pharmacol 2004;82:16–21. [22] Giebing G, Tölle M, Jürgensen J, Eichhorst J, Furkert J, Beyermann M, et al. Arrestin-independent internalization and recycling of the urotensin receptor contribute to long-lasting urotensin II-mediated vasoconstriction. Circ Res 2005;97:707–15. [23] Gohla A, Harhammer R, Schultz G. The G-protein G13 but not G12 mediates signaling from lysophosphatidic acid receptor via epidermal growth factor receptor to Rho. J Biol Chem 1998;273:4653–9. [24] Gong H, Wang Y-X, Zhu Y-Z, Wang W-W, Wang M-J, Yao T, et al. Cellular distribution of GPR14 and the positive inotropic role of urotensin II in the myocardium in adult rat. J Appl Physiol 2004;97:2228–35. [25] Gray GA, Jones MR, Sharif I. Human urotensin II increases coronary perfusion pressure in the isolated rat heart: potentiation by nitric oxide synthase and cyclooxygenase inhibition. Life Sci 2001;69:175–80.
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D. Guidolin et al. / Peptides 31 (2010) 1219–1224
[26] Guidolin D, Albertin G, Oselladore B, Sorato E, Rebuffat P, Mascarin A et al. The pro-angiogenic activity of urotensin-II on human vascular endothelial cells involves ERK1/2 and PI3K signaling pathways. Regul Pept, 2010, doi:10.1016/j.regpep.2010.02.009. [27] Gutkind JS, Offermanns S. A new Gq-initiated MAPK signaling pathway in the heart. Dev Cell 2009;16:163–4. [28] Hassan GS, Douglas SA, Ohlstein EH, Giaid A. Expression of urotensin-II in human coronary atherosclerosis. Peptides 2005;26:2464–72. [29] Heil M, Schaper W. Cellular mechanisms of arteriogenesis. In: Clauss M, Breier G, editors. Mechanisms of angiogenesis. Bern: Birkhäuser Verlag; 2005. p. 181–91. [30] Heil M, Eitenmüller I, Schmitz-Rixen T, Schaper W. Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 2006;10:45–55. [31] Heringlake M, Kox T, Uzun O, Will B, Bahlmann L, Klaus S, et al. The relationship between urotensin II plasma immunoreactivity and left ventricular filling pressures in coronary artery disease. Regul Pept 2004;121:129–36. [32] Itoh H, McMaster D, Lederis K. Functional receptors for fish neuropeptide urotensin II in major rat arteries. Eur J Pharmacol 1988;149:61–6. [33] Lang I, Schweizer A, Hiden U, Ghaffari-Tabrizi N, Hagendorfer G, Bilban M, et al. Human fetal placental endothelial cells have a mature arterial and a juvenile venous phenotype with adipogenic and osteogenic differentiation potential. Differentiation 2008;76:1031–43. [34] Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams Jr DL, et al. Identification of urotensin II as the endogenous ligand for the orphan G-protein coupled receptor GPR14. Biochem Biophys Res Commun 1999;266:174–8. [35] Liu Z-M, Chen GG, Vlantis AC, Tse GM, Shum CKY, van Hasselt CA. Calciummediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells. Cell Mol Life Sci 2007;64:1428–36. [36] Loirand G, Rolli-Derkinderen M, Pacaud P. Urotensin II and atherosclerosis. Peptides 2008;29:778–82. [37] Lorenz K, Schmitt JP, Schmitteckert EM, Lohse MJ. A new type of ERK1/2 autophosphorilation causes cardiac hypertrophy. Nat Med 2009;15:75–83. [38] Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br J Pharmacol 2000;131:441–6. [39] Maguire JJ, Davenport AP. Is urotensin-II the new endothelin? Br J Pharmacol 2002;137:579–88. [40] Maguire JJ, Kuc RE, Wiley KE, Kleinz MJ, Davenport AP. Cellular distribution of immunoreactive urotensin-II in human tissues with evidence of increased expression in atherosclerosis and a greater constrictor response of small compared to large coronary arteries. Peptides 2004;25:1767–74. [41] Maguire JJ, Kuc RE, Kleinz MJ, Davenport AP. Immunocytochemical localization of the urotensin-II receptor, UT, to rat and human tissues: relevance to function. Peptides 2008;29:735–42. [42] Malagon MM, Molina M, Gahete MD, Duran-Prado M, Martinez-Fuente AJ, Alcain FJ, et al. Urotensin II and urotensin II-related peptide activate somatostatin receptor subtypes 2 and 5. Peptides 2008;29:711–20. [43] Marinissen MJ, Gutkind JS. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 2001;22:368–76. [44] Matsusaka S, Wakabayashi I. Enhancement of vascular smooth muscle cell migration by urotensin II. Naunyn Schmiedeberg’s Arch Pharmacol 2006;373:381–6. [45] Matsushita M, Shichiri M, Imai T, Iwashina M, Tanaka H, Takasu N, et al. Coexpression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues. J Hypertens 2001;19:2185–90. [46] Matsushita M, Shichiri M, Fukai N, Ozawa N, Yoshimoto T, Takasu N, et al. Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1. Endocrinology 2003;144:1825–31. [47] New DC, Wong YH. Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression. J Mol Signal 2007;2:2. [48] Onan D, Hannan RD, Thomas WG. Urotensin-II: the old kid in town. Trends Endocrinol Metab 2004;15:175–82. [49] Onan D, Pipolo L, Yang E, Hannan RD, Thomas WG. Urotensin II promotes hypertrophy of cardiac myocytes via mitogen-activated protein kinases. Mol Endocrinol 2004;18:2344–54. [50] Papadopoulos P, Bousette N, Giaid A. Urotensin-II and cardiovascular remodeling. Peptides 2008;29:764–9. [51] Papadopoulos P, Bousette N, Al-Ramli W, You Z, Behm DJ, Ohlstein EH, et al. Targeted overexpression of the human urotensin receptor transgene in smooth muscle cells: effect of UT antagonism in ApoE knockout mice fed with western diet. Atherosclerosis 2009;204:395–404. [52] Peng X, Yin H, Wang LH, Chai SB, Shu JL, Tang CS. Content and activity of the focal adhesion kinase in cultured vascular smooth muscle cells enhanced by urotensin II. Sheng Li Xue Bao 2000;52:455–8. [53] Proulx CD, Holleran BJ, Lavigne P, Escher E, Guillemette G, Leduc R. Biological properties and functional determinants of the urotensin-II receptor. Peptides 2008;29:691–9. [54] Rakowski E, Hassan GS, Dhanak D, Ohlstein EH, Douglas SA, Giaid A. A role for urotensin II in restenosis following balloon angioplasty: use of a selective UT receptor blocker. J Mol Cell Cardiol 2005;39:785–91.
[55] Ribatti D, Conconi MT, Nussdorfer GG. Nonclassic endogenous regulators of angiogenesis. Pharmacol Rev 2007;59:185–205. [56] Ribatti D, Nico B, Crivellato E, Roccaro AM, Vacca A. The history of the angiogenic switch concept. Leukemia 2007;21:44–52. [57] Richards AM, Charles C. Urotensin II in the cardiovascular system. Peptides 2004;25:1795–802. [58] Risau W. Mechanisms of angiogenesis. Nature 1997;386:671–4. [59] Russell FD, Molenaar P, O’Brien DM. Cardiostimulant effects of urotensin-II in human heart in vitro. Br J Pharmacol 2001;132:5–9. [60] Russell FD, Meyers D, galbraith AJ, Bett N, Toth I, Kearns P, et al. Elevated plasma levels of human urotensin-II immunoreactivity in congestive heart failure. Am J Physiol Heart Circ Physiol 2003;285:1576–81. [61] Saetrum Opgaard O, Nothacker H, Ehlert FJ, Krause DN. Human urotensin II mediates vasoconstriction via an increase in inositol phosphates. Eur J Pharmacol 2000;406:265–71. [62] Sauzeau V, Le Mellionec E, Bertoglio J, Scalbert E, Pacaud P, Loirand G. Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ Res 2001;88:1102–4. [63] Scheel KW, Fitzgerald EM, Martin RO, Larsen RA. The possible role of mechanical stresses on coronary collateral development during gradual coronary occlusion. In: Schaper W, editor. The pathophysiology of myocardial perfusion. Amsterdam: Elsevier/North-Holland; 1979. p. 489–518. [64] Segain JP, Rolli-Derkinderen M, Gervois N, Raingeard de la Blètière D, Loirand G, Pacaud P. Urotensin II is a new chemotactic factor for UT receptor-expressing monocytes. J Immunol 2007;179:901–9. [65] Shi X-D, Li Z-L, Wu H-C, Wang T-H, Fu Q, Yan Q-N, et al. Mechanism of urotensin II-stimulated adrenomedullin secretion in human vascular endothelial cells. Di Yi Jun Yi Da Xue Xue Bao 2005;25:791–3. [66] Shi L, Ding W, Li D, Wang Z, Jiang H, Zhang J, et al. Proliferation and anti-apoptotic effects of human urotensin II on human endothelial cells. Atherosclerosis 2006;188:260–4. [67] Spinazzi R, Albertin G, Nico B, Guidolin D, Di Liddo R, Rossi GP, et al. UrotensinII and its receptor (UT-R) are expressed in rat brain endothelial cells, and urotensin-II via UT-R stimulates angiogenesis in vivo and in vitro. Int J Mol Med 2006;18:1107–12. [68] Staton CA, Stribbling SM, Tazzyman S, Hughes R, Brown NJ, Lewis CE. Current methods for assaying angiogenesis in vitro and in vivo. Int J Exp Pathol 2004;85(5):233–48. [69] Tian L, Li C, Qi J, Fu P, Yu X, Li X, et al. Diabetes-induced upregulation of urotensin-II and its receptor plays an important role in TGF-1-mediated renal fibrosis and dysfunction. Am J Physiol Endocrinol Metab 2008;295:E1234–42. [70] Tsai C-S, Loh S-H, Liu J-C, Lin J-W, Chen Y-L, Chen C-H, et al. Urotensin IIinduced endothelin-1 expression and cell proliferation via epidermal growth factor receptor transactivation in rat aortic smooth muscle cells. Atherosclerosis 2009;206:86–94. [71] Tzanidis A, Hannan RD, Thomas WG, Onan D, Autelitano DJ, See F, et al. Direct actions of urotensin II on the heart. Implications for cardiac fibrosis and hypertrophy. Circ Res 2003;93:246–53. [72] Wang H, Mehta JL, Chen K, Zhang X, Li D. Human urotensin II modulates collagen synthesis and the expression of MMP-1 in human endothelial cells. J Cardiovasc Pharmacol 2004;44:577–81. [73] Watanabe T, Pakala R, Katagiri T, Benedict CR. Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation 2001;104:16–8. [74] Watanabe T, Suguro T, Kanome T, Sakamoto Y, Kodate S, Hagiwara T, et al. Human urotensin II accelerates foam cell formation in human monocyte derived macrophages. Hypertension 2005;46:738–44. [75] Watanabe T, Takahashi K, Kanome T, Hongo S, Miyazaki A, Koba S, et al. Human uritensin-II potentiates the mitogenic effect of mildly oxidized low-density lipoprotein on vascular smooth muscle cells: comparison with other vasoactive agents and hydrogen peroxide. Hypertens Res 2006;29:821–31. [76] Watanabe T, Arita S, Shiraishi Y, Suguro T, Sakai T, Hongo S, et al. Human urotensin II promotes hypertension and atherosclerotic cardiovascular diseases. Curr Med Chem 2009;16:550–63. [77] Xu S, Jiang H, Wu B, Yang J, Chen S. Urotensin II induces migration of endothelial progenitor cells via activation of the RhoA/Rho kinase pathway. Tohoku J Exp Med 2009;219:283–8. [78] Yoshimoto T, Matsushita M, Hirata Y. Role of urotensin II in periferal tissues as an autocrine/paracrine growth factor. Peptides 2004;25:1775–81. [79] Zhang YM, Liu WJ, Shi YZ, Gao YF, Wang LL, Cheng MX. Expressions of urotensin II and its receptor in pulmonary arteries in rats with chronic thromboembolic pulmonary hypertension. Zhonghua Jie He He Hu Xi Za Zhi 2008;31:37–41. [80] Zhang Y, Fisher N, Newey SE, Smythe J, Tatton L, Tsaknakis G, et al. The impact of proliferative potential of umbilical cord-derived endothelial progenitor cells and hypoxia on vascular tubule formation in vitro. Stem Cells Dev 2009;18:359–75. [81] Ziltener P, Mueller C, Haenig B, Scherz MW, Nayler O. Urotensin II mediates ERK1/2 phosphorilation and proliferation in GPCR14-transfected cell lines. J Recept Signal Trans Res 2002;22:155–68.
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Review
Urotensin-II as an angiogenic factor Diego Guidolin a,∗ , Giovanna Albertin a , Domenico Ribatti b a b
Department of Human, Anatomy and Physiology (Section of Anatomy), University of Padova Medical School, Via Gabelli, 65, I-35121 Padova, Italy Department of Human, Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11, I-79124 Bari, Italy
a r t i c l e
i n f o
Article history: Received 18 February 2010 Received in revised form 17 March 2010 Accepted 17 March 2010 Available online 24 March 2010 Keywords: Angiogenesis Antiangiogenesis Urotensin
a b s t r a c t Angiogenesis, the process through which new blood vessels arise from pre-existing ones, is regulated by numerous “classic” factors and other “nonclassic” regulators of angiogenesis. Among these latter urotensin-II is a cyclic 11-amino acid (human) or 15-amino acid (rodent) peptide, originally isolated from the fish urophysis, which exerts a potent systemic vasoconstrictor and hypertensive effect. This review article summarizes the literature data concerning the involvement of urotensin-II in angiogenesis. © 2010 Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . U-II/UT expression in vascular tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . U-II modulation of the angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . U-II and arterial remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signaling pathways mediating the structure modifying activity of U-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Angiogenesis, the process through which new blood vessels arise from pre-existing ones, is regulated by numerous “classic” factors, among which vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), transforming growth factors (TGFs), angiopoietins (Angs), platelet derived growth factor (PDGF), and other “nonclassic” regulators of angiogenesis. These latter include numerous endogenous peptides, among which erythropoietin (Epo), angiotensin II (Ang II), endothelins (ETs), adrenomedullin (AM), proadrenomedullin N-terminal 20 peptide (PAMP), urotensin-II (U-II), leptin, adiponectin, resistin, neuropeptide-Y, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), and substance P [55]. Findings also indicated that the pro-angiogenic action of many of these peptides could be at least partly mediated by the stimulation of VEGF and FGF-2 [55].
∗ Corresponding author. Tel.: +39 049 8272316; fax: +39 049 8272319. E-mail address: [email protected] (D. Guidolin). 0196-9781/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2010.03.022
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U-II is a cyclic 11-amino acid (human) or 15-amino acid (rodent) peptide, originally isolated from the fish urophysis, which exerts a potent systemic vasoconstrictor and hypertensive effect. U-II has been identified as an endogenous ligand of the orphan GPR-14, which has been renamed urotensin receptor (UT) [2,15]. This review article summarizes the literature data concerning the involvement of U-II in angiogenesis. 2. U-II/UT expression in vascular tissues Table 1 summarizes U-II and UT expression in vascular tissues of rats and humans. In the early studies using hybridization methods, U-II messenger RNA (mRNA) was thought to be expressed in very restricted organs such as spinal cord and medulla oblongata [2]. More sensitive real time-PCR methods, however, have revealed that mRNA encoding U-II and UT was well expressed in the heart and blood vessels, including internal thoracic artery, pulmonary artery and great saphenous vein [14,18,34,45,57,79]. Accordingly, immunohistochemical studies detected U-II-like immunoreactivity in the endothelial cells (EC) of human vascu-
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Table 1 Distribution of urotensin-II (U-II) and urotensin-II receptor (UT) in cardiovascular tissues and cells (selected references in square brackets). U-II mRNA Human
Heart
[18,45]
Aorta
[45]
Coronary arteries
Rat
Protein [18] [40] (small vessels) [7] [40] (EC) [40] (EC)
Peripheral arteries
[46]
Saphenous vein Cultured umbilical vein EC Cultured aorta EC Cultured saphenous vein EC Cultured jugular vein EC Inflammatory cells
[45] [1] [1]
[40] (EC) [60] [40] (EC) [1] [1]
[7]
[7]
Heart
[14]
Aorta Pulmonary artery Mesenteric artery Cultured cardiomyocytes Cultured neuromicrovascular EC
UT mRNA [2,18,45]
[2,45] [2]
Protein [2,18] [41] (SMC and cardiomyocytes) [41]
[45]
[38] [41] (SMC and EC) [41] (SMC)
[45] [1] [1] [1] [1] [7]
[1,41] [1] [1] [1] [7]
[34]
[79]
[79]
[79]
[67]
[67]
[67]
[24] [41] (cardiomyocytes) [32,38] [79] [32] [24] [67]
EC = endothelial cells; SMC = smooth muscle cells.
lature. Positive staining localized to the EC of large conductance arteries (including aorta, epicardial coronary, internal mammary and umbilical arteries) and capacitance vessels such as saphenous and umbilical veins with almost no detectable staining in the underlying smooth muscle or in the adventitial layer [40]. In addition, expression was detected in small resistance vessels within heart, kidney, lung, placenta, adrenal gland and in vasa vasorum of epicardial coronary arteries. Among blood vessels, U-II levels are highest in aorta > femoral artery > pulmonary artery, suggesting production in the pulmonary vasculature or the aorta with clearance of U-II in the systemic microcirculation [11,60,79]. As far as UT is concerned, the receptor appeared to be ubiquitously expressed in the cardiovascular system [57]. By using radioligand binding it was identified in human myocardium and in blood vessels of both rats and humans [24,32,38], and immunohistochemical and autoradiographical analyses confirmed the widespread localization of UT receptor protein to vascular smooth muscle cells (SMC) and EC of human arteries and veins [41]. A similar pattern of UT expression was also observed in rat vascular tissues, with the exception of rat vascular EC which exhibited levels of UT immunoreactivity generally lower than human EC or undetectable [41]. Data from studies on cultured cells are in general agreement with the expression pattern observed in tissue studies. As revealed by PCR and immunocytochemistry, rat neuromicrovascular EC were found to express U-II and UT mRNA and proteins [67] and a recent in vitro study [1] involving four populations of human EC of venous (saphenous, jugular, umbilical) and arterial (aorta) origin indicated that UT was expressed (at both mRNA and protein level) by all the EC examined, while the expression of U-II resulted more heterogeneous when compared to tissue studies. It has to be observed, however, that the expression of the peptide could be under control of paracrine regulatory processes, as demonstrated in some cell types, such as renal epithelium [69], suggesting (see [1]) the need of an intact tissue environment (lacking in the in vitro setup) for a physiological U-II expression. In particular, it was shown that U-II and UT expressions are regulated by inflammatory mediators and neurohumoral peptides. More specifically, interleukin-6, interleukin-1 and interferon-␥ increase U-II levels and UT expression [5].
Interestingly, other types of cells (such as monocytes, macrophages and lymphocytes), which do not belong to vascular tissues but interact with them, significantly express the urotensin system. In particular, monocytes and macrophages are the major cell types expressing UT receptors; lymphocytes express relatively little concentrations, although they are undoubtedly the largest producers of U-II [7]. Altogether these data strongly support the idea that, physiologically, U-II is a locally acting mediator of hemodynamic actions [40] and increasing evidence indicate that it may also play a significant part in the remodeling of vascular tissues (see [50] for a review). 3. U-II modulation of the angiogenesis The changes in function of EC play important roles in the development of the angiogenic process and a number of studies have shown that U-II can significantly modulate several EC activities. Gendron et al. [21] demonstrated a role for U-II in EC hyperpermeability, leading to an enhancement of plasma extravasations in specific vascular districts. The action of U-II appeared specific, since it was independent of the ET-1 and platelet activating factor pathways. A study by Wang et al. [72] showed that U-II up regulates the expression of collagen-I and decreases the expression and activity of matrix metalloproteinase-1 (MMP1) in human umbilical vein EC (HUVEC). In this EC type U-II was also shown to inhibit apoptosis induced by serum withdrawal [66], and in human coronary EC the peptide stimulated the expression of adhesion molecules, such as VCAM-1/ICAM-1 [12]. Furthermore, U-II has also been shown to exert a marked mitogenic action on many cell phenotypes [78]. Since EC destabilization, proliferation and migration through a remodeled extra cellular matrix are key events during the angiogenic process [58], these data strongly suggest a possible role for U-II in the regulation of angiogenesis. This point was specifically addressed by recent studies, based on in vitro and in vivo angiogenesis models (see [68]). In a study by Spinazzi et al. [67] U-II markedly stimulated the formation of capillary-like tubes by rat neuromicrovascular EC cultured on Matrigel, and image analysis showed that the effect of the peptide was of the same order of magnitude as that of FGF-2. Accordingly, U-II added to chick embryo chorioallantoic membrane (CAM),
D. Guidolin et al. / Peptides 31 (2010) 1219–1224
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Table 2 U-II-induced effects potentially relevant for angiogenesis and artery remodeling (selected references in square brackets). Endothelial cells
Hyper-permeability Inhibition of apoptosis Stimulation of cell proliferation Stimulation of the expression of adhesion molecules Stimulation of cell migration Stimulation of the capillary-like structures formation Stimulation of an angiogenic response in the CAM assay Stimulation of adrenomedullin secretion
[21] [66] [1,66] [12] [26,77] [1,67] [67] [65]
Smooth muscle cells
Stimulation of cell proliferation Induction of endothelin-1 expression Transactivation of EGFR Reduction of myointimal thickening in atherosclerotic arteries following U-II antagonism
[62,73] [70] [70] [51,54]
Monocytes/macrophages
Chemo attraction of monocytes Acceleration of foam cells formation
Cardiomyocytes
Induction of hypertrophic growth Transactivation of EGFR
[36, 64] [74] [49] [49]
CAM = chorioallantoic membrane; EGFR = epidermal growth factor receptor.
induced a strong angiogenic response. Both in vitro and in vivo pro-angiogenic effects of U-II were counteracted by Palosuran, a specific antagonist of UT (see [13]), indicating that they were mediated by the binding of U-II to its receptor. In this study FGF-2 also raised the EC proliferation rate, whereas U-II did not. Consistent with the above-mentioned data obtained on animal EC are the result of a recent study focused on different human vascular EC populations of both venous and arterial origin [1]. When tested in the Matrigel assay (see [3]) all the investigated EC exhibited a strong angiogenic response to the peptide, with the formation of a meshwork of capillary-like structures of increased density and complexity when compared to the unstimulated condition. The effect was comparable to that of FGF-2 and was counteracted by Palosuran. Interestingly, in this study U-II did not affect the proliferation rate of EC derived from adult vessels. On the contrary, U-II induced a moderate but significant increase of cell proliferation in HUVEC, a result probably linked to the peculiar profile of the fetal venous EC (see [33,80]). A U-II-stimulated increase of proliferation in HUVEC was also observed by Shi et al. [66], and U-II was also shown to promote the migration of this type of EC [26]. As reported by Xu et al. [77] UT is also expressed in endothelial progenitor cells and U-II is able to stimulate their migration. A summary of the pro-angiogenic activities of U-II is provided in Table 2. Taken together, the available data confirm that the peptide may be included in the group of “nonclassic” pro-angiogenic cytokines expressed in EC [55]. 4. U-II and arterial remodeling Angiogenesis is defined [58] as sprouting of new capillaries (intussusception is described as an alternative mechanism, see [16]) from pre-existing vessels resulting in new capillary networks. In contrast arteriogenesis describes the growth of functional collateral arteries from pre-existing arterio-arteriolar anastomoses [29]. Angiogenesis and arteriogenesis are initiated by distinct initial triggers [30]. In fact, while angiogenesis is mainly a reaction to hypoxia, initial triggers of arteriogenesis are physical forces, such as pressure changes [63] and altered shear forces [30], which induce structural adaptations including vascular wall cell proliferation and migration, and reorganization of the fibrillar or non-fibrillar extra cellular matrix of the vessel wall. In this respect it has to be observed that U-II is the most potent mammalian vasoconstrictor identified to date (see [17]). In human blood vessels studied in vitro, U-II has been shown to induce a potent vasoconstrictive effect in almost all types of arteries and veins tested [4], with approximately 10-fold, 100-fold, and 300-
fold greater potency than ET-1, serotonin, and nor-adrenaline, respectively, as evaluated in human right atrial muscles [59]. This response is attributed to direct activation of UT receptors [2,4]. However, vasoconstrictor response to U-II may be modified by the presence of an intact endothelium [39], because U-II also acts as an endothelium-dependent vasodilator [6,25,38]. Thus, the hemodynamic properties of U-II in conjunction with its significant mitogenic action [78] strongly suggest it may play a significant part in the remodeling of arteries. In this context of particular relevance data are available on U-II in pathological conditions (see [76] for a review), such as atherosclerosis and coronary artery disease (CAD). Patients with CAD were found to have significantly higher U-II plasma levels than normal patients and the severity of the disease increased proportionally to the U-II plasma levels [31]. Interestingly, U-II (both protein and mRNA) was abundantly expressed in endothelial cells, myointimal and medial smooth muscle cells of atherosclerotic human coronary arteries [18,28] in comparison to healthy arteries. As indicated by some studies, however, in atherosclerotic lesions of the human coronary arteries, U-II was mainly detected within the region of infiltrating macrophages, but not contractile SMC of tunica media or proliferated SMC of the thickened intima [39,40]. Macrophages represent important contributors in the atherosclerotic remodeling of coronary arteries. Via scavenger receptors, they take up low-density lipoprotein (LDL) and oxidizedLDL. Eventually, they become foam cells which accumulate with time, forming progressively the necrotic fibro fatty core of the lesion [50]. These cells express quite high levels of UT and it has been shown that U-II accelerates the human macrophage-derived foam cell formation [74] and acts as a chemo attractant for UT-expressing monocytes [36,64]. Another atherosclerotic remodeling process occurring in the early stages of plaque formation is intimal thickening, which involves proliferation of EC and SMC, in concert with fibroblastmediated collagen deposition. U-II was shown to positively modulate some of these cell changes: it suppresses cellular apoptosis [66] and stimulates smooth muscle cell proliferation [62,73]. Interestingly, in a rat model of carotid artery stenosis the use of UT antagonists reduced myointimal thickening and increased lumen size [54]. UT antagonism was also shown to induce a significant reduction of vessel remodeling in a mouse model of atherosclerosis [51]. Thus, several lines of evidence suggest that U-II has a functional part in the arterial remodeling processes that occur during cardiovascular disease. Table 2 reports a summary of the available data on the U-II-induced cellular events of potential relevance in this context.
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Fig. 1. Mechanisms of urotensin II-induced trophic actions in macrophages (see [74]), endothelial cells (see [26]), vascular smooth muscle cells (see [73]) and cardiomyocytes (see [49]). PLC, phospholipase-C; PKC, protein kinase C; ROCK, Rho kinase; ACAT-1, acyl-coenzyme A:cholesterol acyltransferase-1; PI3K, phosphoinositide 3-kinase; JNK, Jun N-terminal kinase; p38-MAPK, p38 mitogen-activated protein kinase; SR, scavenger receptor class A; EGFR, epidermal growth factor receptor.
5. Signaling pathways mediating the structure modifying activity of U-II At both recombinant and natively expressed UT receptors, the dissociation of U-II is essentially irreversible [76]: after 90 min only approximately 15% of [125 I] U-II was dissociated by the addition of an excess of unlabeled U-II in human SJRH30 rhabdomyosarcoma cells [19]. Furthermore, Giebing et al. [22] have demonstrated that the U-II/UT complex is internalized in a dynamin-dependent but arrestin-independent manner. After dissociation from U-II, the receptor recycles back to the plasma membrane. Thus, on removal of the agonist, the level of UT expressed at the cell surface recovers to that before U-II stimulation, indicating quantitative recycling. Both these characteristics of the U-II binding to UT are important determinants of UT functionality and may provide the molecular basis for long-lasting U-II-mediated responses. UT belongs to the class A family of G protein-coupled receptors (GPCR), which are homologous with the rhodopsin receptor and many structural features of this family can be found in UT ([48], see [53] for a review). The main transduction mechanism associated with UT is the coupling and activation of the G␣q/11 subtype of heterotrimeric G proteins [71], leading to the activation of phospholipase-C and to an increase in inositol triphosphates [61] with mobilization of intracellular Ca2+ [2]. In addition, UT may also couple to G␣i/0 proteins [81]. An increase of intracellular Ca2+ following UT stimulation by UII was reported to occur in endothelial cells from human aorta [8] and recently presented data provided evidence that in HUVEC the phospholipase-C/IP3 pathway was involved, since the cytoplasmic Ca2+ increase induced by the binding of U-II to UT is inhibited by the phospholipase-C inhibitor U73122 [26]. A significant increase of cytosolic free calcium concentration following U-II administration to cultured smooth muscle cells was observed by Chen et al. [10]. In SMC UT activation was also reported to enable a RhoA-dependent increase of cell contraction, cytoskeleton organization and proliferation [62]. Since Rho activation is usually associated with G␣12/13 coupling in GPCR, this result would suggest that UT may couple
to G␣12/13 in addition to G␣q/11 and G␣i/0 . On the other hand some controversy exists as to the role of G␣q/11 in Rho activation (see for instance [20,23]). Thus, the possibility that UT couples to G␣12/13 remains to be demonstrated. As far as the downstream signaling pathways are concerned, the involvement of extra cellular signal-regulated kinase (ERK1/2) as a result of UT stimulation is a common finding in the available literature, suggesting that this pathway plays a key role in the structure modifying effects mediated by U-II. It appeared to be activated in concert with other signaling cascades and it is noteworthy that the observed pattern of U-II-induced intracellular events exhibits differences depending on the cell type. This is not surprising, because after signal initiation from a GPCR, cell growth and differentiation are regulated by a network of interrelated signaling pathways, the relative contribution of each differs not only between receptors but also between cell types (see [43] for a review). Ziltener et al. [81] showed that U-II induced signal transduction pathways leading to the long-lasting activation ERK1/2 and PI3K-dependent cascade, with increase in cell proliferation of recombinant Chinese hamster ovary (CHO) cells expressing UT. In vascular SMC the ERK pathway was associated with the suppression of cellular apoptosis by U-II [66] and with cell migration [44] and Watanabe et al. [73] showed that U-II acts in synergy with mildly oxidized-LDL (ox-LDL) to induce vascular smooth muscle cells proliferation. The intracellular signaling mechanisms underlying this synergistic interaction were found to be through the activation of protein kinase C (PKC)/ERK and RhoA/Rho kinaserelated pathways by U-II along with simultaneous activation of the JNK pathway by ox-LDL [52,62,75]. The U-II-accelerated formation of foam cells from human macrophages was associated with an up-regulation of acylcoenzyme A:cholesterol acyltransferase-1 [74]. The intracellular mechanistic pathways involved are UT/Gq protein/c-Src/PKC/ERK and RhoA/Rho kinase in human monocyte-derived macrophages [74]. In cardiac myocytes [49] U-II was shown to potently activate both ERK1/2 and p38-MAPK (but not PI3K). Blocking these kinases
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with PD098059 and SB230580, respectively, significantly inhibited U-II-mediated hypertrophic growth and phenotipic changes (including cell enlargement and sarcomere reorganization) in these cells. Similarly using specific inhibitors of various steps of the signaling cascade the U-II-induced self-organization of HUVEC into capillary-like structures in vitro was associated with the activation of ERK1/2 and PI3K, but not p38-MAPK [26], and evidence of the involvement of ERK1/2 activation in U-II-mediated EC proliferation and inhibition of EC apoptosis was provided by Shi et al. [66]. Recently, the U-II-stimulated migration of endothelial progenitor cells was shown to involve the RhoA/Rho kinase pathway [77]. Consistent with the above mentioned patterns of downstream signaling is a study by Matsushita et al. [46] showing that in an epithelial cell line U-II can potently induce protooncogene cMyc, an immediate early response gene related to cell growth and differentiation. Thus, it could represent the end step of the abovementioned signaling cascades mediating the trophic effects of U-II. Fig. 1 summarizes the principal transduction pathways associated with U-II. It has also to be observed that some of the signaling pathways activated as a consequence of the binding of U-II to UT can, in principle, be started in several ways. Following UT stimulation, ERK1/2 can be directly activated through a cascade involving PLC and PKC (see [9,46,47,73,81]). In addition, the recently reported mechanism of ERK1/2 autophosphorilation triggered by the ␥ subunits released from activated Gq proteins [27,37] could contribute as well to the U-II-stimulated ERK1/2 activation. As far as PI3K-dependent pathways are concerned, they could be simply initiated by the elevation of intracellular calcium concentration induced by the binding between U-II and UT, as demonstrated by Liu et al. [35]. Alternative hypotheses, however, have to be considered. In fact GPCR can also indirectly activate these pathways by inducing the synthesis and release of growth factors and/or via receptor tyrosyne kinase transactivation [47]. In this respect, Shi et al. [65] showed that U-II stimulates adrenomedullin secretion in human vascular endothelial cells and Tsai et al. [70] demonstrated that in aortic smooth muscle cells the peptide induced ET-1 expression. Both these factors are characterized by well known pro-angiogenic properties (see [55]). The activation of receptors other than UT, however, also seems to play critical roles in U-II signal transduction. U-II-induced transactivation of epidermal growth factor receptor was demonstrated in SMC [70] and in cardiac myocytes [49], and Malagon et al. [42] showed a direct activation of somatostatin receptor subtypes 2 and 5 by U-II in transfected CHOK1 cells. Although further investigation is required, altogether the available data suggest that all these mechanisms could be involved in mediating the trophic and tissue remodeling activity of U-II.
6. Concluding remarks Angiogenesis is controlled by the balance between molecules that have a positive and negative regulatory activity. This concept led to the notion of the “angiogenic switch”, which depends on an increased production of one or more positive regulators of angiogenesis [56]. The contribution of each “classic” and/or “nonclassic” angiogenic factor play a different role in the definition of the angiogenic phenotype. Increased production of angiogenic stimuli and/or reduced production of “classic” and/or “nonclassic” angiogenic inhibitors may lead to abnormal neovascularization, such as that occurring in cancer, chronic inflammation, diabetic retinopathy, macular degeneration and cardiovascular disorders. Detailed knowledge of the mechanism of action and expression as well as the interaction of the “nonclassic” regulators of angiogenesis with their receptors, such as U-II, will provide new insight
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that are essential for the development of new compounds that could act as antiangiogenic molecules, useful in the treatment of angiogenesis-dependent diseases. References [1] Albertin G, Guidolin D, Sorato E, Spinazzi R, Mascarin A, Oselladore B, et al. Proangiogenic activity of Urotensin-II on different human vascular endothelial cell populations. Regul Pept 2009;157:64–71. [2] Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999;401:282–6. [3] Arnaoutova I, George J, Kleinman HK, Benton G. The endothelial cell tube formation assay on basement membrane turns 20: state of the science and the art. Angiogenesis 2009;12:267–74. [4] Behm DJ, Harrison SM, Ao Z, Maniscalco K, Pickering SJ, Grau EV, et al. Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout mice. Br J Pharmacol 2003;139:464–72. [5] Birker-Robaczewska M, Boukhandra C, Studer R, Mueller C, Binkert C, Nayler O. The expression of urotensin II receptor (U2R) is up regulated by interferon-␥. J Recept Signal Transduct Res 2003;23:289–305. [6] Bottrill FE, Douglas SA, Hiley CR, White R. Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries. Br J Pharmacol 2000;130:1865–70. [7] Bousette N, Patel L, Douglas SA, Ohlstein EH, Giaid A. Increased expression of urotensin-II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta. Atherosclerosis 2004;176:117–23. [8] Brailoiu E, Jiang X, Brailoiu GC, Yang J, Chang JK, Wang H, et al. State-dependent calcium mobilization by urotensin-II in cultured human endothelial cells. Peptides 2008;29:721–6. [9] Chen Y, Zhao M, Liu X, Yao W, Yang J, Zhang Z, et al. Urotensin II receptor in the rat airway smooth muscle and its effect on the rat airway smooth muscle cells proliferation. Chin Med Sci J 2001;16:231–5. [10] Chen YH, Zhao MW, Yao WZ, Pang YZ, Tang CS. The signal transduction pathway in the proliferation of airway smooth muscle cells induced by urotensin II. Chin Med J (Engl) 2004;117:37–41. [11] Chen YH, Yandle TG, Richards AM, Palmer SC. Urotensin II immunoreactivity in the human circulation: evidence for widespread tissue release. Clin Chem 2009;55:2040–8. [12] Cirillo P, De Rosa S, Pacileo M, Gargiulo A, Angri V, Fiorentino I, et al. Human urotensin II induces tissue factor and cellular adhesion molecules expression in human coronary endothelial cells: an emerging role for urotensin II in cardiovascular disease. J Thromb Haemost 2008;6:726–36. [13] Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, et al. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methylquinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther 2004;311:204–12. [14] Coulouarn Y, Jegou S, Tostivint H, Vaudry H, Lihrmann I. Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett 1999;457:28–32. [15] Davenport AP, Maguire JJ. Urotensin II: fish neuropeptide catches orphan receptor. Trends Pharmacol Sci 2000;21:80–92. [16] Djonov V, Makanya AN. New insights into intussusceptive angiogenesis. In: Clauss M, Breier G, editors. Mechanisms of angiogenesis. Bern: Birkhäuser Verlag; 2005. p. 17–33. [17] Douglas SA, Ohlstein EH. Urotensin receptors. In: Girdlestone D, editor. The IUPHAR compendium of receptor characterization and classification. London: IUPHAR Media; 2000. p. 365–72. [18] Douglas SA, Tayara L, Ohlstein EH, Halawa N, Giaid A. Congestive heart failure and expression of myocardial urotensin II. Lancet 2002;359:1990–7. [19] Douglas SA, Naselsky D, Ao Z, Disa J, Herold CL, Lynch F, et al. Identification and pharmacological characterization of native, functional human urotensin-II receptors in rhabdomyosarcoma cell lines. Br J Pharmacol 2004;142:921–32. [20] Dutt P, Kjoller L, Giel M, Hall A, Toksoz D. Activated Galphaq family members induce Rho GTPase activation and Rho-dependent actin filament assembly. FEBS Lett 2002;531:565–9. [21] Gendron G, Simard B, Gobeil F, Sirois P, D’Orleans-Juste P, Regoli D. Human urotensin-II enhance extravasation in specific vascular districts in Wistar rats. Can J Physiol Pharmacol 2004;82:16–21. [22] Giebing G, Tölle M, Jürgensen J, Eichhorst J, Furkert J, Beyermann M, et al. Arrestin-independent internalization and recycling of the urotensin receptor contribute to long-lasting urotensin II-mediated vasoconstriction. Circ Res 2005;97:707–15. [23] Gohla A, Harhammer R, Schultz G. The G-protein G13 but not G12 mediates signaling from lysophosphatidic acid receptor via epidermal growth factor receptor to Rho. J Biol Chem 1998;273:4653–9. [24] Gong H, Wang Y-X, Zhu Y-Z, Wang W-W, Wang M-J, Yao T, et al. Cellular distribution of GPR14 and the positive inotropic role of urotensin II in the myocardium in adult rat. J Appl Physiol 2004;97:2228–35. [25] Gray GA, Jones MR, Sharif I. Human urotensin II increases coronary perfusion pressure in the isolated rat heart: potentiation by nitric oxide synthase and cyclooxygenase inhibition. Life Sci 2001;69:175–80.
1224
D. Guidolin et al. / Peptides 31 (2010) 1219–1224
[26] Guidolin D, Albertin G, Oselladore B, Sorato E, Rebuffat P, Mascarin A et al. The pro-angiogenic activity of urotensin-II on human vascular endothelial cells involves ERK1/2 and PI3K signaling pathways. Regul Pept, 2010, doi:10.1016/j.regpep.2010.02.009. [27] Gutkind JS, Offermanns S. A new Gq-initiated MAPK signaling pathway in the heart. Dev Cell 2009;16:163–4. [28] Hassan GS, Douglas SA, Ohlstein EH, Giaid A. Expression of urotensin-II in human coronary atherosclerosis. Peptides 2005;26:2464–72. [29] Heil M, Schaper W. Cellular mechanisms of arteriogenesis. In: Clauss M, Breier G, editors. Mechanisms of angiogenesis. Bern: Birkhäuser Verlag; 2005. p. 181–91. [30] Heil M, Eitenmüller I, Schmitz-Rixen T, Schaper W. Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 2006;10:45–55. [31] Heringlake M, Kox T, Uzun O, Will B, Bahlmann L, Klaus S, et al. The relationship between urotensin II plasma immunoreactivity and left ventricular filling pressures in coronary artery disease. Regul Pept 2004;121:129–36. [32] Itoh H, McMaster D, Lederis K. Functional receptors for fish neuropeptide urotensin II in major rat arteries. Eur J Pharmacol 1988;149:61–6. [33] Lang I, Schweizer A, Hiden U, Ghaffari-Tabrizi N, Hagendorfer G, Bilban M, et al. Human fetal placental endothelial cells have a mature arterial and a juvenile venous phenotype with adipogenic and osteogenic differentiation potential. Differentiation 2008;76:1031–43. [34] Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams Jr DL, et al. Identification of urotensin II as the endogenous ligand for the orphan G-protein coupled receptor GPR14. Biochem Biophys Res Commun 1999;266:174–8. [35] Liu Z-M, Chen GG, Vlantis AC, Tse GM, Shum CKY, van Hasselt CA. Calciummediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells. Cell Mol Life Sci 2007;64:1428–36. [36] Loirand G, Rolli-Derkinderen M, Pacaud P. Urotensin II and atherosclerosis. Peptides 2008;29:778–82. [37] Lorenz K, Schmitt JP, Schmitteckert EM, Lohse MJ. A new type of ERK1/2 autophosphorilation causes cardiac hypertrophy. Nat Med 2009;15:75–83. [38] Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br J Pharmacol 2000;131:441–6. [39] Maguire JJ, Davenport AP. Is urotensin-II the new endothelin? Br J Pharmacol 2002;137:579–88. [40] Maguire JJ, Kuc RE, Wiley KE, Kleinz MJ, Davenport AP. Cellular distribution of immunoreactive urotensin-II in human tissues with evidence of increased expression in atherosclerosis and a greater constrictor response of small compared to large coronary arteries. Peptides 2004;25:1767–74. [41] Maguire JJ, Kuc RE, Kleinz MJ, Davenport AP. Immunocytochemical localization of the urotensin-II receptor, UT, to rat and human tissues: relevance to function. Peptides 2008;29:735–42. [42] Malagon MM, Molina M, Gahete MD, Duran-Prado M, Martinez-Fuente AJ, Alcain FJ, et al. Urotensin II and urotensin II-related peptide activate somatostatin receptor subtypes 2 and 5. Peptides 2008;29:711–20. [43] Marinissen MJ, Gutkind JS. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 2001;22:368–76. [44] Matsusaka S, Wakabayashi I. Enhancement of vascular smooth muscle cell migration by urotensin II. Naunyn Schmiedeberg’s Arch Pharmacol 2006;373:381–6. [45] Matsushita M, Shichiri M, Imai T, Iwashina M, Tanaka H, Takasu N, et al. Coexpression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues. J Hypertens 2001;19:2185–90. [46] Matsushita M, Shichiri M, Fukai N, Ozawa N, Yoshimoto T, Takasu N, et al. Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1. Endocrinology 2003;144:1825–31. [47] New DC, Wong YH. Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression. J Mol Signal 2007;2:2. [48] Onan D, Hannan RD, Thomas WG. Urotensin-II: the old kid in town. Trends Endocrinol Metab 2004;15:175–82. [49] Onan D, Pipolo L, Yang E, Hannan RD, Thomas WG. Urotensin II promotes hypertrophy of cardiac myocytes via mitogen-activated protein kinases. Mol Endocrinol 2004;18:2344–54. [50] Papadopoulos P, Bousette N, Giaid A. Urotensin-II and cardiovascular remodeling. Peptides 2008;29:764–9. [51] Papadopoulos P, Bousette N, Al-Ramli W, You Z, Behm DJ, Ohlstein EH, et al. Targeted overexpression of the human urotensin receptor transgene in smooth muscle cells: effect of UT antagonism in ApoE knockout mice fed with western diet. Atherosclerosis 2009;204:395–404. [52] Peng X, Yin H, Wang LH, Chai SB, Shu JL, Tang CS. Content and activity of the focal adhesion kinase in cultured vascular smooth muscle cells enhanced by urotensin II. Sheng Li Xue Bao 2000;52:455–8. [53] Proulx CD, Holleran BJ, Lavigne P, Escher E, Guillemette G, Leduc R. Biological properties and functional determinants of the urotensin-II receptor. Peptides 2008;29:691–9. [54] Rakowski E, Hassan GS, Dhanak D, Ohlstein EH, Douglas SA, Giaid A. A role for urotensin II in restenosis following balloon angioplasty: use of a selective UT receptor blocker. J Mol Cell Cardiol 2005;39:785–91.
[55] Ribatti D, Conconi MT, Nussdorfer GG. Nonclassic endogenous regulators of angiogenesis. Pharmacol Rev 2007;59:185–205. [56] Ribatti D, Nico B, Crivellato E, Roccaro AM, Vacca A. The history of the angiogenic switch concept. Leukemia 2007;21:44–52. [57] Richards AM, Charles C. Urotensin II in the cardiovascular system. Peptides 2004;25:1795–802. [58] Risau W. Mechanisms of angiogenesis. Nature 1997;386:671–4. [59] Russell FD, Molenaar P, O’Brien DM. Cardiostimulant effects of urotensin-II in human heart in vitro. Br J Pharmacol 2001;132:5–9. [60] Russell FD, Meyers D, galbraith AJ, Bett N, Toth I, Kearns P, et al. Elevated plasma levels of human urotensin-II immunoreactivity in congestive heart failure. Am J Physiol Heart Circ Physiol 2003;285:1576–81. [61] Saetrum Opgaard O, Nothacker H, Ehlert FJ, Krause DN. Human urotensin II mediates vasoconstriction via an increase in inositol phosphates. Eur J Pharmacol 2000;406:265–71. [62] Sauzeau V, Le Mellionec E, Bertoglio J, Scalbert E, Pacaud P, Loirand G. Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ Res 2001;88:1102–4. [63] Scheel KW, Fitzgerald EM, Martin RO, Larsen RA. The possible role of mechanical stresses on coronary collateral development during gradual coronary occlusion. In: Schaper W, editor. The pathophysiology of myocardial perfusion. Amsterdam: Elsevier/North-Holland; 1979. p. 489–518. [64] Segain JP, Rolli-Derkinderen M, Gervois N, Raingeard de la Blètière D, Loirand G, Pacaud P. Urotensin II is a new chemotactic factor for UT receptor-expressing monocytes. J Immunol 2007;179:901–9. [65] Shi X-D, Li Z-L, Wu H-C, Wang T-H, Fu Q, Yan Q-N, et al. Mechanism of urotensin II-stimulated adrenomedullin secretion in human vascular endothelial cells. Di Yi Jun Yi Da Xue Xue Bao 2005;25:791–3. [66] Shi L, Ding W, Li D, Wang Z, Jiang H, Zhang J, et al. Proliferation and anti-apoptotic effects of human urotensin II on human endothelial cells. Atherosclerosis 2006;188:260–4. [67] Spinazzi R, Albertin G, Nico B, Guidolin D, Di Liddo R, Rossi GP, et al. UrotensinII and its receptor (UT-R) are expressed in rat brain endothelial cells, and urotensin-II via UT-R stimulates angiogenesis in vivo and in vitro. Int J Mol Med 2006;18:1107–12. [68] Staton CA, Stribbling SM, Tazzyman S, Hughes R, Brown NJ, Lewis CE. Current methods for assaying angiogenesis in vitro and in vivo. Int J Exp Pathol 2004;85(5):233–48. [69] Tian L, Li C, Qi J, Fu P, Yu X, Li X, et al. Diabetes-induced upregulation of urotensin-II and its receptor plays an important role in TGF-1-mediated renal fibrosis and dysfunction. Am J Physiol Endocrinol Metab 2008;295:E1234–42. [70] Tsai C-S, Loh S-H, Liu J-C, Lin J-W, Chen Y-L, Chen C-H, et al. Urotensin IIinduced endothelin-1 expression and cell proliferation via epidermal growth factor receptor transactivation in rat aortic smooth muscle cells. Atherosclerosis 2009;206:86–94. [71] Tzanidis A, Hannan RD, Thomas WG, Onan D, Autelitano DJ, See F, et al. Direct actions of urotensin II on the heart. Implications for cardiac fibrosis and hypertrophy. Circ Res 2003;93:246–53. [72] Wang H, Mehta JL, Chen K, Zhang X, Li D. Human urotensin II modulates collagen synthesis and the expression of MMP-1 in human endothelial cells. J Cardiovasc Pharmacol 2004;44:577–81. [73] Watanabe T, Pakala R, Katagiri T, Benedict CR. Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation 2001;104:16–8. [74] Watanabe T, Suguro T, Kanome T, Sakamoto Y, Kodate S, Hagiwara T, et al. Human urotensin II accelerates foam cell formation in human monocyte derived macrophages. Hypertension 2005;46:738–44. [75] Watanabe T, Takahashi K, Kanome T, Hongo S, Miyazaki A, Koba S, et al. Human uritensin-II potentiates the mitogenic effect of mildly oxidized low-density lipoprotein on vascular smooth muscle cells: comparison with other vasoactive agents and hydrogen peroxide. Hypertens Res 2006;29:821–31. [76] Watanabe T, Arita S, Shiraishi Y, Suguro T, Sakai T, Hongo S, et al. Human urotensin II promotes hypertension and atherosclerotic cardiovascular diseases. Curr Med Chem 2009;16:550–63. [77] Xu S, Jiang H, Wu B, Yang J, Chen S. Urotensin II induces migration of endothelial progenitor cells via activation of the RhoA/Rho kinase pathway. Tohoku J Exp Med 2009;219:283–8. [78] Yoshimoto T, Matsushita M, Hirata Y. Role of urotensin II in periferal tissues as an autocrine/paracrine growth factor. Peptides 2004;25:1775–81. [79] Zhang YM, Liu WJ, Shi YZ, Gao YF, Wang LL, Cheng MX. Expressions of urotensin II and its receptor in pulmonary arteries in rats with chronic thromboembolic pulmonary hypertension. Zhonghua Jie He He Hu Xi Za Zhi 2008;31:37–41. [80] Zhang Y, Fisher N, Newey SE, Smythe J, Tatton L, Tsaknakis G, et al. The impact of proliferative potential of umbilical cord-derived endothelial progenitor cells and hypoxia on vascular tubule formation in vitro. Stem Cells Dev 2009;18:359–75. [81] Ziltener P, Mueller C, Haenig B, Scherz MW, Nayler O. Urotensin II mediates ERK1/2 phosphorilation and proliferation in GPCR14-transfected cell lines. J Recept Signal Trans Res 2002;22:155–68.