ET-1 participates in the remodeling of large and small arteries found in hypertension (18). In some models of experimental hypertension, particularly those that are salt-induced, such as DOCA-salt hypertension or in Dahl salt-sensitive rats, as well as in severe hypertension, there is typically hypertrophic remodeling of resistance arteries with increased cross-sectional area rather than the eutrophic remodeling without true vascular hypertrophy more often found in essential hypertension and in spontaneously hypertensive rats (SHR) (18). This hypertrophic remodeling appears to be the signature of an effect of ET-1 (19,20), in contrast to the effects of endogenous Ang II, which is associated with eutrophic remodeling (21). Collagen deposition participates in the remodeling occurring in hypertension. EGF receptor transactivation appears to play an important role in the vascular fibrotic component of remodeling (22). In transgenic mice harboring the luciferase gene under the control of the collagen I-a2 chain promoter, ET-1 induced a rapid phosphorylation of the mitogen-activated protein kinase (MAPK) and activation of the collagen I gene in aorta, effect that was blocked by an EGF receptor phospho-rylation inhibitor, and by a blocker of MAPK. The EGF receptor inhibitor also reduced vasoconstrictor effects in vitro and pressor responses in vivo to ET-1.
We recently created a genetically engineered mouse that transgenically expresses human preproET-1 limited to the endothelium (by use of the endothelium-specific promoter Tie-2) (23). This induced a phenotype that, in the absence of significant blood pressure elevation, was associated with small artery hypertrophic remodeling and endothelial dysfunction, in support of our previous proposal that ET-1 induced vascular hypertrophy directly and independently of blood pressure elevation (19,20). Interestingly, NADPH oxidase activity was enhanced, indicating increased generation of superoxide anion that could contribute to the decreased endothelium-dependent relaxation through reduced NO bioavailability.
Bakker et al. have investigated in organoid culture some of the mechanisms involved in the remodeling induced by ET-1 in small arteries (24). Three-day activation with ET-1 induced vasoconstriction and eutrophic remodeling, which could be enhanced by an antibody directed to ^-integrin. Inward eutrophic remodeling was shown to be a response to sustained contraction, which may involve collagen reorganization through ^-integrins. The same group showed that stimulation with ET-1 induced significant increase in c-fos mRNA, which could not be blocked by inhibitors of tyrosine kinases, MAP kinases, or conventional protein kinase C, but was inhibited by staurosporine and the calcium chelator BAPTA, suggesting a role for intracellular calcium (25). Thus, ET-1 induced increased expression of c-fos independent of MAP kinase via a calcium-dependent mechanism in the absence of wall stress.
ETb receptors have been suggested to play a pro-apoptotic role (26), whereas ETA receptors mediate cell growth and apoptosis through NFkB activation (27). However, the overall effect of ET-1 appears to be a survival and anti-apoptotic action and is associated with attenuation of the caspase-3 pathway activation (28).
Reactive oxygen species (ROS), which are involved in the pathophysiology of hypertension and in vascular damage, are potent inducers of ET-1 synthesis in endothelial cells (29). In addition, as already mentioned in relation to endothelial dysfunction, ET-1 is able to activate NADPH oxidase in smooth muscle cells and in blood vessels (20). Its mitogenic effects may be in part mediated via an increase in the production of ROS (30), as already mentioned. In aldosterone-infused rats exposed to a normal salt diet, systolic blood pressure, plasma ET, systemic oxidative stress, and vascular NADPH activity increased in association with small artery hypertrophic remodeling. Laser confocal microscopy showed increased collagen, fibronectin, and intercellular adhesion molecule (ICAM-1) content in the vessel wall of aldosterone-infused rats. ETA receptor antagonism decreased oxidative stress, normalized the hypertrophic remodeling, decreased collagen and fibronectin deposition, and reduced ICAM-1 abundance in the vascular wall of aldosterone-infused rats, whereas hydralazine lowered blood pressure and reduced NADPH activity in aorta but did not affect the other vascular changes. ET blockade thus exerts beneficial effects on vascular remodeling, fibrosis, oxidative stress, and adhesion molecule expression in aldos-terone-induced hypertension (31). In salt-loaded stroke-prone SHR (SHR-SP) rats, whose hypertension has an ET-1 component, administration of antioxidants such as the superoxide dismutase mimetic Tempol decreased the media to lumen ratio of mesenteric arteries (32). However, whereas in mice NADPH oxidase appears to be of major importance in mediation of ROS generation induced by ET-1 (23,33), in rats and in human smooth muscle cells ET-1 appears to induce superoxide anion formation also through activation of other mechanisms, including xanthine oxidase and mitochondrial sources of free radicals (34). It is known that ET-1 influences mitochondrial function and ROS formation in cultured cardiomyocytes (35). Interestingly, superoxide anion from different sources including mitochondrial ROS modulates ET-1 production (35,36). Ang II-induced redox-sensitive ERK signaling plays a role in ET-1 gene expression in rat aortic smooth muscle cells (37) and ET-1 synthesis depends on intracellular ROS generation in human VSMCs (38). Increased ET-1 could in turn stimulate mitochondrial-derived ROS production. Although Ang II activates p38MAPK, JNK, and ERK5 primarily through NAD(P)H oxidase-generated ROS (34), ET-1 stimulates these kinases via redox-sensitive processes that involve mitochondrial-derived ROS. Thus, redox-dependent activation of MAPKs by Ang II and ET-1 occurs through distinct ROS-generating systems that contribute to the differential signaling in vascular smooth muscle cells by these agents.
ET-1 stimulates cell migration and VEGF production (39,40), which could imply its involvement in angiogenesis. ET-1 antagonists block angiogenesis and tumor progression (41). However, ETa/ETb antagonism has improved survival after myocardial infarction, which may relate to improved perfusion resulting from triggering of an angiogenic response (42). In a model of hindlimb ischemia the ET system is activated and ET antagonists increase neovascularization (43). Capillary density in the left ventricular myocardium is decreased in DOCA-salt rats (44). This rarefaction may be prevented by use of an ETa receptor blocker, which suggests that ET-1 has detrimental effects on the microcirculation, whereas ETa receptor blockers favor angiogenesis. The role of ET-1 in angiogenesis post-ischemia or on tumor growth remains therefore undefined. A recent study examined the role of ET-1 in the development of coronary vasa vasorum in experimental hypercholesterolemia in pigs using microscopic-computed tomography (45). Vasa vasorum density was higher in the hypercholesterolemic group associated with increased VEGF expression in the coronary arterial wall. These changes were abrogated by an ETA receptor antagonist, supporting an involvement of ET in vasa vasorum neovascularization in early coronary atherosclerosis.
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