Endothelium-Restricted Overexpression of Human Endothelin-1 Causes Vascular Remodeling and Endothelial Dysfunction

Abstract

Background-Endothelin (ET)-1 is a potent vasoconstrictor that contributes to vascular remodeling in hypertension and other cardiovascular diseases. Endogenous ET-1 is produced predominantly by vascular endothelial cells. To directly test the role of endothelium-derived ET-1 in cardiovascular pathophysiology, we specifically targeted expression of the human preproET-1 gene to the endothelium by using the Tie-2 promoter in C57BL/6 mice. Methods and Results-Ten-week-old male C57BL/6 transgenic (TG) and nontransgenic (wild type; WT) littermates were studied. TG mice exhibited 3-fold higher vascular tissue ET-1 mRNA and 7-fold higher ET-1 plasma levels than did WT mice but no significant elevation in blood pressure. Despite the absence of significant blood pressure elevation, TG mice exhibited marked hypertrophic remodeling and oxidant excess-dependent endothelial dysfunction of resistance vessels, altered ET-1 and ET-3 vascular responses, and significant increases in ET B expression compared with WT littermates. Moreover, TG mice generated significantly higher oxidative stress, possibly through increased activity and expression of vascular NAD(P)H oxidase than did their WT counterparts. Conclusions-In this new murine model of endothelium-restricted human preproET-1 overexpression, ET-1 caused structural remodeling and endothelial dysfunction of resistance vessels, consistent with a direct nonhemodynamic effect of ET-1 on the vasculature, at least in part through the activation of vascular NAD(P)H oxidase.

Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

“…11 This points to a transient upregulation of the endothelin system during the development of hypertension. ET-1 is not only a very potent vasoconstrictor 12 but is also a proinflammatory agent, 15 has mitogenic effects on vascular smooth muscle cells, 13 is pro-angiogenic, 16 pro-oxidant 33 and promotes fibrosis. 14 Moreover, endothelium restricted overexpression of ET-1 causes vascular remodeling and endothelial dysfunction in the absence of a hemodynamic effect.…”

Carotid atherosclerosis in elderly hypertensive patients: potential role of endothelin and plasma antioxidant capacity

“…ET-1 increases oxidative stress through the activation of NAD(P)H oxidase-a key enzymatic source for superoxide anion in the vascular wall. 12,13,16,27 Excessive oxidative stress activates several redox-sensitive signalling pathways resulted in activation of MAP kinase family, tyrosine kinases, transcription factors nuclear factor kB, activator protein-1, vascular cellular adhesion molecule-1 and increase release of proinflammatory cytokines. 8,13,26,28,29 The contribution of ET-1, NAD(P)H oxidase and reactive oxygen species in VSMC proliferation was confirmed by the possibility of blocking this process by pre-incubation of VSMC with ET A receptor antagonist, 13 NAD(P)H oxidase inhibitor 12,16 or with antioxidants; 12,13,16 however, it was documented for extracellular superoxide dismutase, 13 and among the antioxidants included in FRAP for ascorbic acid.…”

“…12,13,16,27 Excessive oxidative stress activates several redox-sensitive signalling pathways resulted in activation of MAP kinase family, tyrosine kinases, transcription factors nuclear factor kB, activator protein-1, vascular cellular adhesion molecule-1 and increase release of proinflammatory cytokines. 8,13,26,28,29 The contribution of ET-1, NAD(P)H oxidase and reactive oxygen species in VSMC proliferation was confirmed by the possibility of blocking this process by pre-incubation of VSMC with ET A receptor antagonist, 13 NAD(P)H oxidase inhibitor 12,16 or with antioxidants; 12,13,16 however, it was documented for extracellular superoxide dismutase, 13 and among the antioxidants included in FRAP for ascorbic acid. 12,16 It was also shown that vitamin C inhibited activation of mitogen-activated protein kinase and VSMC proliferation in cultured rat aortic smooth muscle cells, 26 and in an in vivo experiment it was demonstrated that vitamin C supplementation decreased activation of NADPH oxidase and superoxide anion generation, prevented vascular hypertrophy and increased plasma total antioxidant status and superoxide dismutase in arterial wall in stroke-prone spontaneously hypertensive rats.…”

“…10,11 It has been documented that ET-1 is involved in the interplay between oxidative stress and the development of hypertension-and diabetes-induced cardiovascular complications. 12,13 Reactive oxygen species increase ET-1 production in endothelial and VSMCs, 14,15 and on the other hand, they function as intracellular messengers modulating the ET-1 signalling pathway. 12,16 As we have shown recently in hypertensive and diabetic patients, higher plasma ET-1 level is independently associated with lower plasma antioxidant capacity (assessed by ferricreducing ability of plasma-FRAP) and decreased vitamin C concentration, which may be a result of increased oxidative stress in these diseases.…”

“…12,13 Reactive oxygen species increase ET-1 production in endothelial and VSMCs, 14,15 and on the other hand, they function as intracellular messengers modulating the ET-1 signalling pathway. 12,16 As we have shown recently in hypertensive and diabetic patients, higher plasma ET-1 level is independently associated with lower plasma antioxidant capacity (assessed by ferricreducing ability of plasma-FRAP) and decreased vitamin C concentration, which may be a result of increased oxidative stress in these diseases. 17 The aim of this study was to evaluate the relationship between plasma ET-1 level and plasma antioxidant capacity, as well as the thickness of common carotid artery intima-media thickness (CCA-IMT) and the presence of atherosclerotic plaque in CCA or in the bulb in elderly patients treated for hypertension.…”