Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction

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, w...

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Published in:Circulation (New York, N.Y.) N.Y.), 2004-10, Vol.110 (15), p.2233-2240
Main Authors: AMIRI, Farhad, VIRDIS, Agostino, FRITSCH NEVES, Mario, IGLARZ, Marc, SEIDAH, Nabil G, TOUYZ, Rhian M, REUDELHUBER, Timothy L, SCHIFFRIN, Ernesto L
Format: Article
Language:English
Subjects:
Animals
Antioxidants - pharmacology
Atherosclerosis (general aspects, experimental research)
Biological and medical sciences
Blood and lymphatic vessels
Blood vessels and receptors
Cardiology. Vascular system
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Endothelin-1 - genetics
Endothelin-1 - physiology
Endothelin-3 - biosynthesis
Endothelin-3 - genetics
Endothelium, Vascular - drug effects
Endothelium, Vascular - pathology
Endothelium, Vascular - physiopathology
Fundamental and applied biological sciences. Psychology
Humans
Hypertrophy
Male
Medical sciences
Mesenteric Arteries - drug effects
Mesenteric Arteries - physiology
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Transgenic
NADPH Oxidases - physiology
NG-Nitroarginine Methyl Ester - pharmacology
Nitric Oxide - metabolism
Oxidative Stress
Reactive Oxygen Species
Receptor, Endothelin A - biosynthesis
Receptor, Endothelin A - genetics
Receptor, Endothelin B - biosynthesis
Receptor, Endothelin B - genetics
Receptor, TIE-2 - genetics
Recombinant Fusion Proteins - physiology
RNA, Messenger - biosynthesis
Vascular Resistance - drug effects
Vasoconstriction - drug effects
Vasoconstrictor Agents - pharmacology
Vasodilator Agents - pharmacology
Vertebrates: cardiovascular system
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Summary: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. 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. 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.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.CIR.0000144462.08345.B9