on October 4, 2004
Circulation. 2004
Published online before print October 4, 2004, doi: 10.1161/01.CIR.0000144462.08345.B9
Published online before print October 4, 2004, doi: 10.1161/01.CIR.0000144462.08345.B9
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Submitted on September 18, 2003
From the Experimental Hypertension (F.A., A.V., M.F.N., M.I., R.M.T., E.L.S.) and Molecular Biochemistry of Hypertension (T.L.R.) Laboratories of the CIHR Multidisciplinary Research Group on Hypertension, and the Laboratory of Biochemical Neuroendocrinology (N.G.S.), Clinical Research Institute of Montreal, Montreal, Canada. * To whom correspondence should be addressed. E-mail: ernesto.schiffrin{at}ircm.qc.ca.
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 ETB 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.
Revised on May 20, 2004
Accepted on May 21, 2004
Endothelium-Restricted Overexpression of Human Endothelin-1 Causes Vascular Remodeling and Endothelial Dysfunction
Farhad Amiri PhD,
Key words: endothelin • remodeling • cardiovascular diseases • endothelium • free radicals
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