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


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.
Experimental Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Farhad
F
Amiri
Agostino
A
Virdis
Mario Fritsch
MF
Neves
Marc
M
Iglarz
Nabil G
NG
Seidah
Rhian M
RM
Touyz
Timothy L
TL
Reudelhuber
Ernesto L
EL
Schiffrin
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019332:Endothelin-1 / Q000235:genetics / Q000502:physiology*; D019334:Endothelin-3 / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D006984:Hypertrophy; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A / Q000096:biosynthesis / Q000235:genetics; D044023:Receptor, Endothelin B / Q000096:biosynthesis / Q000235:genetics; D042787:Receptor, TIE-2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D019332:Endothelin-1; D019334:Endothelin-3; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011993:Recombinant Fusion Proteins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019255:NADPH Oxidases; D042787:Receptor, TIE-2; D019331:NG-Nitroarginine Methyl Ester