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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:38.)
© 2003 American Heart Association, Inc.

Vascular Biology

Estrogen Reduces Angiotensin II–Induced Nitric Oxide Synthase and NAD(P)H Oxidase Expression in Endothelial Cells

Ferrante S. Gragasin^*; Yi Xu^*; Ivan A. Arenas; Neelam Kainth; Sandra T. Davidge

From the Departments of Obstetrics & Gynecology and Physiology, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada.

Correspondence to Sandra T. Davidge, PhD, 232 Heritage Medical Research Centre, Perinatal Research Centre, University of Alberta, Edmonton, AB, Canada, T6G 2S2. E-mail sandra.davidge{at}ualberta.ca

Objective— Angiotensin II (AII) has been shown to increase endothelial NAD(P)H oxidase activity, which is a source of superoxide anion that in turn may induce the formation of peroxynitrite. Estrogen (E₂) has been reported to have vascular protective effects. In this study, we hypothesized that E₂ reduces the AII-induced expression of NAD(P)H oxidase and peroxynitrite in endothelial cells.

Methods and Results— Endothelial cells were cultured and stimulated with AII in the absence or presence of E₂. Western blots were used to assess nitric oxide synthase (NOS) and NAD(P)H oxidase expression. Immunofluorescence of nitrotyrosine provided evidence of peroxynitrite formation. Our data indicate that AII increased the expression of endothelial NOS, inducible NOS, and NAD(P)H oxidase in a dose-dependent manner, which was attenuated by incubation with either E₂, superoxide dismutase, or the AII type 1 receptor (AT₁R) inhibitor candesartan. Estrogen as well as superoxide dismutase also inhibited AII-induced AT₁R expression and nitrotyrosine staining. The effects of E₂ on the AII responses were not inhibited by the E₂ receptor antagonist ICI-182,780.

Conclusions— AII stimulation of endothelial cells increases expression of NAD(P)H oxidase and NOS, which may contribute to oxidative stress, as evidenced by peroxynitrite formation. E₂ inhibits these AII effects, possibly through reduced AT₁R expression.

Key Words: estrogen • angiotensin • oxidative stress • endothelium • peroxynitrite

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