Estrogen-induced contraction of coronary arteries is mediated by superoxide generated in vascular smooth muscle
Although previous studies demonstrated beneficial effects of estrogen on cardiovascular function, the Women's Health Initiative has reported an increased incidence of coronary heart disease and stroke in post-menopausal women taking hormone replacement therapy. The objective of the present study was to identify a molecular mechanism whereby estrogen, a vasodilatory hormone, could possibly increase the risk of cardiovascular disease. Isometric contractile force recordings were performed on endothelium-denuded porcine coronary arteries, whereas molecular and fluorescence studies identified estrogen signaling molecules in coronary smooth muscle. Estrogen (1-1,000 nM) relaxed arteries in an endothelium-independent fashion; however, when arteries were pretreated with agents to uncouple nitric oxide (NO) production from NO synthase (NOS), estrogen contracted coronary arteries with an EC50 of 7.3 Â± 4 nM. Estrogen-induced contraction was attenuated by reducing superoxide (O 2-). Estrogen-stimulated O2- production was detected in NOS-uncoupled coronary myocytes. Interestingly, only the type 1 neuronal NOS isoform (nNOS) was detected in myocytes, making this protein a likely target mediating both estrogen-induced relaxation and contraction of endothelium-denuded coronary arteries. Estrogen-induced contraction was completely inhibited by 1 Î¼M nifedipine or 10 Î¼M indomethacin, indicating involvement of dihydropyridine-sensitive calcium channels and contractile prostaglandins. We propose that a single molecular mechanism can mediate the dual and opposite effect of estrogen on coronary arteries: by stimulating type 1 nNOS in coronary arteries, estrogen produces either vasodilation via NO or vasoconstriction via O2-. Copyright Â© 2005 the American Physiological Society.
American Journal of Physiology - Heart and Circulatory Physiology
White, Richard E.; Han, Guichun; Dimitropoulou, Christiana; Zhu, Shu; Miyake, Katsuya; Fulton, David; Dave, Shaylee; and Barman, Scott A., "Estrogen-induced contraction of coronary arteries is mediated by superoxide generated in vascular smooth muscle" (2005). PCOM Scholarly Papers. 699.