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Muller-Delp, Judy M., Dennis B. Lubahn, Kathryn E. Nichol, Brian J. Philips, Elmer M. Price, Edward M. Curran, and M. Harold Laughlin. Regulation of nitric oxide-dependent vasodilation in coronary arteries of estrogen receptor-s-deficient mice. Am J Physiol Heart Circ Physiol 285: H2150-H2157, 2003. First published July 24, 2003; 10.1152/ajpheart.00966.2002.--Estrogen has been shown to increase endothelium-dependent vasodilation and expression of endothelial nitric oxide (NO) synthase (eNOS); however, the role of estrogen receptors in mediating estrogen effects on endothelial function remains to be elucidated. The purpose of this study was to test the hypothesis that estrogen modulates NO-dependent vasodilation of coronary arteries through its action on estrogen receptor-[alpha] (ER-[alpha]) to increase protein levels of eNOS and Cu/Zn superoxide dismutase (SOD-1). Vasodilation to acetylcholine (ACh) and sodium nitroprusside was assessed in isolated coronary arteries from intact and ovariectomized female wild-type (WT) and ER-[alpha] knockout ([ER.sub.[alpha]]KO) mice. Protein levels for eNOS and SOD-1 were also evaluated. Vasodilation to ACh was not significantly altered in [ER.sub.[alpha]]KO mice compared with WT mice. Ovariectomy reduced responsiveness to ACh in [ER.sub.[alpha]]KO mice but not WT mice. Responses to sodium nitroprusside were not altered by disruption of ER-[alpha] or by ovariectomy. Supplementation with estrogen restored ACh-induced vasodilation in ovariectomized [ER.sub.[alpha]]KO mice. eNOS protein was reduced in [ER.sub.[alpha]]KO mice compared with WT mice. Ovariectomy caused a further reduction in eNOS protein in [ER.sub.[alpha]]KO mice, but this reduction was reversed by estrogen treatment. SOD-1 protein levels were increased by disruption of ER-[alpha]. Ovariectomy reduced SOD-1 protein in [ER.sub.[alpha]]KO mice, but this reduction was partially reversed by estrogen replacement. These results suggest that estrogen modulation of eNOS protein content is mediated in part through ER-[alpha]. NO-dependent responses are preserved in [ER.sub.[alpha]]KO mice, possibly through increased SOD-1 expression and enhanced bioavailability of NO. endothelial nitric oxide synthase; superoxide dismutase; acetylcholine; ovariectomy; sodium nitroprusside