Background Cardiovascular events are less prevalent in premenopausal women and women receiving estrogen replacement than in postmenopausal women or men.Endothelium-derived relaxing factor (EDRF) is an important local modulator of vascular tone, and abnormal endothelial function is related, in part, to the oxidative modification of low-density lipoprotein (LDL). Estrogens possess substantial antioxidant activity and inhibit LDL modification in vitro.Methods and Results We investigated the effects of 17 beta -estradiol (E2) on endothelial vasomotor function in cholesterol-fed miniature swine. Animals underwent ovariectomy or a sham procedure and received E2or placebo via implant yielding three groups: sham, ovariectomy (E2placebo), and implant (E2implant). After 16 weeks, coronary arteries were harvested and endothelial function was examined in vitro. Vessels from the sham and implant groups demonstrated preserved endothelium-dependent relaxation to bradykinin, substance P, and A23187. Vessels from the ovariectomy group exhibited impaired relaxation to bradykinin and substance P (P<.05 versus sham and implant groups) but not to A23187. Plasma E2levels were strongly correlated with the response to bradykinin (R=.82, P<.001), substance P (R=.64, P<.01), and A23187 (R=.65, P<.01). Compared with the ovariectomy group, LDL derived from the sham and implant groups was markedly resistant to ex vivo oxidation (P<.05), and this effect correlated with preserved endothelium-dependent relaxation to bradykinin (R=.62, P<.03) and substance P (R=.61, P<.03).Conclusions Thus, E2preserves endothelial function in cholesterol-fed swine in association with protection of LDL against oxidative modification. These data suggest that E2may, in part, favorably affect vascular function and coronary artery disease by virtue of its antioxidant properties. (Circulation. 1994;89:2251-2259.)