Dual and Opposite Effects of Estrogen on Coronary Arteries Mediated by Type 1 (N) Nitric Oxide Synthase via Nitric Oxide and Superoxide

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 postmenopausal women taking hormone replacement therapy (HRT). 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 porcine coronary arteries. In addition, molecular, fluorescence, and patch-clamp studies identified estrogen signaling molecules in coronary smooth muscle. Estrogen (1–1000nM) relaxed arteries in an endotheliumindependent fashion; however, when arteries were pretreated with agents to uncouple NO production from nitric oxide synthase (NOS), estrogen contracted coronary arteries with an EC50 of 7.3 4nM. Estrogen-induced contraction was inhibited or prevented by reducing superoxide (O2 - ). Estrogen-stimulated oxidant production was detected in NOS-uncoupled coronary myocytes. Interestingly, only the Type 1 NOS isoform (nNOS) was detected in myocytes, making this protein a likely target mediating both estrogen-induced relaxation and contraction of coronary arteries. Estrogen-induced contraction was completely inhibited by 1μM nifedipine or 10μM indomethacin, indicating involvement of dihydropyridine-sensitive calcium channels and contractile prostaglandins. In conclusion, we propose that a single molecular mechanism can mediate the dual and opposite effect of estrogen on coronary arteries: by stimulating Type 1 (n)NOS in coronary arteries, estrogen produces either vasodilation via NO or vasoconstriction via O2- . Because cofactors necessary for NO production diminish with age, estrogen would generate mostly O2- in older women, and thereby render HRT harmful. In younger women, however, estrogen would be expected to produce primarily salutary effects on cardiovascular function (as occurs with oral contraceptives).