Novel role of estrogen receptors in vascular endothelium

Abstract

Estrogen has a variety of effects on the vascular wall including rapid vasodilation due to the stimulation of endothelial nitric oxide synthase (eNOS). Studies in cultured endothelium indicate that the hormone cause acute, direct activation of eNOS that is unaffected by actinomycin D but fully inhibited by estrogen receptor (ER) antagonism. Overexpression of ERalpha leads to marked enhancement of the acute response to estrogen, and this process is blocked by ER antagonism and requires the ERalpha hormone binding domain. The acute response of eNOS to estrogen can also be reconstituted in COS-7 cells cotransfected with ERalpha and eNOS, but not by transfection with eNOS alone. The inhibition of calcium influx, or tyrosine kinases or mitogen-activated protein (MAP) kinase prevents eNOS stimulation by estrogen, and estrogen causes rapid ER-dependent activation of MAP kinase. Thus, the acute effect of estrogen on eNOS is mediated by ERalpha functioning in a novel, nongenomic manner to activate the enzyme via calcium-dependent, MAP kinase-dependent mechanisms.