Rapid activation of endothelial nitric oxide synthase by estrogen

Estrogen is an important atheroprotective molecule that causes the rapid dilation of blood vessels by stimulating endothelial nitric oxide synthase (eNOS). There is also evidence that estrogen modulates airway epithelial NO production, thereby potentially affecting bronchial hyperresponsiveness. Studies in cultured endothelial and airway epithelial cells indicate that physiologic concentrations of estrogen cause rapid direct activation of eNOS that is unaffected by actinomycin D, but fully inhibited by estrogen receptor (ER) antagonism. Overexpression of ER alpha leads to marked enhancement of the acute response to estrogen, and this process is blocked by ER antagonism it is specific to estrogen, and it requires the ER alpha hormone binding domain. In addition, the acute response of eNOS to estrogen can be reconstituted in COS-7 cells cotransfected with wild-type ER alpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of calcium influx, or tyrosine kinases or MAP kinase prevents the stimulation of eNOS by estrogen, and estrogen causes rapid ER-dependent activation of MAP kinase. These findings indicate that the acute effects of estrogen on both endothelial and airway epithelial eNOS are mediated by ER alpha functioning in a novel, nongenomic manner to activate the enzyme via calcium-dependent, MAP kinase-dependent mechanisms. (C) 1999 Elsevier Science Inc. All rights reserved.