title: Rapid activation of endothelial nitric oxide synthase by estrogen.
abstract: 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 ERalpha 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 ERalpha hormone binding domain. In addition, the acute response of eNOS to estrogen can be reconstituted in COS-7 cells cotransfected with wild-type ERalpha 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 ERalpha functioning in a novel, nongenomic manner to activate the enzyme via calcium-dependent, MAP kinase-dependent mechanisms.
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D004789:Enzyme Activation; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000502:physiology*; D007700:Kinetics; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D013552:Swine