© 1997 American Heart Association, Inc.
Articles |
17ß-Estradiol Regulation of Human Endothelial Cell Basal Nitric Oxide Release, Independent of Cytosolic Ca2+ Mobilization
From the Division of Cardiovascular Medicine and the Raymond and Beverly Sackler Foundation Laboratory (T.C.-G., J.R.B.), the Department of Pharmacology (G.G.-C., W.C.S.), the Departments of Obstetrics and Gynecology and Psychiatry (P.S.), and the Molecular Cardiobiology Program, Boyer Center for Molecular Medicine (T.C.-G., G.G.-C., W.C.S., J.R.B.), Yale University School of Medicine, New Haven, Conn.
Correspondence to Jeffrey R. Bender, MD, Yale University School Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave, Room 454, New Haven, CT 06536-0812. E-mail jeffrey_bender{at}quickmail.yale.edu.
Abstract Estradiol retards the development of atherosclerosis. Animal models have suggested that NO may be a critical effector molecule in this cardiovascular protection. In this study, female human umbilical vein endothelial cells (HUVECs) were propagated in phenol red–free gonadal hormone–free medium and pretreated with 17ß-estradiol (E2). Reduced NO2- and NO3- (NOX) concentration, determined by chemiluminescence, demonstrated a rapid increase in basal HUVEC NO release in response to physiological concentrations of E2. The estrogen receptor (ER) antagonist ICI 164,384 inhibited the augmented NO release, demonstrating an ER-mediated component of this response. Because endothelial NO synthase (eNOS) activity is largely regulated by cytosolic Ca2+, relative [Ca2+]i in response to E2 was determined in a fluorometric assay. E2 did not promote HUVEC Ca2+ fluxes. Furthermore, eNOS activity in E2-pretreated endothelial whole-cell lysates was not dependent on additional Ca2+. Despite involving the ER, this is a nongenomic effect of E2, as demonstrated by maintained responses in transcriptionally inhibited cells and by the rapidity (10 minutes) of cGMP formation in an NO bioassay. We demonstrate, for the first time, that independent of cytosolic Ca2+ mobilization, there is augmentation of eNOS activity with a resultant increase in HUVEC basal NO release in response to short-term estradiol exposure. Implications for the cardiovascular protective role of estrogen are discussed.
Key Words: atherosclerosis • estrogen • vascular endothelium • nitric oxide • nitric oxide synthase
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