Circulation, Vol 89, 1943-1950, Copyright © 1994 by American Heart Association
RH Karas, BL Patterson and ME Mendelsohn
BACKGROUND: The decreased incidence of coronary artery disease observed in
postmenopausal women given estrogen (E2) replacement demonstrates an
atheroprotective effect of E2 that is generally believed to be mediated by
indirect, E2-induced changes in cardiovascular risk factor profiles. We
hypothesized that the atheroprotective effect of E2 may be in part mediated
by a direct effect of E2 on vascular smooth muscle cells (VSMCs).
Therefore, a series of experiments was performed to determine whether human
VSMCs contain a competent E2 receptor, a ligand-activated transcription
factor known to mediate E2-induced effects in nonvascular cells. METHODS
AND RESULTS: Ribonuclease protection assays, with a probe derived from the
human E2 receptor, were used to demonstrate E2- receptor mRNA in human
saphenous vein VSMCs. To show that VSMCs contain E2-receptor protein as
well as message, immunoblotting and immunofluorescence studies with a
monoclonal anti-E2-receptor antibody were performed, and E2-receptor
protein was detected by both methods. Transient transfection assays using a
specific E2-responsive reporter system were used next to determine whether
the VSMC E2 receptor is capable of E2-induced transcriptional
transactivation. Initial studies using mammary artery-derived VSMCs
resulted in a 2.4-fold increase in reporter activity in response to 10(-7)
mol/L E2. Subsequent studies using saphenous vein VSMCs demonstrated
increasing levels of reporter activation as the concentration of E2 was
increased from 10(-9) mol/L (1.3-fold increase; SEM, 0.07; P = .05, n = 3)
to 10(-7) mol/L (1.6- fold increase; SEM, 0.04; P = .002, n = 6). The
specificity of the E2- induced transactivation of the reporter gene was
shown by dose- dependent inhibition of transactivation by the pure E2
antagonist ICI 164,384 and by enhancement of the transactivation by
simultaneous overexpression of the E2 receptor. CONCLUSIONS: We have
demonstrated for the first time that human VSMCs express E2-receptor mRNA
and protein and that the E2 receptor in VSMCs is capable of estrogen-
dependent gene activation. These data suggest a mechanism by which estrogen
may directly alter VSMC function.
ARTICLES
Human vascular smooth muscle cells contain functional estrogen receptor
Molecular Cardiology Research Center, New England Medical Center, Tufts University School of Medicine, Boston, Mass. 02111.
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