Circulation Research. 2002
Published online before print September 19, 2002, doi: 10.1161/01.RES.0000038304.62046.4C
Published online before print September 19, 2002, doi: 10.1161/01.RES.0000038304.62046.4C
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Submitted on April 24, 2002
Revised on August 23, 2002
Accepted on September 9, 2002
Estrogen Causes Dynamic Alterations in Endothelial Estrogen Receptor Expression
Christopher E. Ihionkhan ;
From the Department of Pediatrics (C.E.I., K.L.C., L.L.G., L.D.H., P.W.S.), University of Texas Southwestern Medical Center, Dallas, and the Molecular Cardiology Research Institute (M.E.M.), New England Medical Center and Tufts University School of Medicine, Boston, Mass.
* To whom correspondence should be addressed. E-mail: pshaul{at}mednet.swmed.edu.
Estrogen receptor (ER)
mediates many of the effects of estrogen on the vascular endothelium. The purpose of the present study was to determine whether estrogen modifies endothelial ER expression. In experiments in cultured ovine endothelial cells, physiological concentrations of 17ß-estradiol (E2, 10-10 to 10-8 mol/L) caused an increase in ER protein abundance that was evident after 6 hours of hormone exposure. Shorter (2-hour) E2 treatment caused ER downregulation. In contrast to the upregulation in ER after long-term E2, the expression of the other ER isoform, ERß, was downregulated. Both nonselective ER antagonism with ICI 182,780 and the inhibition of gene transcription with actinomycin D blocked the increase in ER with E2. In studies using the human ER gene promoter P-1 coupled to luciferase, an increase in ER gene transcription was evident in endothelial cells within 4 hours of E2 exposure. The transcriptional activation was fully blocked by ICI 182,780, whereas the specific ERß antagonist RR-tetrahydrochrysene yielded partial blockade. Overexpression of ER or ERß caused comparable 10- and 8-fold increases, respectively, in ER promoter activation by E2. Thus, long-term exposure to E2 upregulates ER expression in endothelial cells through the actions of either ER or ERß on ER gene transcription; in contrast, E2 causes ERß downregulation in the endothelium. We postulate that E2-induced changes in ER and ERß expression modify the effects of the hormone on vascular endothelium.
Key words: endothelium • estrogen • estrogen receptor
•
estrogen receptor ß
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