Estrogen causes dynamic alterations in endothelial estrogen receptor expression

Estrogen receptor (ER)a mediates many of the effects of estrogen on the vascular endothelium. The purpose of the present study was to determine whether estrogen modifies endothelial ERalpha expression. In experiments in cultured ovine endothelial cells, physiological concentrations of 17beta-estradiol (E-2, 10(-10) to 10(-8) mol/L) caused an increase in ERalpha protein abundance that was evident after 6 hours of hormone exposure. Shorter (2-hour) E-2 treatment caused ERalpha downregulation. In contrast to the upregulation in ERalpha after long-term E-2, the expression of the other ER isoform, ERbeta, was downregulated. Both nonselective ER antagonism with ICI 182,780 and the inhibition of gene transcription with actinomycin D blocked the increase in ERalpha with E-2. In studies using the human ERa gene promoter P-1 coupled to luciferase, an increase in ERa 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 ERbeta antagonist RR-tetrahydrochrysene yielded partial blockade. Overexpression of ERalpha or ERbeta caused comparable 10- and 8-fold increases, respectively, in ERalpha promoter activation by E-2. Thus, long-term exposure to E-2 upregulates ERalpha expression in endothelial cells through the actions of either ERalpha or ERbeta on ERalpha gene transcription; in contrast, E-2 causes ERbeta downregulation in the endothelium. We postulate that E-2-induced changes in ERalpha and ERbeta expression modify the effects of the hormone on vascular endothelium.