Estrogen causes dynamic alterations in endothelial estrogen receptor expression.
Estrogen receptor (ER)alpha 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 (E2, 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) E2 treatment caused ERalpha downregulation. In contrast to the upregulation in ERalpha after long-term E2, 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 E2. In studies using the human ERalpha gene promoter P-1 coupled to luciferase, an increase in ERalpha 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 E2. Thus, long-term exposure to E2 upregulates ERalpha expression in endothelial cells through the actions of either ERalpha or ERbeta on ERalpha gene transcription; in contrast, E2 causes ERbeta downregulation in the endothelium. We postulate that E2-induced changes in ERalpha and ERbeta expression modify the effects of the hormone on vascular endothelium.
Ihionkhan
Christopher E
CE
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75390-9063, USA.
Chambliss
Ken L
KL
Gibson
Linda L
LL
Hahner
Lisa D
LD
Mendelsohn
Michael E
ME
Shaul
Philip W
PW
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D015151:Immunoblotting; D011401:Promoter Regions, Genetic / Q000502:physiology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011960:Receptors, Estrogen; D004958:Estradiol