Estrogen receptors alpha and beta have similar activities in multiple endothelial cell pathways.
The presence of both estrogen receptor alpha (ERalpha) and ERbeta in vascular cells has greatly increased the complexity of potential estrogen regulatory pathways in the cardiovascular system. Here, human umbilical vein endothelial cells were engineered using adenovirus vectors to express either ERalpha or ERbeta. The activities of ERalpha and ERbeta were compared in three distinct gene regulatory pathways, including inhibition of IL-1beta induction of E-selectin expression, inhibition of basal endothelin-1 production, and the ability to induce two matrix-stabilizing enzymes: tissue transglutaminase and a novel member of the lysyl oxidase family. Both ERs were active on these end points, although ERbeta was typically less efficacious than ERalpha. As no class of gene regulation could differentiate ERalpha from ERbeta activity, we characterized a novel steroid (7alpha-thiophenyl-E2) that bound with similar affinities to ERalpha and ERbeta, but functioned as an ERalpha agonist and ERbeta antagonist for all of these endothelial responses. This pattern of receptor subtype-selective activity was not unique to endothelial cells, but was also seen in metabolically active HepG2 cells, suggesting potential in vivo utility. The panel of endothelial responses coupled with a selective modulator should provide a means to characterize the roles of ERalpha and ERbeta in endothelial cells in vivo.
Evans
Mark J
MJ
Women's Health Research Institute, Collegeville, Pennsylvania 19426, USA. evansm@wyeth.com
Harris
Heather A
HA
Miller
Chris P
CP
Karathanasis
Sotirios K
SK
Adelman
Steven J
SJ
D000594:Amino Acid Oxidoreductases; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D008249:Protein-Lysine 6-Oxidase; D011506:Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
C466764:7-thiophenylestradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009363:Neoplasm Proteins; D011506:Proteins; D011960:Receptors, Estrogen; C038865:estrogen regulated protein; D004958:Estradiol; D000594:Amino Acid Oxidoreductases; C445682:LOXL4 protein, human; D008249:Protein-Lysine 6-Oxidase