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Estrogen Receptors and ß Have Similar Activities in Multiple Endothelial Cell Pathways

Women’s Health Research Institute (M.J.E., H.A.H., S.K.K., S.J.A.) and Department of Chemical Sciences, Wyeth Research (C.P.M.), Collegeville, Pennsylvania 19426

Address all correspondence and requests for reprints to: Dr. Mark J. Evans, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: evansm{at}wyeth.com.

The presence of both estrogen receptor (ER) and ERß 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 ER or ERß. The activities of ER and ERß were compared in three distinct gene regulatory pathways, including inhibition of IL-1ß 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 ERß was typically less efficacious than ER. As no class of gene regulation could differentiate ER from ERß activity, we characterized a novel steroid (7-thiophenyl-E2) that bound with similar affinities to ER and ERß, but functioned as an ER agonist and ERß 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 ER and ERß in endothelial cells in vivo.

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