Differential and Opposing Regulation of PAI-1 Promoter Activity by Estrogen Receptor α and Estrogen Receptor β in Endothelial Cells

To investigate the molecular mechanisms involved in the estrogen-dependent control of plasminogen activator inhibitor-1 (PAI-1) gene expression in vascular cells, we compared the transactivation properties of estrogen receptors (ERα and ERβ) in regulating the activity of a human PAI-1 promoter reporter construct in transfected bovine aortic endothelial cells (BAECs). ERα increased PAI-1 promoter activity in BAECs by an estrogen-dependent mechanism, whereas ERβ suppressed PAI-1 promoter activity by an estrogen-independent mechanism. The suppressive activity of ERβ was dominant over the inductive activity of ERα. Mutation of a putative estrogen response element (ERE) located at position −427 in the proximal promoter abolished the ERα action without influencing the suppressive effects of ERβ. Mutation of either AP1-like site did not eliminate the ERα or ERβ actions at the PAI-1 promoter, suggesting that other promoter elements are involved in these responses. These mutations significantly reduced the −3.4kbp...