Published online before print June 24, 2004, doi: 10.1161/01.RES.0000136521.70093.f1
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Submitted on July 9, 2001
Revised on June 1, 2004
Accepted on June 11, 2004
Differential and Opposing Regulation of PAI-1 Promoter Activity by Estrogen Receptor 
and Estrogen Receptor 
in Endothelial Cells
Layton Harris Smith ;
From the From the Departments of Medicine and Pharmacology, Vanderbilt University Medical Center and Nashville VAMC, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: doug.vaughan{at}mcmail.vanderbilt.edu.
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 (ER
and ER
) in regulating the activity of a human PAI-1 promoter reporter construct in transfected bovine aortic endothelial cells (BAECs). ER increased PAI-1 promoter activity in BAECs by an estrogen-dependent mechanism, whereas ER suppressed PAI-1 promoter activity by an estrogen-independent mechanism. The suppressive activity of ER was dominant over the inductive activity of ER. Mutation of a putative estrogen response element (ERE) located at position -427 in the proximal promoter abolished the ER action without influencing the suppressive effects of ER. Mutation of either AP1-like site did not eliminate the ER or ER actions at the PAI-1 promoter, suggesting that other promoter elements are involved in these responses. These mutations significantly reduced the -3.4kb PAI-1 promoter response to serum. We concluded that ER and ER exert differential effects on the PAI-1 promoter activity in transfected BAECs. ER activated the PAI-1 promoter through a proximal ERE (-427) and possibly additional EREs located within the PAI-1 promoter, whereas ER suppressed the promoter construct via an unidentified mechanism. This is the first demonstration of the differential regulation of a vascular gene promoter by ER and ER.
Key words: estrogen receptors • plasminogen activator inhibitor-1 promoter • estrogen response element • bovine aortic endothelial cell
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