eNOS Promoter Activation by Estrogen in Vascular Cells

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DESCRIPTION (provided by applicant): Understanding the molecular bases for the cardiovasculature protective effects of estrogen is essential in order ultimately to develop ligands for prevention and treatment of cardiovasculature disease in both men and women. Estrogen is protective against damage to the vasculature largely due to direct effects on vascular endothelial cells and smooth muscle cells. Both cell types express estrogen receptors (ERs), the physiological targets of estrogen. Nuclear ERs are hormone-activated, DNA-binding transcription factors. Vascular endothelial cells respond to estrogen both in a rapid "nongenomic" manner and in a longer-term manner, which involves transcriptional regulation of estrogen receptor-target genes. A critical target for estrogen protection of the vasculature is endothelial nitric oxide synthase (eNOS), whose promoter is activated by ligand. The long-term goal of this proposal is to elucidate the molecular mechanism by which ER induces eNOS gene expression. The specific aims include: 1) identifying which ER - ERalpha and/or ERbeta - activates the eNOS promoter, and 2) specifying the promoter elements that promote association with ER, and probing whether endothelial-specific transcription factors are involved in the estrogen response.