eNOS Promoter Activation by Estrogen in Vascular Cells

描述(由申请人提供)：了解雌激素对心血管系统保护作用的分子基础对于最终开发用于预防和治疗男性和女性心血管疾病的配体至关重要。雌激素对血管系统的损伤具有保护作用，这主要是由于它直接作用于血管内皮细胞和平滑肌细胞。这两种细胞都表达雌激素受体(ER)，雌激素的生理靶点。核内ER是激素激活的、DNA结合的转录因子。血管内皮细胞对雌激素的反应既有快速的“非基因组”方式，也有长期的方式，这涉及到雌激素受体靶基因的转录调控。雌激素保护血管系统的一个重要靶点是内皮型一氧化氮合酶(ENOS)，其启动子由配体激活。这一建议的长期目标是阐明ER诱导eNOS基因表达的分子机制。其具体目的包括：1)确定哪个ER-ERα和/或ER-β激活eNOS启动子，以及2)指定促进与ER关联的启动子元件，并探索内皮特异性转录因子是否参与雌激素反应。

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.