VASCULAR GENE EXPRESSION IN AGING WOMEN

新兴技术为探索与衰老相关的生理条件对基因表达的影响提供了新的机会。在女性中，许多临床相关的年龄相关疾病与卵巢衰老和绝经导致的雌激素丢失有关。冠心病是男性和女性的主要死亡原因，但在绝经前妇女中并不常见。然而，在绝经后妇女中，该疾病变得越来越普遍，使得CHD成为60岁以上妇女的主要死亡原因。雌激素替代疗法已被证明可以降低绝经后妇女CHD的发病率，并在卵巢切除动物模型中抑制饮食诱导的动脉粥样硬化的进展。只有一部分的保护作用可以解释为传统的危险因素的改变，越来越多的证据表明，雌激素对动脉的直接作用在这种保护中是重要的。然而，雌激素对动脉作用的细胞和分子机制还不清楚。雌激素受体存在于血管床和细胞中，表明雌激素通过其特异性受体调节血管功能的潜力。雌激素受体可以通过1）与靶基因调控区中的雌激素反应元件相互作用或2）与其他转录因子如核因子-kB（NF-kB）、AP-1（c-fos、c-jun）和PPAR-gamma相互作用来调节基因表达。因此，虽然雌激素可能调控许多基因，但关于雌激素对血管细胞转录事件影响的范围和深度，liftle是已知的。最近开发的技术允许快速和同时筛选许多已知功能的靶分子的mRNA水平，并提供了一个很好的方法来确定雌激素效应的广度。这些研究的中心假设是雌激素抑制动脉粥样硬化的发生和发展，部分是通过直接的雌激素受体依赖性作用于血管基因表达。具体目的是确定雌激素对血管平滑肌（VSMC）和内皮细胞（vEC）转录事件的直接影响，以深入了解疾病的进展以及预防这种年龄相关疾病的潜在疗法。

Emerging technologies offer new opportunities to explore effects of physiologic conditions associated with aging on gene expression. In women, many clinically relevant age-related diseases are associated with the loss of estrogen which occurs as a result of ovarian senescence and menopause. Coronary heart disease (CHD), the leading cause of death in both men and women, is infrequent in pre-menopausal women. However, in post-menopausal women the disease becomes increasingly prevalent such that CHD becomes the leading cause of death in women over 60. Estrogen replacement therapy has been shown to reduce the incidence of CHD in post-menopausal women, and to inhibit the progression of diet- induced atherosclerosis in ovariectomized animal models. Only a portion of the protective effect can be explained by alterations in traditional risk factors, and increasing evidence demonstrates that direct actions of estrogen on the artery are important in this protection. However, the cellular and molecular mechanisms of estrogen action on the artery are poorly defined. Estrogen receptors are present in vascular beds and cells, demonstrating the potential for estrogen to regulate vascular function through its specific receptors.Estrogen receptors may regulate gene expression through l) interactions with estrogen response elements in regulatory regions of target genes, or 2) interaction with other transcription factors, such as nuclear factor-kB (NF-kB), AP-1 (c-fos, c- jun), and PPAR-gamma. Thus, while there is potential for many genes to be regulated by estrogen, liftle is known regarding the range and depth of effects of estrogen on transcriptional events in vascular cells. Recently developed technologies allow the rapid and simultaneous screenin of the mRNA levels for many target molecules of known function and provide an excellent method for determination of the breadth of estrogen effects. The central hypothesis of the proposed studies is that estrogen inhibits the initiation and progression of atherogenesis in part through direct estrogen receptor-dependent effects on vascular gene expression. The specific aims are to determine the direct effects of estrogen on transcriptional events in vascular smooth muscle (VSMC) and endothelial cells (vEC) in order to gain insights into the progression of the disease as well as potential therapies to prevent this age-related disease.