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。在妇女中，许多临床相关的年龄相关疾病都与卵巢衰老和更年期导致的雌激素丧失有关。冠心病（CHD）是男性和女性死亡的主要原因，在绝经前妇女中并不常见。然而，在绝经后的妇女中，这种疾病变得越来越普遍，以至于冠心病成为60岁以上妇女死亡的主要原因。在切除卵巢的动物模型中，雌激素替代疗法已被证明可以降低绝经后妇女冠心病的发病率，并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通过改变传统的危险因素来解释，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很重要。然而，雌激素作用于动脉的细胞和分子机制尚不明确。雌激素受体存在于血管床和细胞中，表明雌激素可能通过其特异性受体调节血管功能。雌激素受体可能通过1)与靶基因调控区域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 - γ相互作用来调节基因表达。因此，虽然雌激素有可能调节许多基因，但对于雌激素对血管细胞转录事件的影响范围和深度知之甚少。最近发展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，并为确定雌激素作用的广度提供了一种极好的方法。提出的研究的中心假设是，雌激素抑制动脉粥样硬化的发生和进展，部分是通过雌激素受体对血管基因表达的直接依赖作用。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，以便深入了解疾病的进展以及预防这种年龄相关疾病的潜在治疗方法。

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.