ESTROGEN EFFECTS ON VASCULAR SMOOTH MUSCLE CELL GROWTH

雌激素对血管平滑肌细胞生长的影响

• 批准号: 2211078
• 负责人: RICHARD H KARAS
• 金额: $ 8.15万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2211078
• 关键词: RNase protection assay; aorta; biological signal transduction; cardiovascular disorder; cell cycle; cell growth regulation; coronary artery; estradiol; estrogen receptors; gene expression; genetic regulatory element; hormone regulation /control mechanism; human tissue; immunofluorescence technique; muscle cells; polymerase chain reaction; radiotracer; receptor expression; reporter genes; sex hormones; tissue /cell culture; transfection; vascular smooth muscle; western blottings

The incidence of coronary artery disease (CAD) in women is increased in estrogen (E2) deficient states and decreased with postmenopausal E2 replacement. Previous hypotheses to explain this observation are based primarily on indirect effects of E2 on cardiovascular risk factors. Since vascular smooth muscle cell (VSMC) proliferation plays a critical role in the development of CAD, l propose to investigate the hypothesis that steroid sex hormones directly modulate the growth responses of VSMC. Based on preliminary cell culture studies, we provide data demonstrating: (a) the presence of estrogen receptor in human VSMC and (b) an inhibitory effect of E2 on VSMC proliferation. This proposal seeks to pursue three Specific Aims. Specific Aim 1 includes characterization of the abundance, distribution and function of steroid sex hormone receptors in VSMC. Specific Aim 2 involves investigation of the effect of steroid sex hormones on the proliferation of VSMC. Specific Aim 3 is to study the molecular pathways mediating growth-regulatory effects of steroid sex hormones on VSMC, including experiments to: (a) identify steroid sex hormone-induced changes in gene expression, and (b) explore "cross-talk" between cell surface receptor and steroid sex hormone receptor-mediated pathways. Cells from different vascular beds and from normal and diseased tissues will be studied using VSMC cultured from human saphenous vein, mammary artery, aorta, and coronary atherectomy specimens. These studies have important implications for understanding the pathophysiology and treatment of CAD in both men and women, and are therefore of central relevance to cardiovascular biology.

女性冠状动脉疾病（CAD）的发病率增加 雌激素（E2）不足状态，并随绝经后E2减少 替代品。以前的假设来解释该观察是基于 主要基于E2对心血管危险因素的间接影响。自从 血管平滑肌细胞（VSMC）增殖在 CAD的发展，L提出调查以下假设。 类固醇性激素直接调节VSMC的生长反应。基于 关于初步细胞培养研究，我们提供数据证明：（a） 人VSMC和（b）抑制性雌激素受体的存在 E2对VSMC增殖的影响。该提议试图追求三个 具体目标。特定的目标1包括表征丰度， 类固醇性激素受体在VSMC中的分布和功能。 特定目标2涉及对类固醇性别的作用进行调查 VSMC增殖的激素。特定目标3是研究 分子途径介导类固醇性别的生长调节作用 VSMC上的激素，包括：（a）识别类固醇性别的实验 激素诱导的基因表达变化，（b）探索“交叉对话” 在细胞表面受体和类固醇性激素受体介导的之间 途径。来自不同血管床以及正常和患病的细胞 将使用从人类隐静脉培养的VSMC研究组织， 乳腺动脉，主动脉和冠状动脉动脉切除术标本。这些研究 对理解病理生理学和 男性和女性的CAD治疗，因此是中心的 与心血管生物学有关。