ESTROGEN AND ENDOTHELIAL MIGRATION AND DIFFERENTIATION

来自临床和实验室观察的大量证据 显示了男性和女性在血管生物学方面的显著差异。 其中一些发现表明，女性性腺类固醇，尤其是 雌激素，影响内皮细胞对各种 刺激物。目前的赠款申请是基于这样的假设： 绝经前妇女性激素的心脏保护作用 部分原因是激素促进了内皮细胞的行为 与再内皮化相关(主要是在大血管中)和 血管生成(主要)。在小船上)。我们的初步数据， 对培养的人脐静脉内皮细胞进行研究， 表明雌二醇会增加细胞分裂、黏附、 这些细胞的迁移和组织/分化。我们在这里求婚 为确定培养的人冠状动脉内皮细胞 (HCAEC)对女性性腺类固醇表现出类似的敏感性，并研究 这些激素增强内皮细胞反应的机制。 提出了三个具体目标。首先，我们将评估增长， HCAEC在体外的黏附、迁移和形态分化 在有或没有雌二醇或孕酮的情况下。这个机制是通过 哪些雌激素调节这些行为将由 描述与迁移相关的活动以及 分化，包括基质蛋白的合成，表达 基质蛋白整合素受体与胞外产物 基质蛋白酶。雌激素活性抑制剂将进行测试，以确定 调节这些活动的能力。第二，我们将确定是否 雌激素反应性反映HCAEC雌激素受体的表达， 并检测细胞-基质相互作用对雌激素受体的影响 表情。第三，我们建议模拟内皮损伤 培养细胞以降低氧分压。雌二醇对大鼠血管紧张素转换酶的影响 我们的检测系统中的低氧反应将被检查。这些研究 应提供有关内皮细胞调节的有用数据 女性性腺类固醇激素的行为，并可能提供对 绝经前妇女冠状动脉疾病的改善情况。

A significant body of evidence from clinical and laboratory observation demonstrates marked differences in the vascular biology of men and women. Some of these findings suggest that female gonadal steroids, especially estrogens, affect the responsiveness of endothelial cells to a variety of stimuli. The present grant application is based on the hypothesis that the cardioprotective effects of female sex hormones in premenopausal women result in part from hormonal enhancement of endothelial cell behaviors associated with reendothelialization (mostly in large vessels) and angiogenesis (primarily). in small vessels). Our preliminary data, obtained studying cultured human umbilical vein endothelial cells, indicate that estradiol increases rates of cell division, adhesion, migration and organization/differentiation by these cells. We propose here to determine whether cultured human coronary artery endothelial cells (HCAEC) show similar sensitivity to female gonadal steroids, and to study the mechanisms by which these hormones enhance endothelial cell responses. Three specific aims are proposed. First, we will evaluate growth, adhesion, migration, and morphological differentiation of HCAEC in vitro, in the presence or absence of estradiol or progesterone. The mechanism by which estrogen modulates these behaviors will be examined by characterizing activities that have been associated with migration and differentiation, including matrix protein synthesis, expression of integrin receptors for matrix proteins, and production of extracellular matrix proteases. Inhibitors of estrogen activity will be tested for the ability to modulate these activities. Second, we will determine whether estrogen responsiveness reflects estrogen receptor expression by HCAEC, and examine the effects of cell-matrix interactions on estrogen receptor expression. Third, we propose to simulate endothelial injury by subjecting cultured cells to decreased oxygen tension. The effect of estradiol on hypoxic responses in our assay systems will be examined. These studies should provide useful data regarding modulation of endothelial cell behavior by female gonadal steroids, and may provide insight into the amelioration of coronary artery disease observed in pre-menopausal women.