ESTROGEN AND ENDOTHELIAL MIGRATION AND DIFFERENTIATION

来自临床和实验室观察的大量证据 显示了男性和女性血管生物学的显著差异。 其中一些发现表明，女性性腺类固醇，特别是 雌激素，影响内皮细胞对多种 刺激。目前的赠款申请是基于这样的假设， 女性性激素对绝经前妇女心脏的保护作用 部分原因是内皮细胞行为的激素增强 与再内皮化相关（主要在大血管中）， 血管生成（主要）。小型船舶）。我们的初步数据， 通过研究培养的人脐静脉内皮细胞获得， 表明雌二醇增加细胞分裂，粘附， 迁移和组织/分化。我们在此提议 以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相似的敏感性， 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， 体外培养HCAEC的粘附、迁移和形态分化， 雌二醇或孕酮的存在或不存在。的机制 哪种雌激素调节这些行为将由 说明与移徙有关的活动的特点， 分化，包括基质蛋白合成，表达 基质蛋白的整合素受体，以及细胞外 基质蛋白酶将测试雌激素活性抑制剂的 能够调节这些活动。其次，我们将确定 雌激素反应性反映了HCAEC的雌激素受体表达， 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， 培养的细胞降低氧张力。雌二醇对 将检查我们的测定系统中的缺氧反应。这些研究 应该提供关于内皮细胞调节有用数据 女性性腺类固醇的行为，并可能提供深入了解 在绝经前妇女中观察到的冠状动脉疾病的改善。

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.