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.
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