Decreased atherosclerotic cardiovascular disease in premenopausal women and enhancement of reflex vessel relaxation by estrogen suggest that estrogen has a significant effect on endothelial cell biology. The mechanisms underlying many of these effects are unknown. The applicant has previously determined that estrogen acts through an estrogen receptor to enhance endothelial cell attachment, proliferation, migration and organization; these actions may promote angiogenesis and endothelial healing. Moreover, 17b-estradiol stimulates activity of the p44mapk/p42mapk (ERK1/2) MAP kinases in endothelial cells by stimulating production and release of the autocrine hormone, bFGF. Preliminary findings indicate that estradiol treatment stimulates bFGF gene transcription, activates specific protein kinase C isozymes, increases the ERK response in cells treated with bFGF, and enhances endothelial cell-matrix interactions. Together, these findings support the hypothesis that estrogen increases growth factor-induced endothelial cell signal transduction. The overall goal of this project is to determine the mechanism(s) by which estrogen modulates endothelial cell signaling.
Three specific aims are proposed:
Aim 1 is designed to determine the mechanism(s) by which estrogen stimulates bFGF gene expression, examining effects of estrogen on bFGF mRNA stability and gene transcription.
Aim 2 will test the hypothesis that estrogen augments growth factor-related endothelial cell signaling transduction, testing the hypothesis that estrogen amplifies activity of specific PKC isozymes to modulate cell signaling and behavior.
Aim 3 will test the hypothesis that estrogen enhances cell-matrix interactions that facilitate endothelial cell signal transduction by examining the effect of estradiol on fibronectin-induced bFGF release, activation of endothelial cell integrins, formation and organization of focal adhesions and pp125FAK activity. These studies will elucidate regulatory effects of estradiol on endothelial cell function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Pathology A Study Section (PTHA)
Program Officer
Liang, Isabella Y
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Northwestern University at Chicago
Schools of Medicine
United States
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