Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053918-06
Application #
6125880
Study Section
Pathology A Study Section (PTHA)
Project Start
1994-08-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
6
Fiscal Year
2000
Total Cost
$219,646
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Groten, Tanja; Pierce, Amy A; Huen, Arthur C et al. (2005) 17 beta-estradiol transiently disrupts adherens junctions in endothelial cells. FASEB J 19:1368-70
Chavers, B; Schnaper, H W (2001) Risk factors for cardiovascular disease in children on maintenance dialysis. Adv Ren Replace Ther 8:180-90
Albuquerque, M L; Waters, C M; Savla, U et al. (2000) Shear stress enhances human endothelial cell wound closure in vitro. Am J Physiol Heart Circ Physiol 279:H293-302
Schnaper, H W; McGuire, J; Runyan, C et al. (2000) Sex steroids and the endothelium. Curr Med Chem 7:519-31
Schnaper, H W (1999) Estrogen: it's not just for reproduction any more. Kidney Int 55:1577-9
Poncelet, A C; de Caestecker, M P; Schnaper, H W (1999) The transforming growth factor-beta/SMAD signaling pathway is present and functional in human mesangial cells. Kidney Int 56:1354-65
Eddy, A A; Schnaper, H W (1998) The nephrotic syndrome: from the simple to the complex. Semin Nephrol 18:304-16
Kim-Schulze, S; Lowe Jr, W L; Schnaper, H W (1998) Estrogen stimulates delayed mitogen-activated protein kinase activity in human endothelial cells via an autocrine loop that involves basic fibroblast growth factor. Circulation 98:413-21
Albuquerque, M L; Akiyama, S K; Schnaper, H W (1998) Basic fibroblast growth factor release by human coronary artery endothelial cells is enhanced by matrix proteins, 17beta-estradiol, and a PKC signaling pathway. Exp Cell Res 245:163-9
Schnaper, H W; McGowan, K A; Kim-Schulze, S et al. (1996) Oestrogen and endothelial cell angiogenic activity. Clin Exp Pharmacol Physiol 23:247-50

Showing the most recent 10 out of 13 publications