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(Circulation. 1998;98:413-421.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Estrogen Stimulates Delayed Mitogen-Activated Protein Kinase Activity in Human Endothelial Cells via an Autocrine Loop That Involves Basic Fibroblast Growth Factor

Seunghee Kim-Schulze, PhD; William L. Lowe, Jr, MD; ; H. William Schnaper, MD

From the Division of Nephrology, Department of Pediatrics, Northwestern University Medical School and the Children's Memorial Institute for Education and Research (S.K.-S., H.W.S.), and the Department of Medicine (W.L.L.), VA Chicago Healthcare System, Northwestern University Medical School, Chicago, Ill.

Correspondence to Seunghee Kim-Schulze, PhD, Pediatrics W-140, 303 E Chicago Ave, Chicago, IL 60611-3008. E-mail ski057{at}nwu.edu

Background—Estrogen plays a significant role in protecting premenopausal women from cardiovascular disease. We have found that estradiol augments endothelial cell activities related to vascular healing and that human coronary artery and umbilical vein endothelial cells express estrogen receptors (ERs). Classically, the ER functions as a transcription factor, but the cytoplasmic targets of this genomic effect have not been defined for endothelial cells. In the present study, we examined the potential role of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 as mediators of estrogen action.

Methods and Results—Human umbilical vein endothelial cells were estrogen depleted by culturing in hormone-free medium for 48 hours before experiments. 17ß-Estradiol (E2) stimulated a delayed (3 hours) 5- to 7-fold induction of ERK1/2 activity requiring activation of ER and new transcription/translation. Conditioned media from cells stimulated for 3 hours with E2 induced immediate ERK1/2 activation and phosphorylation of the basic fibroblast growth factor (bFGF) receptor. Moreover, ERK1/2 activation by E2 or by conditioned media was abrogated by treatment with neutralizing anti-bFGF antibody.

Conclusions—These data describe an autocrine mechanism for E2 induction of ERK1/2 in HUVEC. Because our previous studies suggested that certain cardioprotective effects of estrogen are genomic in nature, the results are consistent with the hypothesis that autocrine stimulation of endothelial ERK1/2 activity by bFGF may play a role in the beneficial effects of estrogen on cardiovascular biology.

Key Words: fibroblast growth factor, basic • endothelium • signal transduction • p 42 (MAP K) kinase

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