ESTROGEN STIMULATES DELAYED MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITYIN HUMAN ENDOTHELIAL-CELLS VIA AN AUTOCRINE LOOP THAT INVOLVES BASIC FIBROBLAST-GROWTH-FACTOR

Background-Estrogen plays a significant role in protecting premenopaus al women from cardiovascular disease. We have found that estradiol aug ments endothelial cell activities related to vascular healing and that human coronary artery and umbilical vein endothelial cells express es trogen receptors (ERs). Classically, the ER functions as a transcripti on 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 ERK 1 and ERK2 as mediators of estrogen action. Methods and Results-Human umbilical vein endothelial cells were estrogen depleted by culturing i n hormone-free medium for 48 hours before experiments. 17 beta-Estradi ol (E2) stimulated a delayed (3 hours) 5- to 7-fold induction of ERK1/ 2 activity requiring activation of ER and new transcription/translatio n. Conditioned media from cells stimulated for 3 hours with E2 induced immediate ERK1/2 activation and phosphorylation of the basic fibrobla st growth factor (bFGF) receptor. Moreover, ERK1/2 activation by E2 or by conditioned media was abrogated by treatment with neutralizing ant i-bFGF antibody. Conclusions-These data describe an autocrine mechanis m for E2 induction of ERK1/2 in HUVEC, Because our previous studies su ggested that certain cardioprotective effects of estrogen are genomic in nature, the results are consistent with the hypothesis that autocri ne stimulation of endothelial ERK1/1 activity by bFGF may play a role in the beneficial effects of estrogen on cardiovascular biology.