Published online before print July 31, 2003, doi: 10.1161/01.RES.0000088640.18462.42
© 2003 American Heart Association, Inc.
Molecular Medicine |
Specific Contribution of Estrogen Receptors on Mitogen-Activated Protein Kinase Pathways and Vascular Cell Activation
From the Research Center (P.G., M.G.S., J.-F.T.), Montreal Heart Institute, and Departments of Medicine (P.G., J.-F.T.) and Pharmacology (M.G.S.), University of Montreal, Montreal, Quebec, Canada.
Correspondence to Dr Jean-François Tanguay, Research Center, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec, H1T 1C8, Canada. E-mail tanguay{at}icm.umontreal.ca
Randomized clinical trials have not provided conclusive data that hormone replacement therapy confers cardioprotection against coronary artery disease in postmenopausal women. However, other studies have shown that estrogens can induce beneficial effects on the vasculature. Nevertheless, the specific contribution of estrogen receptors (ERs) 
and ß on vascular cells is not well characterized. Therefore, we used an antisense gene therapy approach to investigate the contribution of ER and ERß on p38 and p42/44 mitogen-activated protein kinase (MAPK) activation and on vascular cell responsiveness. Treatment of porcine smooth muscle cells (PSMCs) with platelet-derived growth factor-BB induced p38 and p42/44 MAPK activation and their migration and proliferation. These effects were prevented by pretreatment with 17ß-estradiol (17ßE). The inhibitory effects of 17ßE on PSMCs were abrogated by the downregulation of ERß protein expression with selective ERß mRNA antisense oligomers, whereas the downregulation of ER had no effect. However, treatment of porcine aortic endothelial cells with 17ßE promoted p38 and p42/44 MAPK phosphorylation and their migration and proliferation. These effects were ER dependent, as defined by antisense gene therapy. These results suggest that in PSMCs, 17ßE reduces p42/44 and p38 MAPK activity through ERß stimulation, whereas in contrast, in porcine aortic endothelial cells, 17ßE induces p42/44 and p38 MAPK through ER activation. 17ßE may contribute to the vascular healing process and to the prevention of restenosis by improving reendothelialization through ER activation and by decreasing smooth muscle cell migration and proliferation through ERß stimulation.
Key Words: 17ß-estradiol • estrogen receptors • vascular cells • mitogen-activated protein kinase
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