Specific contribution of estrogen receptors on mitogen-activated protein kinase pathways and vascular cell activation

Abstract

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) α and β on vascular cells is not well characterized. Therefore, we used an antisense gene therapy approach to investigate the contribution of ERα and ERβ 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 17β-estradiol (17βE). The inhibitory effects of 17βE on PSMCs were abrogated by the downregulation of ERβ protein expression with selective ERβ mRNA antisense oligomers, whereas the downregulation of ERα had no effect. However, treatment of porcine aortic endothelial cells with 17βE promoted p38 and p42/44 MAPK phosphorylation and their migration and proliferation. These effects were ERα dependent, as defined by antisense gene therapy. These results suggest that in PSMCs, 17βE reduces p42/44 and p38 MAPK activity through ERβ stimulation, whereas in contrast, in porcine aortic endothelial cells, 17βE induces p42/44 and p38 MAPK through ERα activation. 17βE may contribute to the vascular healing process and to the prevention of restenosis by improving reendothelialization through ERα activation and by decreasing smooth muscle cell migration and proliferation through ERβ stimulation.