A NEW GENE THERAPY USING ANTISENSE STRATEGY TO ESTROGEN RECEPTORS (ER .ALPHA. AND/OR ER .BETA.) TO OPTIMIZE VASCULAR HEALING AND CARDIOPROTECTION AFTER VASCULAR INJURY

摘要

Restenosis is a major limitation of percutaneouscoronary intervention. Migration and proliferation of vascular cells remaina cornerstone in neointimal formation and vascular healing. Recently, wehave shown that local delivery of 17-beta-estradiol (17.beta.E) preventsrestenosis following angioplasty by improving vascular healing. Indeed,17.beta.E inhibited muscle cell proliferation but, on the contrary, favorizedtheendothelial cell proliferation and function. We herein investigate the effectof an acute administration of 17.beta.E on mitogen-activated protein kinase(MAPK) activity, migration and proliferation of porcine aortic endothelialcells (PAEC) and smooth muscle cells (PSMC). On cultured PAEC andPSMC, we evaluated the effect of 17.beta.E (10 -10 to 10 -7 M) ~ selective17.beta.Eantagonists (Tamoxifen (Tam), 4OH-Tamoxifen (4OH-Tam) and Raloxifen(Ral)) on cell migration and proliferation. The results suggest that inPSMC, chemotatic and mitogenic effect of PDGF-BB as well as p38 andp42/44 MAPK phosphorylation are inhibited by 17.beta.E. In contrast, 17.beta.Epromotes in PAEC the phosphorylation of p42/44 and p38 MAPK as wellas the migration and proliferation of these cells. The effects of 17.beta.Earereversed by the antagonists on these markers in both cell types. Inconclusion, 17.beta.E may improve the vascular healing process by promotingPAEC proliferation and migration and by inhibiting the same events inPSMC. Since at least two estrogen receptors are (ER .alpha. and ER .beta.) areinvolved in estrogens activity, we propose to silence with antisensemolecules the expression of one or both receptors, alone or incombination with the administration of 17.beta.E, to optimize the effect ofestrogens on vascular target cells, as well as on other estrogen-responsive cells.