Background

Abstract-The cardiovascular effect of estrogen is currently under intense investigation, but the role of androgens in vascular biology has attracted little attention. Because endothelial repair and vascular smooth muscle cell (VSMC) proliferation affect atherogenesis, we analyzed the effects of 17␤-estradiol (E 2 ), dihydrotestosterone (DHT), and sex hormone antagonists on DNA synthesis in human umbilical VSMCs and in E304 cells (a human umbilical endothelial cell line). In VSMCs, both E 2 and DHT had a biphasic effect on [ 3 H]thymidine incorporation into DNA: low concentrations (0.3 nmol/L for E 2 , 3 nmol/L for DHT) stimulated [ 3 H]thymidine incorporation (ϩ35% and ϩ41%, respectively), whereas high concentrations (30 nmol/L for E 2 , 300 nmol/L for DHT) inhibited [ 3 H]thymidine incorporation (Ϫ40%). In contrast, E 2 (0.3 to 300 nmol/L) and DHT (3 to 3000 nmol/L) dose-dependently enhanced [ 3 H]thymidine incorporation in E304 cells (peak, ϩ85% for both). In VSMCs, high concentrations of E 2 and DHT inhibited platelet-derived growth factor (PDGF)-or insulin-like growth factor (IGF-1)-induced DNA synthesis (Ϫ50% to 80%), whereas PDGF-or IGF-1-dependent DNA synthesis in E304 cells was further increased by E 2 . The antiestrogens tamoxifen and raloxifene mimicked the effects of E 2 on DNA synthesis in both VSMCs and E304 cells. However, when coincubated with a stimulatory concentration of E 2 (0.3 nmol/L), tamoxifen and raloxifene blocked E 2 -induced