EFFECTS OF GONADAL-STEROIDS AND THEIR ANTAGONISTS ON DNA-SYNTHESIS INHUMAN VASCULAR CELLS

The cardiovascular effect of estrogen is currently under intense inves tigation, but the role of androgens in vascular biology has attracted little attention. Because endothelial repair and vascular smooth muscl e cell (VSMC) proliferation affect atherogenesis, we analyzed the effe cts of 17 beta-estradiol (E-2), dihydrotestosterone (DHT), and sex hor mone antagonists on DNA synthesis in human umbilical VSMCs and in E304 cells (a human umbilical endothelial cell line). In VSMCs, both E-2 a nd DHT had a biphasic effect on [H-3]thymidine incorporation into DNA: low concentrations (0.3 nmol/L for E-2, 3 nmol/L for DHT) stimulated [H-3]thymidine incorporation (+35% and +41%, respectively), whereas hi gh concentrations (30 nmol/L for E-2, 300 nmol/L for DHT) inhibited [H -3]thymidine incorporation (-40%). In contrast, E-2 (0.3 to 300 nmol/L ) and DHT (3 to 3000 nmol/L) dose-dependently enhanced [H-3]thymidine incorporation in E304 cells (peak, +85% for both). In VSMCs, high conc entrations of E-2 and DHT inhibited platelet-derived growth factor (PD GF)-or insulin-like growth factor (IGF-1)-induced DNA synthesis (-50% to 80%), whereas PDGF- or IGF-1-dependent DNA synthesis in E304 cells was further increased by E-2. The antiestrogens tamoxifen and raloxife ne mimicked the effects of E-2 on DNA synthesis in both VSMCs and E304 cells. However, when coincubated with a stimulatory concentration bf E2 (0.3 nmol/L), tamoxifen and raloxifene blocked E-2-induced [H-3]thy midine incorporation in E304 cells but not in VSMCs. Finally, the andr ogen antagonist flutamide inhibited the biphasic effects of DHT on VSM Cs and blocked the increase in DNA elicited by DHT in E304 cells. The results suggest complex, dose-dependent, and cell-specific interaction s of estrogens, androgens, and their respective antagonists in the con trol of cellular proliferation in the vascular wall. Gonadal steroid-d ependent inhibition of VSMC proliferation and stimulation of endotheli al replication may contribute to vascular protection and remodeling re sponses to vascular injury.