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(Hypertension. 1998;32:39-45.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Effects of Gonadal Steroids and Their Antagonists on DNA Synthesis in Human Vascular Cells

Dalia Somjen; Fortune Kohen; Anat Jaffe; Yehudit Amir-Zaltsman; Esther Knoll; ; Naftali Stern

From the Institute of Endocrinology, Tel Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (D.S., A.J., E.K., N.S.) and Department of Biological Regulation, The Weizman Institute of Science, Rehovot (F.K., Y.A.-Z.), Israel.

Correspondence to N. Stern, MD, Institute of Endocrinology, Tel Aviv-Sourasky Medical Center, 6 Weizman St, Tel Aviv 64239, Israel.

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 17ß-estradiol (E₂), 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 E₂ and DHT had a biphasic effect on [³H]thymidine incorporation into DNA: low concentrations (0.3 nmol/L for E₂, 3 nmol/L for DHT) stimulated [³H]thymidine incorporation (+35% and +41%, respectively), whereas high concentrations (30 nmol/L for E₂, 300 nmol/L for DHT) inhibited [³H]thymidine incorporation (-40%). In contrast, E₂ (0.3 to 300 nmol/L) and DHT (3 to 3000 nmol/L) dose-dependently enhanced [³H]thymidine incorporation in E304 cells (peak, +85% for both). In VSMCs, high concentrations of E₂ and DHT inhibited platelet-derived growth factor (PDGF)–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 E₂. The antiestrogens tamoxifen and raloxifene mimicked the effects of E₂ on DNA synthesis in both VSMCs and E304 cells. However, when coincubated with a stimulatory concentration of E₂ (0.3 nmol/L), tamoxifen and raloxifene blocked E₂-induced [³H]thymidine incorporation in E304 cells but not in VSMCs. Finally, the androgen antagonist flutamide inhibited the biphasic effects of DHT on VSMCs and blocked the increase in DNA elicited by DHT in E304 cells. The results suggest complex, dose-dependent, and cell-specific interactions of estrogens, androgens, and their respective antagonists in the control of cellular proliferation in the vascular wall. Gonadal steroid–dependent inhibition of VSMC proliferation and stimulation of endothelial replication may contribute to vascular protection and remodeling responses to vascular injury.

Key Words: estradiol • dihydrotesterone • muscle, smooth, vascular • tamoxifen • raloxifene • flutamide

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