Somjen D, Kohen F, Jaffe A, Amir-Zaltsman Y, Knoll E, Stern N
Institute of Endocrinology, Tel Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, Israel.
Hypertension. 1998 Jul;32(1):39-45. doi: 10.1161/01.hyp.32.1.39.
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 17beta-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.
雌激素对心血管的影响目前正在深入研究，但雄激素在血管生物学中的作用却很少受到关注。由于内皮修复和血管平滑肌细胞（VSMC）增殖会影响动脉粥样硬化的发生，我们分析了17β-雌二醇（E2）、双氢睾酮（DHT）和性激素拮抗剂对人脐VSMC和E304细胞（一种人脐内皮细胞系）中DNA合成的影响。在VSMC中，E2和DHT对[3H]胸腺嘧啶核苷掺入DNA均有双相作用：低浓度（E2为0.3 nmol/L，DHT为3 nmol/L）刺激[3H]胸腺嘧啶核苷掺入（分别增加35%和41%），而高浓度（E2为30 nmol/L，DHT为300 nmol/L）则抑制[3H]胸腺嘧啶核苷掺入（降低40%）。相比之下，E2（0.3至300 nmol/L）和DHT（3至3000 nmol/L）在E304细胞中呈剂量依赖性增强[3H]胸腺嘧啶核苷掺入（峰值时两者均增加85%）。在VSMC中，高浓度的E2和DHT抑制血小板衍生生长因子（PDGF）或胰岛素样生长因子（IGF-1）诱导的DNA合成（降低50%至80%），而E2则进一步增加E304细胞中依赖PDGF或IGF-1的DNA合成。抗雌激素药物他莫昔芬和雷洛昔芬在VSMC和E304细胞中均模拟了E2对DNA合成的作用。然而，当与刺激浓度的E2（0.3 nmol/L）共同孵育时，他莫昔芬和雷洛昔芬阻断了E2诱导的E304细胞中[3H]胸腺嘧啶核苷掺入，但未阻断VSMC中的掺入。最后，雄激素拮抗剂氟他胺抑制了DHT对VSMC的双相作用，并阻断了DHT在E304细胞中引起的DNA增加。结果表明，雌激素、雄激素及其各自拮抗剂在控制血管壁细胞增殖方面存在复杂的、剂量依赖性的和细胞特异性的相互作用。性腺类固醇依赖性抑制VSMC增殖和刺激内皮复制可能有助于血管对血管损伤的保护和重塑反应。
