Cardiovascular and Metabolic Research Unit, Laurentian University, Ontario, Canada.
School of Human Kinetics, Faculty of Health, Laurentian University, Ontario, Canada.
J Endocrinol. 2021 Jan;248(1):17-30. doi: 10.1530/JOE-20-0190.
Both estrogen and hydrogen sulfide (H2S) inhibit the proliferation of vascular smooth muscle cells (SMCs) and development of atherosclerosis. In the absence of endogenous H2S as occurred in CSE-knockout (KO) mouse, however, estrogen stimulates the proliferation of vascular SMCs. The underlying mechanisms for this seemingly controversial vascular effect of estrogen are unclear. In the present study, we demonstrated that the stimulatory effect of estrogen on the proliferation of CSE-KO SMCs was suppressed by the inhibitor of insulin-like growth factor-1 receptor (IGF-1R) or knockdown of IGF-1R protein expression. Estrogen downregulated the expression of insulin-like growth factor-1 (IGF-1) and IGF-1R in aortic tissues or aortic SMCs isolated from WT and CSE-KO mice. Furthermore, endogenous H2S downregulated IGF-1R, but upregulated estrogen receptor (ER)-α, in aortic tissues or SMCs. ER-α and IGF-1R were co-located in SMCs and co-immunoprecipitated, which was decreased by H2S. Finally, both endogenous and exogenous H2S induced the S-sulfhydration of IGF-1R, but not ER-α, in WT-SMCs and CSE-KO SMCs, which underlies the decreased formation of IGF-1R/ER-α hybrid in the presence of H2S. Thus, the absence of H2S favors the interaction of estrogen with IGF-1R/ER-α hybrid to stimulate SMCs proliferation. The appreciation of a critical role of H2S in preventing estrogen-induced SMCs proliferation will help better understand the regulation of complex vascular effects of estrogen and sex-related cardiovascular diseases.
雌激素和硫化氢 (H2S) 均可抑制血管平滑肌细胞 (VSMCs) 的增殖和动脉粥样硬化的发展。然而，在 CSE 敲除 (KO) 小鼠中缺乏内源性 H2S 的情况下，雌激素会刺激血管平滑肌细胞的增殖。雌激素对血管产生这种看似矛盾的作用的潜在机制尚不清楚。在本研究中，我们证明了雌激素对 CSE-KO 血管平滑肌细胞增殖的刺激作用被胰岛素样生长因子-1 受体 (IGF-1R) 抑制剂或 IGF-1R 蛋白表达敲低所抑制。雌激素下调了 WT 和 CSE-KO 小鼠主动脉组织或主动脉平滑肌细胞中胰岛素样生长因子-1 (IGF-1) 和 IGF-1R 的表达。此外，内源性 H2S 下调了主动脉组织或平滑肌细胞中的 IGF-1R，但上调了雌激素受体 (ER)-α。ER-α 和 IGF-1R 位于平滑肌细胞中并发生共免疫沉淀，而 H2S 会降低这种共沉淀。最后，内源性和外源性 H2S 均可诱导 WT-平滑肌细胞和 CSE-KO 平滑肌细胞中 IGF-1R 的 S-巯基化，但不诱导 ER-α 的 S-巯基化，这是由于 H2S 存在时 IGF-1R/ER-α 杂交体的形成减少。因此，缺乏 H2S 有利于雌激素与 IGF-1R/ER-α 杂交体相互作用，从而刺激平滑肌细胞增殖。对 H2S 在防止雌激素诱导的平滑肌细胞增殖中的关键作用的认识，将有助于更好地理解雌激素对复杂血管作用的调节以及与性别相关的心血管疾病。
