Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Korea.
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
Exp Mol Med. 2018 Dec 17;50(12):1-9. doi: 10.1038/s12276-018-0193-z.
Estrogen has diverse effects on cardiovascular function, including regulation of the contractile response to vasoactive substances such as serotonin. The serotonin system recently emerged as an important player in the regulation of vascular tone in humans. However, hyperreactivity to serotonin appears to be a critical factor for the pathophysiology of hypertension. In this study, we examined the modulatory mechanisms of estrogen in serotonin-induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. 17β-Estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aortic strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes are not mediated by estrogen receptor. Patch-clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which was significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK293T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerts vasodilatory effects on serotonin-precontracted arteries via Src, implying a critical role for estrogen in the prevention of vascular hyperreactivity to serotonin.
雌激素对心血管功能有多种影响，包括调节血管活性物质（如 5-羟色胺）的收缩反应。5-羟色胺系统最近成为调节人类血管张力的重要因素。然而，对 5-羟色胺的高反应性似乎是高血压病理生理学的一个关键因素。在这项研究中，我们使用等长张力测量、分子生物学和膜片钳技术的组合方法，研究了雌激素在 5-羟色胺诱导的血管收缩中的调节机制。17β-雌二醇（E2）在从雄性大鼠分离的去内皮主动脉条中引起 5-羟色胺诱导收缩的显著浓度依赖性舒张。即使在雌激素受体拮抗剂他莫昔芬存在的情况下，E2 也引发了 5-羟色胺诱导收缩的舒张，这表明 E2 诱导的变化不是由雌激素受体介导的。大鼠动脉平滑肌细胞的膜片钳研究表明，E2 可防止 5-羟色胺诱导的 Kv 通道抑制。5-羟色胺增加了动脉平滑肌收缩所需的Src 激活，而 E2 显著抑制了这种激活。在不表达雌激素受体的 HEK293T 细胞中，证实了 E2 对 Src 的雌激素受体非依赖性抑制。综上所述，这些结果表明，雌激素通过 Src 对 5-羟色胺预收缩的动脉发挥血管舒张作用，提示雌激素在预防 5-羟色胺引起的血管高反应性方面发挥着关键作用。
