Department of New Biology, DGIST, Daegu, 42988, South Korea.
Department of Medicine, University of Rochester School of Medicine, Rochester, NY, 14642, USA.
Biochem Biophys Res Commun. 2021 Jun 18;558:29-35. doi: 10.1016/j.bbrc.2021.04.019. Epub 2021 Apr 22.
Estrogen therapy is used to treat patients with post-menopausal symptoms, such as hot flashes and dyspareunia. Estrogen therapy also decreases the risk of fractures from osteoporosis in post-menopausal women. However, estrogen increases the risk of venous thromboembolic events, such as pulmonary embolism, but the pathways through which estrogen increase the risk of thromboembolism is unknown. Here, we show that estrogen elicits endothelial exocytosis, the key step in vascular thrombosis and inflammation. Exogenous 17β-estradiol (E2) stimulated endothelial exocytosis of Weibel-Palade bodies (WPBs), releasing von Willebrand factor (vWF) and interleukin-8 (IL-8). Conversely, the estrogen antagonist ICI-182,780 interfered with E2-induced endothelial exocytosis. The ERα agonist propyl pyrazole triol (PPT) but not the ERβ agonist diarylpropionitrile (DPN) induced vWF release, while ERα silencing counteracted vWF release by E2, suggesting that ERα mediates this effect. Exocytosis triggered by E2 occurred rapidly within 15 min and was not inhibited by either actinomycin D or cycloheximide. On the contrary, it was inhibited by the pre-treatment of U0126 or SB203580, an ERK or a p38 inhibitor, respectively, suggesting that E2-induced endothelial exocytosis is non-genomically mediated by the MAP kinase pathway. Finally, E2 treatment enhanced platelet adhesion to endothelial cells ex vivo, which was interfered with the pre-treatment of ICI-182,780 or U0126. Taken together, our data show that estrogen activates endothelial exocytosis non-genomically through the ERα-MAP kinase pathway. Our data suggest that adverse cardiovascular effects such as vascular inflammation and thrombosis should be considered in patients before menopausal hormone treatment.
雌激素治疗用于治疗绝经后妇女的症状，如热潮红和性交困难。雌激素治疗还降低了绝经后妇女骨质疏松性骨折的风险。然而，雌激素会增加静脉血栓栓塞事件（如肺栓塞）的风险，但雌激素增加血栓栓塞风险的途径尚不清楚。在这里，我们表明雌激素会引发内皮细胞胞吐作用，这是血管血栓形成和炎症的关键步骤。外源性 17β-雌二醇（E2）刺激血管内皮细胞 Weibel-Palade 体（WPB）的胞吐作用，释放血管性血友病因子（vWF）和白细胞介素-8（IL-8）。相反，雌激素拮抗剂 ICI-182,780 干扰了 E2 诱导的内皮细胞胞吐作用。雌激素受体α激动剂丙基吡唑三醇（PPT）而不是雌激素受体β激动剂二苯丙腈（DPN）诱导 vWF 释放，而 ERα 沉默则抵消了 E2 诱导的 vWF 释放，表明 ERα 介导了这种作用。E2 触发的胞吐作用在 15 分钟内迅速发生，并且不受放线菌 D 或环己酰亚胺的抑制。相反，它被 U0126 或 SB203580（分别为 ERK 或 p38 抑制剂）的预处理所抑制，表明 E2 诱导的内皮细胞胞吐作用是非基因组介导的通过 MAP 激酶途径。最后，E2 处理增强了血小板在体外与内皮细胞的黏附，这一作用被 ICI-182,780 或 U0126 的预处理所干扰。总之，我们的数据表明，雌激素通过 ERα-MAP 激酶途径非基因组激活内皮细胞胞吐作用。我们的数据表明，在进行绝经激素治疗之前，应考虑雌激素治疗对患者的不良心血管影响，如血管炎症和血栓形成。
