From the Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Medical College, Soochow University, Suzhou, China (Y.H., R.Y., C.Z., Z.Z., M.L., C.W., L.D., T.Z., Y.W., N.D., Q.W.).
Department of Pathophysiology, Medical School of Nantong University, China (Y.H.).
Arterioscler Thromb Vasc Biol. 2018 Jun;38(6):1381-1391. doi: 10.1161/ATVBAHA.118.310940. Epub 2018 Apr 12.
Thrombophilia is a major complication in preeclampsia, a disease associated with placental hypoxia and trophoblast inflammation. Preeclampsia women are known to have increased circulating microparticles that are procoagulant, but the underlying mechanisms remain unclear. In this study, we sought to understand the mechanism connecting placental hypoxia, circulating microparticles, and thrombophilia.
We analyzed protein markers on plasma microparticles from preeclampsia women and found that the increased circulating microparticles were mostly from endothelial cells. In proteomic studies, we identified HMGB1 (high-mobility group box 1), a proinflammatory protein, as a key factor from hypoxic trophoblasts in stimulating microparticle production in human umbilical vein endothelial cells. Immunodepletion or inhibition of HMGB1 in the conditioned medium from hypoxic human trophoblasts abolished the endothelial microparticle-stimulating activity. Conversely, recombinant HMGB1 stimulated microparticle production in cultured human umbilical vein endothelial cells. The microparticles from recombinant HMGB1-stimulated human umbilical vein endothelial cells promoted blood coagulation and neutrophil activation in vitro. Injection of recombinant HMGB1 in pregnant mice increased plasma endothelial microparticles and promoted blood coagulation. In preeclampsia women, elevated placental HMGB1 expression was detected and high levels of plasma HMGB1 correlated with increased plasma endothelial microparticles.
Our results indicate that placental hypoxia-induced HMGB1 expression and release from trophoblasts are important mechanism underlying increased circulating endothelial microparticles and thrombophilia in preeclampsia.
血栓形成倾向是子痫前期的主要并发症，子痫前期是一种与胎盘缺氧和滋养细胞炎症相关的疾病。已知子痫前期妇女的循环中存在促凝的微颗粒增加，但潜在机制尚不清楚。在这项研究中，我们试图了解连接胎盘缺氧、循环微颗粒和血栓形成倾向的机制。
我们分析了子痫前期妇女血浆微颗粒中的蛋白质标志物，发现增加的循环微颗粒主要来自内皮细胞。在蛋白质组学研究中，我们鉴定出 HMGB1（高迁移率族蛋白 B1），一种促炎蛋白，作为缺氧滋养细胞中刺激人脐静脉内皮细胞微颗粒产生的关键因子。免疫耗竭或抑制缺氧人滋养细胞条件培养基中的 HMGB1 可消除内皮微颗粒刺激活性。相反，重组 HMGB1 刺激培养的人脐静脉内皮细胞产生微颗粒。来自重组 HMGB1 刺激的人脐静脉内皮细胞的微颗粒在体外促进血液凝固和中性粒细胞活化。在怀孕小鼠中注射重组 HMGB1 增加了血浆内皮微颗粒并促进了血液凝固。在子痫前期妇女中，检测到胎盘 HMGB1 表达升高，血浆 HMGB1 水平与血浆内皮微颗粒增加相关。
我们的结果表明，胎盘缺氧诱导的滋养细胞 HMGB1 表达和释放是子痫前期循环内皮微颗粒和血栓形成倾向增加的重要机制。
