子痫前期血液高凝状态的分子机制研究

Preeclampsia is a major disease in pregnancy, afflicting maternal and fetal health. Preeclamptic women are often associated with hypercoagulation and prone to thrombosis, which may lead to disseminated intravascular coagulation, organ failure and death. Placental hypoxia plays a key role in the pathogenesis of preeclampsia. In our preliminary studies, we found that placental hypoxia-induced high mobility group box-1 (HMGB1) stimulated endothelial cells to produce microparticles (MPs) that were potent in inducing NETosis, a specific form of neutrophil cell death. Molecules released from neutrophils during NETosis, including DNA, histones and elastase, are highly pro-thrombotic. Based on these results, we hypothesize that under hypoxic conditions, HMGB1 is up-regulated in placental trophoblasts and stimulates maternal endothelial cells to produce MPs, which in turn promote NETosis, thereby contributing to endothelial dysfunction and hypercoagulation in preeclampsia. We plan to conduct cellular and mouse model studies to test our hypothesis. Our studies should help to understand the mechanism underlying placental hypoxia-induced hypercoagulation and the risk of thrombosis, which may help to develop new strategies to prevent and treat pregnancy-associated thrombophilia.

子痫前期是危害母婴健康的重大疾病，患者常伴有血液高凝状态和血栓形成倾向，有发生弥漫性血管内凝血、器官衰竭，甚至死亡的风险。胎盘缺氧在子痫前期的发病机制中发挥着关键的作用。我们初步研究发现胎盘缺氧产生的HMGB1（high mobility group box-1）能刺激内皮细胞释放微粒，进而诱发中性粒细胞胞外诱捕网形成（NETosis）。而NET的主要成分，如DNA、组蛋白和中性粒细胞弹性蛋白酶，具有促凝促血栓形成的作用。依据这些结果，我们提出假说：胎盘缺氧，滋养层细胞HMGB1表达释放增加，进而刺激母体内皮细胞产生微粒，促进NETosis，从而导致子痫前期患者内皮功能障碍和血液高凝状态。本研究将通过细胞生物学和小鼠模型实验来验证我们的假说，了解子痫前期胎盘缺氧导致血液高凝及血栓形成风险增加的分子机制，为妊娠相关血栓性疾病的防治提供新策略。

子痫前期是危害母婴健康的重大疾病，患者常伴有血液高凝状态和血栓形成倾向，有发生弥漫性血管内凝血、器官衰竭，甚至死亡的风险。胎盘缺氧在子痫前期的发病机制中发挥着关键的作用。本项目中我们通过临床样本检测分析、细胞生物学和生物化学实验研究，发现胎盘缺氧滋养细胞表达分泌HMGB1(high mobility group box-1)。HMGB1能刺激内皮细胞释放微粒，进而诱发中性粒细胞胞外诱捕网形成(NETosis)，释放DNA、组蛋白和中性粒细胞弹性蛋白酶等组分，这些NET组分和微粒都 具有促凝促血栓形成的作用。我们还发现子痫前期 患者胎盘HMGB1表达升高，血浆HMGB1水平升高，并且血浆HMGB1水平与患者的凝血指标相关。我们的研究揭示了子痫前期胎盘缺氧导致血液高凝及血栓形成风险增加的分子机制，可为妊娠相关血栓性疾 病的防治提供新策略。