胎盘类固醇激素调节机体凝血-纤溶平衡和妊娠结局的机制

During a healthy pregnancy in the mammalian, maternal organ functions altered physiologically in response to the gestation, which is recognized as pregnancy adaption. The coagulation-fibrinolysis balance is gradually prone to a mild hypercoagulation status, and an exacerbation of the hypercoagulation status has been observed in pregnancy-associated diseases such as preeclampsia (PE). Therefore, a fine-tune regulation of maternal coagulation-fibrinolysis system matters critically to normal pregnancy maintenance. SerpinF2, primarily synthesized in the liver and kidney, is one of the main inhibitors of plasmin, and therefore a principal factor in the coagulation cascade. Our previous findings indicate that placenta-derived steroid hormones may act as stimuli of pregnancy adaption, which regulate maternal production of SerpinF2 from liver, kidney and/or placenta, and accordingly participate in the establishment of hypercoagulation status during pregnancy. .In this project, we will utilize multiple in vitro or in vivo models to investigate the transcriptionally regulatory mechanism of renal or hepatic SerpinF2 by estrogen and androgen that are derived from placenta during human gestation. We will further investigate the mechanism whereby the imbalance in the regulatory signaling leads to aberrant upregulation of SerpinF2 and excessive hypercoagulation as well as impaired pregnancy outcomes. The aim of this proposal is to clarify the molecular basis of the pregnancy adaption regulation on maternal hemostasis, and to deepen our understanding on the precise regulation of pregnancy maintenance, which will scientifically help to improve human reproductive health.

哺乳动物妊娠期间，母体的多个脏器发生生理性的妊娠适应性变化，其中凝血-纤溶平衡倾向于适度的高凝血；这一高凝血状态的异常增强与子痫前期等妊娠疾病密切相关，提示母体凝血-纤溶系统的精确调控对正常妊娠维持至关重要。肝脏/肾脏产生的SerpinF2是纤溶酶的主要抑制因子，是凝血调节通路上的重要成员。我们的前期研究结果提示胎盘产生的类固醇激素可能作为妊娠适应信号，调节母体肝脏、肾脏和/或胎盘SerpinF2的表达，参与妊娠高凝血状态的建立。本项目将利用多种体外和在体模型，研究人类妊娠过程中，胎盘产生的雌激素和雄激素对母体肝脏、肾脏以及胎盘局部SerpinF2转录表达的调节机制，并研究相关调控环节失衡导致SerpinF2异常上调、机体凝血-纤溶失衡以及不良妊娠结局的机制。由此阐释母体凝血-纤溶系统妊娠适应性调节的分子机制，对理解妊娠维持的精确调节机制、提高妇女生殖健康水平具有重要的科学意义。

本项目拟探究胎盘合成的雌雄激素对肝脏和肾脏SerpinF2表达的调控机理，阐释机体凝血-纤溶系统的妊娠适应性调节的分子基础，并探讨这一妊娠适应性调节失衡在子痫前期等不良妊娠结局发生中的作用机制。项目执行期间，通过前瞻性临床样本的分析，发现从妊娠11周至晚期，早发型子痫前期外周血中SerpinF2水平显著高于正常妊娠对照，相应地，雌二醇E2水平显著下降，而睾酮T0水平显著增高，SerpinF2和T0及E2呈现明显相关性。进一步分析表明胎盘中睾酮和雌二醇合成的限速酶（即芳香化酶和17b-HSD3）表达和活性的显著变化，是导致早发型子痫前期E2和T0水平异常的原因。体外细胞模型中的转录调节分析显示，肾脏和胎盘细胞中转录因子FOXA1通过与SerpinF2核心启动子区的结合，辅助AR和ER的作用，介导了T0和E2对SerpinF2表达的反向调节作用。构建孕期高雄导致子痫前期样表型的小鼠模型，证明高雄激素可通过促进肾脏SerpinF2表达造成母体高凝血状态，并进而导致母胎界面血流灌注受阻和胎盘/胎儿发育不良。在这一小鼠模型中利用功能性抗体阻断SerpinF2活性，可有效挽救母胎界面血流灌注不足以及子痫前期样的母儿损伤表型。此外，我们还证明滋养层细胞中由miR-22介导的雌、雄激素合成的平衡调节机制，是阐释子痫前期内分泌失衡的重要分子依据。.本项目从理论上阐释了胎盘雌雄激素合成与母体凝血系统之间的调节，对于认识妊娠适应性调节机制具有重要的科学意义。同时发现可以通过阻断SerpinF2活性对子痫前期的母儿损伤进行干预，具有明显的转化应用前景。本项目发表2篇SCI研究论文，申请一项发明专利。团队成员在重要国际会议进行分会报告4人次，邀请领域知名专家来访交流4人次。培养博士研究生3名，均获得中国科学院大学“三好学生”荣誉；一名博士后出站被聘任为助理研究员。