The thrombomodulin-protein C system is essential for the maintenance of pregnancy
The thrombomodulin-protein C system is essential for the maintenance of pregnancy
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DOI：
10.1038/nm825
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发表时间：
2003-03-01
期刊：
影响因子：
82.9
通讯作者：
Weiler, H
中科院分区：
文献类型：
--
作者：
Isermann, B;Sood, R;Weiler, H
小鼠编码凝血抑制物血栓调节蛋白(Thbd)的基因被破坏，导致胚胎死亡，原因是胎盘中的未知缺陷。我们表明，血栓调节蛋白缺陷胚胎的流产是由组织因子启动的胎儿-母体界面的凝血级联激活引起的。活化的凝血因子通过两种不同的机制诱导胎盘滋养层细胞死亡和生长抑制。巨型滋养层细胞的死亡是由于凝血酶底物纤维蛋白原转化为纤维蛋白并随后形成纤维蛋白降解产物所致。相反，滋养层细胞的生长停滞不是由纤维蛋白介导的，而可能是凝血因子与蛋白酶激活受体(PAR)-2和PAR-4结合的结果。这些发现表明血栓调节蛋白-蛋白C系统在控制胎盘滋养层细胞的生长和存活方面具有新的功能。这一功能对维持妊娠至关重要。
Disruption of the mouse gene encoding the blood coagulation inhibitor thrombomodulin (Thbd) leads to embryonic lethality caused by an unknown defect in the placenta. We show that the abortion of thrombomodulin-deficient embryos is caused by tissue factor-initiated activation of the blood coagulation cascade at the feto-maternal interface. Activated coagulation factors induce cell death and growth inhibition of placental trophoblast cells by two distinct mechanisms. The death of giant trophoblast cells is caused by conversion of the thrombin substrate fibrinogen to fibrin and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors (PAR)-2 and PAR-4 by coagulation factors. These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy.