Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury
Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury
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DOI：
10.1182/blood-2008-12-194258
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发表时间：
2009-04-23
期刊：
影响因子：
20.3
通讯作者：
Girardi, Guillermina
中科院分区：
文献类型：
--
作者：
Redecha, Patricia;van Rooijen, Nico;Girardi, Guillermina
妊娠丢失和宫内生长受限（IUGR）是严重的妊娠并发症，胎盘和胎儿损伤的触发和介导因素尚不完全清楚。利用与人类复发性自然流产和胎儿生长受限具有相同特征的小鼠模型（DBA/2-配对CBA/J小鼠），我们确定了组织因子（TF）是胎盘和胎儿损伤的重要参与因子。我们之前的研究表明，C5a在单核细胞中释放抗血管生成分子sFlt-1，导致DBA/2-配对的CBA/J小鼠胎盘发育缺陷和胎儿死亡。在本研究中，我们发现TF不仅激活凝血途径，而且还介导单核细胞中sFlt-1的释放，导致胎盘发育缺陷和胎儿死亡。单克隆抗体阻断TF可抑制sFlt-1的释放，阻止凝血途径的病理激活，恢复胎盘血流量，防止胎盘氧化应激，挽救妊娠。我们还证明，普伐他汀通过下调单核细胞和滋养细胞上TF的表达，可以防止DBA/2-交配CBA/J小鼠的胎盘损伤和保护妊娠。这些研究表明，TF是胎儿死亡和生长受限的重要介质，他汀类药物可能是复发性流产和IUGR妇女的良好治疗方法。（血液杂志，2009;113:4101-4109）
Pregnancy loss and intrauterine growth restriction (IUGR) are serious pregnancy complications, and the triggers and mediators of placental and fetal damage are not completely understood. Using a mouse model of recurrent spontaneous miscarriages (DBA/2-mated CBA/J mice) that shares features with human recurrent miscarriage and fetal growth restriction, we identified tissue factor (TF) as an essential participating factor in placental and fetal injury. We have previously shown that C5a releases antiangiogenic molecule sFlt-1 in monocytes that causes defective placental development and fetal death in DBA/2-mated CBA/J mice. In this study, we found that TF not only activates the coagulation pathway, but it also mediates sFlt-1 release in monocytes causing defective placental development and fetal death. Blockade of TF with a monoclonal antibody inhibited sFlt-1 release, prevented the pathological activation of the coagulation pathway, restored placental blood flow, prevented placental oxidative stress, and rescued pregnancies. We also demonstrated that pravastatin, by down-regulating TF expression on monocytes and trophoblasts, prevented placental damage and protected pregnancies in DBA/2-mated CBA/J mice. These studies indicate that TF is an important mediator in fetal death and growth restriction and that statins may be a good treatment for women with recurrent miscarriages and IUGR. (Blood. 2009; 113: 4101-4109)