The role of trophoblast cell damage and coagulopathy in the pregnant mice models with preeclamsia-like symptoms

为了探讨胎盘绒毛间间隙高凝状态是否会诱发子痫前期样症状，我们重点研究了带负电荷的磷脂微泡（磷脂酰丝氨酸/磷脂酰胆碱PS/PC）和血管内皮生长因子（VEGF）。我们之前的报道表明，PS/PC微泡诱导宫内生长受限，胎儿和胎盘中缺乏细胞周期蛋白依赖性激酶抑制剂p57kip2的表达，VEGF_<164>的高表达在妊娠小鼠子痫前期样症状的发展中起作用。我们建立了新的子痫前期样症状动物实验模型如下，PS/PC和VEGF对子痫前期样症状的诱导提示其与子痫前期的病理生理有关。1)人工PS/PC囊泡诱导宫内生长受限，收缩压升高。血浆TAT升高和胎盘弥漫性纤维蛋白沉积表明凝血酶形成增强，舒张压显著升高可由胎盘高凝引起。2)外源性VEGF_<164>诱导胎盘循环出现子痫前期样症状和高凝，收缩压明显升高。抗vegf中和抗体抑制弥漫性纤维蛋白沉积胎盘的收缩压升高和组织学改变。这些新建立的动物模型表明，活化血小板衍生的PS/PC和滋养细胞衍生的VEGF引起的高凝状态在子痫前期样症状中起重要作用。在这些实验模型中，对子痫前期的机制有待进一步的研究。

In order to investigate whether the hypercoagulable state in intervillous space in placenta can induce the preeclampsia-like symptoms, we have focused on the negatively-charged phospholipid microvesicles (phosphatidylserine/phosphatidylcholine PS/PC) and vascular endothelial growth factor (VEGF). Our previous reports have shown that PS/PC microvesicles induce intrauterine growth restriction and that the lack of cyclin-dependent kinase inhibitor, p57kip2, expression in the fetus and the placenta with higher expression of VEGF_<164> plays a role in the development of preeclamsia-like symptoms in pregnant mice.Here we have established the novel animal experimental models with preeclamsia-like symptoms as follows and the induction of preeclamsia-like symptoms by PS/PC and VEGF indicates that these are related to the pathophysiology of preeclamsia.1)The artificial PS/PC vesicles induce intrauterine growth restriction with elevations of systolic blood pressure. The elevation of plasma TAT and diffuse fibrin depositions in the placentas indicate enhanced thrombin formation and the significant elevations of SBP can be induced by hypercoagulation in placenta.2)The exogenous murine VEGF_<164> induce preeclamsia-like symptoms and hypercoagulation in the placental circulation with a significant elevation of SBP. Anti-VEGF neutralized antibody suppresses the elevation of SBP and histological changes in placentas with diffuse fibrin depositions.These novel animal models established suggest that hypercoagulable state caused by PS/PC derived from activated platelet and VEGF derived from trophblast is important in preeclamsia-like symptoms. The further research on the mechanisms of preeclamsia will be required in these experimental models.