神经病靶酯酶在子痫前期血管重铸障碍中的作用及其机制研究

Abnormal placental angiogenesis is a key process in the pathogenesis of preeclampsia, but its detailed mechanism remains unknown. In recent years, studies have shown that neuropathy target esterase (NTE) is closely related to the angiogenesis and placental development, and regulates the metabolism of phosphatidylcholine, which was injected into pregnant mice to induce the model of preeclampsia. In addition, our previous study found that NTE expression level in the serum and placenta of preeclampsia decreased significantly compared with normal pregnancy, According to these results, we initially speculated that neuropathy target esterase may be involved in the formation of abnormal blood vessels and pathology of preeclampsia. The study is designed to investigate whether NTE levels of pregnant women serum and placenta tissues are associated with the severity of preeclampsia by ELISA, Western blot, to observe the effects of NTE on the angiogenesis by the model of human umbilical vein endothelial cells and RNA interference in vitro; to observer NTE the effect on trophoblast cell migration and invasion of trophoblast cell by transwell method, to examine NTE the effect on the density of new blood vessels, blood pressure and glomerular endothelial cells in pregnant rats. Our research contribute to investigate the role and mechanism of neuropathy target esterase in the vascular remodeling disorder of preeclampsia and to provide a new target for clinical prediction and treatment of preeclampsia.

血管重铸异常是子痫前期发病的重要环节，其病因未明。近年，研究显示神经病靶酯酶（NTE）与血管形成及胎盘的发育密切相关，且其代谢调节的磷脂酰胆碱，注射至妊娠小鼠体内可诱导出子痫前期的模型。另外，我们前期研究发现：与正常妊娠相比，子痫前期患者血清及胎盘中NTE 表达水平明显下降，故推测神经病靶酯酶可能参与子痫前期异常血管的形成及疾病的发生。本课题拟通过ELISA、免疫印迹等方法分析孕妇血清及胎盘中NTE表达水平的变化与病情严重程度的相关性；通过脐静脉血管内皮细胞模型和RNAi 技术观察NTE对新生血管形成的影响；通过Transwell方法观察NTE对滋养层细胞迁移和侵润的影响。在体胎盘局部注射NTE shRNA干涉腺病毒载体观察其对新生血管的密度、妊娠大鼠的血压及肾小球血管内皮细胞的影响。旨在探讨NTE在子痫前期血管重铸障碍中的作用及其机制，为临床预测及治疗子痫前期提供新的靶点。

血管重铸异常是子痫前期发病的重要环节，其病因未明。近年，研究显示神经病靶酯酶与血管形成及胎盘的发育密切相关，且我们前期研究发现：与正常妊娠相比，子痫前期患者血清及胎盘中NTE 表达水平明显下降，故推测神经病靶酯酶可能参与子痫前期异常血管的形成及疾病的发生。本课题通过脐静脉血管内皮细胞模型和RNAi 技术观察NTE对新生血管形成的影响；通过Transwell方法观察NTE对滋养层细胞迁移和侵润的影响。我们研究发现相对于正常妊娠的胎盘组织，在子痫前期胎盘组织中，NTE mRNA 和蛋白的表达水平均明显下降；NTE 通过MMP-9影响HTR-8/SVneo滋养层细胞的迁移和侵润；ERK1/2 和AKT信号通路参与了NTE对HTR-8/SVneo滋养层细胞的调节。与正常妊娠的胎盘组织相比，在子痫前期胎盘组织及胎盘血管部位NTE蛋白的表达水平均明显下降。NTE抑制后，HUVECs的增殖、迁移和血管管形形成能力均明显减弱。NTE通过调节HUVECs的sFlt-1分泌影响子痫前期胎盘的血管形成。NTE通过调节PC、GPC、LPC代谢，影响子痫前期胎盘血管形成，为临床预测及治疗子痫前期提供新的靶点。