kisspeptins调控母胎界面FSHR在子痫前期血管重铸障碍中的作用及机制研究

The disorder of placental vascular remodification is a key process in the pathogenesis of preeclampsia, but its detailed mechanism remains unknown. In recent years, studies have shown that follicle stimulating hormone receptor (FSHR) plays an important role in the extragonadal tissues, such as placental development, angiogenesis and tumor metastasis. Our previous study found that abnormally elevated kisspeptin in the preeclampsia could significantly inhibit the tube formation of vascular endothelial cells, but had no significant effect on the secretion of VEGF, and had a negative correlation with the expression of vascular endothelial FSHR in the maternal-fetal interface. Accordingly, we speculate kisspeptins may be involved in the formation of abnormal blood vessels and development of preeclampsia by inhibiting the expression of FSHR in the maternal-fetal interface.The study is designed to investigate whether kisspeptins levels of pregnant women in the serum and placenta tissues are associated with the expression of placental vascular endothelial FSHR and the severity of preeclampsia by the preeclampsia patient and animal models, and to observe the kisspeptins on the effect of FSHR expression and the FSHR on the angiogenesis through umbilical vein endothelial cell model and RNAi method, and observe the change of vessels, kidney and the placentas and its relative molecular mechanism in the FSHR interference and RUPP models pregnant rats. The aim of our study aim will clearly investigate the role and mechanism of maternal-fetal interface FSHR regulated by kisspeptins 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。近年研究显示卵泡刺激素受体（FSHR）在性腺外组织也具有重要作用，如与胎盘发育、血管形成及肿瘤转移密切相关。我们前期研究发现：子痫前期异常升高kisspeptin可明显抑制血管内皮细胞管形的形成，而对VEGF分泌无明显影响，但与母胎界面血管内皮FSHR表达负相关。据此推测kisspeptins可能通过抑制母胎界面FSHR参与子痫前期异常血管的形成和疾病发生。本研究以子痫前期患者和动物模型为切入点，研究kisspeptins与血管内皮FSHR表达关系和病情严重程度的相关性；通过血管内皮细胞模型和RNAi 技术观察其对FSHR表达影响以及FSHR对新生血管形成的作用；FSHR干涉和RUPP缺血妊娠大鼠模型血管、肾和胎盘靶器官的变化及分子机制。最终明确其调控母胎界面FSHR在子痫前期血管重铸障碍中作用和机制，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。近年研究显示卵泡刺激素受体（FSHR）在性腺外组织也具有重要作用，如与胎盘发育、血管形成及肿瘤转移密切相关。我们前期研究发现：子痫前期异常升高kisspeptin可明显抑制血管内皮细胞管形的形成，而对VEGF分泌无明显影响，但与母胎界面血管内皮FSHR表达负相关。因此，推测kisspeptins可能通过抑制母胎界面FSHR参与子痫前期异常血管的形成和疾病发生。本项目主要研究了FSHR 蛋白在正常妊娠与子痫前期患者母胎界面胎盘和蜕膜组织表达水平与表达部位的变化；腺外卵泡刺激素受体在小鼠子宫内膜的定位、表达变化及其在妊娠期小鼠子宫内膜蜕膜化中的作用，以及Kisspeptins对血管内皮细胞FSHR表达的影响和FSHR基因干扰后对血管内皮细胞增生、迁移和管形的形成。研究结果显示，在子痫前期胎盘组织中，FSHR mRNA和蛋白的表达水平明显低于正常胎盘。免疫组化染色结果表明，FSHR蛋白强烈表达于绒毛的血管内皮细胞中。同时，表达于绒毛间质细胞，但不表达于胎盘滋养层细胞。与正常对照组相比，在子痫前期胎盘绒毛FSHR阳性面积染色强度明显降低。在妊娠早期，FSHR时空性的表达于妊娠小鼠子宫内膜母胎界面，且其表达部位和表达量变化受E2、P4及子宫内膜蜕膜化的影响；小剂量FSH可促进子宫内膜基质细胞的增殖和蜕膜化；FSHR干扰后，子宫内膜基质细胞的蜕膜化受到显著的抑制，说明FSHR具有促进子宫内膜蜕膜化的作用。明显升高的kisspeptins能明显抑制异FSHR表达的表达。FSHR基因可明显降低血管内皮细胞增生、迁移和管形的形成。但在体kisspeptins处理大鼠后，未明显观察其对大鼠血流动学、血管功能和形态的影响。总之，kisspeptins可通过抑制母胎界面FSHR，从而抑制蜕膜的形成和血管的内皮细胞增生、增殖、迁移及管形的形成。最终明确其调控母胎界面FSHR在子痫前期血管重铸障碍中作用和机制，为临床预测及治疗子痫前期提供新的靶点。