外泌体携带HSP20对子痫前期的发生机制及预测价值研究

Preeclampsia (PE) is a pregnancy-relative disorder characteristic of hypertension and proteinuria. It has been the leading cause of maternal and fetal morbidity and mortality over many years. Insufficient remodeling of uterine spiral arteries has been considered as one of the initial factors causing PE, which involves in the interaction of trophoblast cells and a variety of other cells, and requires accurate regulation and exchange of information. Exosomes are important mediators of cell-cell exchange of information, and small molecule heat shock protein 20 (HSP20) can affect the synthesis and secretion of exosomes. In addition, our previous research showed that HSP20 can also inhibit the proliferation and apoptosis of trophoblast and promote its transformation into invasive phenotype, and the level of HSP20 in the placenta-derived exosomes of PE patients was significantly reduced, suggesting that dysfunction of exosome-carrying HSP20 may play an important role in the inadequate remodeling of spiral arteries in PE. In this study, we will explore the influence of exosomal HSP20 excreted by trophoblast cells on the biological behavior of cells associated with spiral artery remodeling, and evaluate the sensitivity and specificity of serum placental-derived exosomal HSP20 in predicting the occurrence of PE. We aim to provide a brand new idea of PE mechanism and develop a new treatment target of PE. Our work may offer new measures of early intervention and treatment for PE and a solid basis for further research.

子痫前期（PE）是妊娠期特有并发症，是孕产妇和围产儿死亡的重要原因。子宫螺旋动脉重铸障碍是导致PE发病的始发因素之一，这个过程涉及滋养细胞与多种细胞之间的信息交流和相互作用。外泌体是细胞-细胞之间信息交流的重要媒介，而小分子热休克蛋白20（HSP20）可以影响外泌体的分泌和效应。课题组前期研究表明HSP20可以抑制滋养细胞增殖和凋亡，促进其转化为侵袭表型，且PE患者血清胎盘来源的外泌体中HSP20的水平显著降低，提示外泌体携带HSP20表达异常可能在PE螺旋动脉重铸障碍中发挥重要作用。本研究拟从细胞间信息交流这一层面出发，借助体外实验结合PE动物模型，全方位探究滋养细胞分泌的外泌体携带HSP20对与子宫螺旋动脉重铸相关的细胞生物学行为的影响，同时评估血清中胎盘来源的外泌体携带的HSP20水平预测PE的敏感性和特异性。本项目将为PE发病机制和早期预测的研究提供新的思路和研究基础。

子宫螺旋动脉重铸涉及滋养细胞与多种细胞之间的信息交流和相互作用，重铸不足是导致子痫前期（PE）发病的重要机制之一。本项目以外泌体携带HSP20表达异常可能在PE螺旋动脉重铸障碍中发挥重要作用为切入点，借助体外实验和靶向干预技术，探究HSP20对EVT增殖、凋亡、侵袭及分泌外泌体的能力的影响，及EVT分泌的外泌体携带 HSP20 在内皮细胞、平滑肌细胞中的转运、交流情况及产生的效应。通过研究，本项目发现：1、HSP20可抑制滋养细胞增殖和凋亡，促进其转化为更具侵袭性的表型。Akt信号通路可能在HSP20对滋养细胞的功能调控中发挥重要作用，有利于螺旋动脉重构。2、HSP20过表达可促进滋养细胞外泌体产生，可能与调控外泌体生成相关蛋白有关。过表达HSP20滋养细胞分泌的外泌体形态、大小无明显差异，其HSP20蛋白表达较对照组明显升高。3、HSP20过表达HTR-8/Svneo分泌的外泌体可促进原代HUVECs细胞的迁移能力，促进缺氧诱导的HUVECs细胞凋亡，可能通过上述对HUVECs细胞的功能调控促进螺旋动脉重铸的发生。4、HSP20过表达HTR-8/Svneo分泌的外泌体可促进原代绒毛膜板动脉平滑肌细胞（CPASMCs）的迁移能力，促进缺氧诱导的CPASMCs细胞凋亡，抑制其增殖，同时诱导其由收缩表型向合成表型转化，可能通过上述对CPASMCs细胞的功能调控促进螺旋动脉重铸的发生。本项目为PE发病机制研究提供了新的思路和研究基础。