胎盘滋养层细胞外泌体lnc-INSL4-8-1调控子痫前期血管内皮细胞损伤机制研究

Some placenta-derived factors may be released increasingly into the maternal circulation, resulting in systemic, diffuse maternal endothelial dysfunction, which is believed as a potential mechanism for the occurrence and development of preeclampsia. However, the nature of the pathogenic factors above is still not very clear. Exosomal long non-coding RNAs (lncRNAs) play an important role in intercellular communication pathways. However, the role of exosomal lncRNAs in vascular endothelial injury in preeclampsia has not been reported yet. Previously (1) RNA-seq showed plasma lnc-INSL4-8-1 was significantly increased in preeclampsia patients, and bioinformatics analysis indicated that lnc-INSL4-8-1 could regulate JAK2 expression; (2) placenta-derived exosomal lnc-INSL4-8-1 from the circulation of preeclampsia patients could significantly inhibit JAK2 phosphorylation, and induce vascular endothelial cell damage. Therefore, we hypothesize that the placental syncytiotrophoblast-derived exosomal lnc-INSL4-8-1 could cause the damage of vascular endothelial cells by inhibiting JAK2 phosphorylation, which eventually contributed to the occurrence and development of preeclampsia. The aim of this present work is to elucidate the underlying mechanisms of exosomal lnc-INSL4-8-1 in regulating vascular endothelial cell injury, and to provide novel insights into the possible prevention and treatment of preeclampsia.

子痫前期时胎盘释放“毒性因子”经血液循环损害母体血管内皮功能，是子痫前期发生发展的重要机制，但这些“毒性因子”组分及致病机理尚不完全清楚。外泌体可负载lncRNAs实现细胞间信息交流，在多种妊娠期疾病中发挥重要作用，但其在子痫前期血管内皮损伤中的作用尚无报道。我们前期发现：（1）转录组测序显示子痫前期患者血浆lnc-INSL4-8-1表达显著增加，生物信息学分析提示其可能靶向调控JAK2表达；（2）子痫前期患者血浆胎盘源性外泌体lnc-INSL4-8-1可进入原代血管内皮细胞，降低JAK2磷酸化水平，引起细胞损伤。因此，我们假设：在病理状态下，胎盘滋养层细胞释放外泌体lnc-INSL4-8-1增加，抑制血管内皮细胞JAK2磷酸化，引起细胞损伤，促进子痫前期发生发展。本研究拟从细胞和在体水平阐明外泌体lnc-INSL4-8-1调控子痫前期母体血管内皮细胞损伤新机制，寻找子痫前期防治新靶点。

妊娠期高血压疾病（HDP）严重威胁母婴健康，但发生机制尚不完全清楚且缺乏早期预警和防治方法。本研究：1、成功筛选并验证8个血清lncRNAs可作为妊娠早中期（＜20孕周）预警HDP发生的生物标志物；2、证实ENST00000527727和ENST00000415029分别是HDP患者发生胎儿生长受限和胎盘植入的独立危险因素；3、证实lncRNA TCONS_00008014可通过调控MAPK信号通路，影响滋养层细胞生物学行为，引起胎盘功能障碍，导致HDP；4、成功建立妊娠期寒冷暴露子代大鼠模型；5、发现妊娠期寒冷暴露可改变母乳菌群，影响子代肠道菌群定植；6、阐明妊娠期寒冷暴露使子代肠道菌群失调，促进心房纤维化和凋亡，增加心房颤动（房颤）易感性；7、证实补充双歧杆菌可抑制寒冷子代大鼠机体免疫炎症反应，改善心房纤维化和心肌细胞凋亡，降低房颤易感性。本项目首次发现妊娠早中期血清8个lncRNAs可作为HDP发生的早期预警标志物，并评估其预测价值及其与妊娠结局的关系，为HDP早期预警和防治提供重要依据。首次阐明妊娠期寒冷暴露会改变母乳菌群，导致双歧杆菌在子代肠道异常定植，促进子代心房纤维化和凋亡，增加子代房颤易感性；补充双歧杆菌可部分逆转上述改变，为防治妊娠期寒冷暴露所致子代房颤的新药研发提供更多方向。在本课题支持下，相关研究内容已完成并取得预期成果；研究期间，负责人作为第一或通讯作者发表SCI文章2篇、中文核心期刊文章1篇，参与完成SCI文章1篇；负责人获黑龙江省科学技术一等奖和医疗卫生新技术应用一等奖各1项，授权国家发明专利2项；协助培养博士研究生3名，硕士研究生1名。