Sexual Dimorphism of Preeclampsia-Dysregulated Transcriptomic Profiles and Endothelial Function in Fetal Endothelial Cells. Sexual Dimorphism of Preeclampsia-Dysregulated Transcriptomic Profiles and Endothelial Function in Fetal Endothelial Cells

Preeclampsia-offspring have increased risks of developing cardiovascular disorders in adulthood, implicating that preeclampsia programs fetal vasculature in utero. Fetal sex is associated with the risk of preeclampsia but the underlying mechanisms are unclear. We hypothesize that preeclampsia alters fetal endothelial gene expression and disturbs cytokines and growth factors-induced endothelial function in a fetal sex-specific manner. Methods: RNAseq analysis was performed with female and male unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic (PE) pregnancies and verified by RT-qPCR. Results: PE dysregulate 926 and 172 genes in female and male P0-HUVECs, respectively. PE differentially dysregulates cardiovascular diseases (i.e. heart failure) and endothelial function (i.e. endothelial cell migration, calcium, eNOS, and iNOS signaling)-associated genes in female and male P0-HUVECs. PE also differentially dysregulates TNF-, TGFβ1-, FGF2-, and VEGFA-regulated gene networks in female and male P0-HUVECs. Conclusions: There are sexual dimorphisms of PE-dysregulated cardiovascular diseases and endothelial function-associated genes/pathways in fetal endothelial cells in association with sexual dimorphisms of PE-dysregulated fetal endothelial function. Overall design: Examination of unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic (PE) pregnancies with female (F) and male (M) fetuses.

子痫前期（preeclampsia）子代在成年后罹患心血管疾病的风险升高，提示子痫前期可在子宫内程序化调控胎儿血管系统。胎儿性别与子痫前期发病风险相关，但其背后的分子机制尚未阐明。本研究假设子痫前期会以胎儿性别特异性的方式，改变胎儿内皮细胞的基因表达，并扰乱细胞因子与生长因子介导的内皮细胞功能。
方法：本研究对来自正常血压妊娠与子痫前期（PE）妊娠的雌、雄胎儿未传代（P0）人脐静脉内皮细胞（human umbilical vein endothelial cells, HUVECs）进行RNA测序（RNAseq）分析，并通过实时定量聚合酶链反应（RT-qPCR）进行验证。
结果：子痫前期分别在雌性与雄性P0-HUVECs中失调926个与172个基因。子痫前期在雌、雄P0-HUVECs中差异性失调心血管疾病（如心力衰竭）与内皮功能（如内皮细胞迁移、钙信号、内皮型一氧化氮合酶（eNOS）及诱导型一氧化氮合酶（iNOS）信号通路）相关基因。子痫前期还在雌、雄P0-HUVECs中差异性失调肿瘤坏死因子α（TNF-α）、转化生长因子β1（TGFβ1）、成纤维细胞生长因子2（FGF2）及血管内皮生长因子A（VEGFA）调控的基因网络。
结论：胎儿内皮细胞中，子痫前期失调的心血管疾病与内皮功能相关基因/通路存在性别二态性，且该现象与子痫前期失调的胎儿内皮细胞功能的性别二态性相关。
整体实验设计：对来自正常血压妊娠与子痫前期（PE）妊娠的雌（F）、雄（M）胎儿未传代（P0）人脐静脉内皮细胞（HUVECs）进行检测。