From the Department of Obstetrics and Gynecology, University of Wisconsin-Madison (C.Z., Q.Y., Q.-Y.Z., X.-Q.Z., C.T.T., I.M.B., J.Z.).
Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, China (Q.Y.).
Hypertension. 2019 Jul;74(1):154-163. doi: 10.1161/HYPERTENSIONAHA.118.12569. Epub 2019 Jun 3.
Preeclampsia impairs fetoplacental vascular function and increases risks of adult-onset cardiovascular disorders in children born to preeclamptic mothers, implicating that preeclampsia programs fetal vasculature in utero. However, the underlying mechanisms remain elusive. We hypothesize that preeclampsia alters fetal endothelial gene expression and disturbs cytokines- and growth factors-induced endothelial responses. RNA sequencing analysis was performed on unpassaged human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic pregnancies. Functional assays for endothelial monolayer integrity, proliferation, and migration were conducted on passage 1 HUVECs from normotensive and preeclamptic pregnancies. Compared with normotensive cells, 926 and 172 genes were dysregulated in unpassaged female and male HUVECs from preeclamptic pregnancies, respectively. Many of these preeclampsia-dysregulated genes are associated with cardiovascular diseases (eg, heart failure) and endothelial function (eg, cell migration, calcium signaling, and endothelial nitric oxide synthase signaling). TNF (tumor necrosis factor)-α-, TGF (transforming growth factor)-β1-, FGF (fibroblast growth factor)-2-, and VEGFA (vascular endothelial growth factor A)-regulated gene networks were differentially disrupted in unpassaged female and male HUVECs from preeclamptic pregnancies. Moreover, preeclampsia decreased endothelial monolayer integrity in responses to TNF-α in both female and male HUVECs. Preeclampsia decreased TGF-β1-strengthened monolayer integrity in female HUVECs, whereas it enhanced FGF-2-strengthened monolayer integrity in male HUVECs. Preeclampsia promoted TNF-α-, TGF-β1-, and VEGFA-induced cell proliferation in female, but not in male HUVECs. Preeclampsia inhibited TNF-α-induced cell migration in female HUVECs, but had an opposite effect on male HUVECs. In conclusion, preeclampsia differentially dysregulates cardiovascular diseases- and endothelial function-associated genes/pathways in female and male fetal endothelial cells in association with the sexual dimorphisms of preeclampsia-dysregulated fetal endothelial function.
子痫前期损害胎儿胎盘血管功能，并增加子痫前期母亲所生孩子成年后发生心血管疾病的风险，这表明子痫前期会在子宫内对胎儿血管进行编程。然而，其潜在机制仍难以捉摸。我们假设子痫前期会改变胎儿内皮细胞的基因表达，并扰乱细胞因子和生长因子诱导的内皮反应。对来自正常血压和子痫前期妊娠的未传代人脐静脉内皮细胞（HUVEC）进行 RNA 测序分析。对来自正常血压和子痫前期妊娠的第 1 代 HUVEC 进行内皮单层完整性、增殖和迁移的功能测定。与正常血压细胞相比，未传代的子痫前期女性和男性 HUVEC 分别有 926 和 172 个基因失调。这些子痫前期失调基因中的许多与心血管疾病（如心力衰竭）和内皮功能（如细胞迁移、钙信号和内皮型一氧化氮合酶信号）相关。TNF（肿瘤坏死因子）-α、TGF（转化生长因子）-β1、FGF（成纤维细胞生长因子）-2 和 VEGFA（血管内皮生长因子 A）调节的基因网络在未传代的子痫前期女性和男性 HUVEC 中均被差异破坏。此外，子痫前期降低了 TNF-α对女性和男性 HUVEC 内皮单层完整性的作用。子痫前期降低了 TGF-β1 增强的女性 HUVEC 单层完整性，而增强了 FGF-2 增强的男性 HUVEC 单层完整性。子痫前期促进了 TNF-α、TGF-β1 和 VEGFA 诱导的女性 HUVEC 增殖，但对男性 HUVEC 没有影响。子痫前期抑制了 TNF-α诱导的女性 HUVEC 迁移，但对男性 HUVEC 则产生相反的效果。总之，子痫前期在与子痫前期失调胎儿内皮功能的性别二态性相关的女性和男性胎儿内皮细胞中，差异失调与心血管疾病和内皮功能相关的基因/通路。
