Fetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases. Gene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n = 11) versus control (n = 8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression of LGALS1, FPR3 and NRM and upregulation of lincRNA RP5-855F14.1 in FGR compared to controls. DNA methylation was similar for LGALS1 between study groups, but relative hypomethylation of FPR3 and hypermethylation of NRM were present in FGR, especially in male offspring. Absolute differences in methylation were, however, small. This study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression of NRM and upregulated expression of lincRNA RP5-855F14.1 in FGR samples; NRM is involved in cardiac remodeling, and lincRNAs are correlated with cardiovascular diseases. Future studies should elucidate whether the downregulated LGALS1 and FPR3 expressions in FGR are angiogenesis-modulating regulators leading to placental insufficiency-induced FGR or whether the expression of these genes can be used as a biomarker for increased cardiovascular risk. Altered DNA methylation might partly underlie FPR3 and NRM differential gene expression differences in a sex-dependent manner.

中文翻译：

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胎儿生长受限后人脐带静脉内皮细胞的发育编程


胎儿生长受限（FGR）与成年后各种非传染性疾病（包括心血管和肾脏疾病）的易感性增加有关。据推测，在 FGR 期间，子宫胎盘血流量、胎儿的氧气和营养供应减少会对心血管和肾脏编程产生不利影响。本研究探讨了从胎盘功能不全引起的 FGR 妊娠中收集的人脐静脉内皮细胞 (HUVEC) 与正常生长妊娠相比，发育编程谱（尤其是与心血管和肾脏系统相关的发育编程谱）是否存在差异。我们的方法涉及通过 RNA 测序进行转录组分析、重点关注心血管和肾脏基因集的基因集富集分析以及靶向 DNA 甲基化测定，有助于识别长期心血管和肾脏疾病的靶标。基因集富集分析显示了几个下调的基因集，其中大多数涉及免疫或炎症途径或细胞周期途径。与对照 (n = 8) 相比，FGR (n = 11) 中 22 个与肾脏发育相关的显着上调基因组中的 7 个以及与心血管健康和功能相关的 4 个基因组下调。通过 RNA 测序进行的转录组分析显示，与对照相比，FGR 中 LGALS1、FPR3 和 NRM 的表达下调，而 lincRNA RP5-855F14.1 的表达上调。研究组之间 LGALS1 的 DNA 甲基化相似，但 FPR3 的相对低甲基化和 NRM 的高甲基化在 FGR 中存在，尤其是在雄性后代中。然而，甲基化的绝对差异很小。 这项研究表明，与对照供体相比，从患有 FGR 的妊娠中收集的 HUVEC 中与肾脏发育相关的基因组上调。与心血管功能和健康相关的差异表达基因集可能与FGR样本中NRM表达下调和lincRNA RP5-855F14.1表达上调一致； NRM参与心脏重塑，lincRNA与心血管疾病相关。未来的研究应该阐明FGR中下调的LGALS1和FPR3表达是否是血管生成调节因子，导致胎盘功能不全诱导FGR，或者这些基因的表达是否可以作为心血管风险增加的生物标志物。 DNA 甲基化的改变可能部分是 FPR3 和 NRM 基因表达差异的性别依赖性差异的基础。