Division Woman and Baby, Department of Obstetrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Postbus 85090, 3508 AB, Utrecht, The Netherlands.
Department for Developmental Origins of Disease, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Clin Epigenetics. 2020 Nov 30;12(1):185. doi: 10.1186/s13148-020-00980-9.
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.
胎儿生长受限（FGR）与成年后各种非传染性疾病的易感性增加有关，包括心血管和肾脏疾病。在 FGR 中，胎儿的子宫胎盘血流、氧气和营养供应减少，据推测会对心血管和肾脏的发育产生不利影响。本研究旨在探讨胎盘功能不全引起的 FGR 妊娠与正常生长妊娠相比，人类脐静脉内皮细胞（HUVEC）的发育编程谱，特别是与心血管和肾脏系统相关的编程谱是否存在差异。我们的方法涉及通过 RNA 测序进行转录组谱分析和基因集富集分析，重点关注心血管和肾脏基因集，并进行靶向 DNA 甲基化检测，有助于确定长期心血管和肾脏疾病的潜在靶点。
基因集富集分析显示，有几个下调的基因集，其中大多数涉及免疫或炎症途径或细胞周期途径。在 FGR（n=11）与对照组（n=8）相比，有 22 个显著上调的与肾脏发育相关的基因集中有 7 个下调，4 个与心血管健康和功能相关的基因集也下调。与对照组相比，FGR 中 LGALS1、FPR3 和 NRM 的表达下调，lincRNA RP5-855F14.1 的表达上调。RNA 测序的转录组谱分析显示，LGALS1 在研究组之间的 DNA 甲基化相似，但 FPR3 相对低甲基化和 NRM 高甲基化存在于 FGR 中，尤其是在男性后代中。然而，甲基化的绝对差异很小。
本研究表明，与对照组供体相比，FGR 妊娠中 HUVEC 中与肾脏发育相关的基因集上调。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 的下调表达和 lincRNA RP5-855F14.1 的上调表达一致；NRM 参与心脏重塑，而 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 表达是否是导致胎盘功能不全引起的 FGR 的血管生成调节因子，或者这些基因的表达是否可以用作心血管风险增加的生物标志物。FPR3 和 NRM 差异基因表达的改变部分可能与性别依赖的 DNA 甲基化有关。
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