Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction

Abstract

Background 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. Results 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. Conclusion 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.

Novel insights for the role of nitric oxide in placental vascular function during and beyond pregnancy

“…Conversely, very few studies have considered sex-specific differences, an effect that impacts the differential cardiovascular risk and in which an epigenetic basis must be considered. Recent research suggests that transcriptomic changes resulting from FGR are accompanied by some sex-specific epigenetic modifications (Terstappen et al, 2020), however, these seminal data deserve further confirmation. This also should be applied to life-course changes in epigenetic profiles, which could account for the diversity of physiological responses that precede the instauration of vascular dysfunction.…”

The Update of Fetal Growth Restriction Associated with Biomarkers

“…69,70 Reduced uteroplacental blood flow and oxygen and nutrient delivery could cause aberrant fetal growth where the main physiological mechanisms are fetal hemodynamic redistribution and epigenetic alterations. First discussion of the concept of epigenetic programing of cardio-renal disease in FGR included nurim involved in cardiac remodeling, 71 long intergenic non-coding RNAs involved in cardiovascular disease. 71,72 Yzydorczyk et al 73 indicate early endothelial dysfunction may relate with long-term cardiovascularrelated diseases, decreased NO bioavailability, impaired eNOS functionality, oxidative stress, endothelial progenitor cells dysfunction, epigenetic factors, and vascular senescence.…”

Quantifying Fetal Reprogramming for Biomarker Development in the Era of High-Throughput Sequencing

“…Another study examined the changes in developmental programming profiles in the human umbilical vein endothelial cells following FGR [32]. Using RNA sequencing and transcriptome analysis, they identified four differentially expressed genes (downregulation of LGALS1, FPR3, and NRM; upregulation of RP5-855F14.1).…”

“…While blood collected at time of birth may provide a comprehensive picture of the sum of antenatal stress and is reasonable for use in neonatal outcome prediction, it does not provide an opportunity for assessing the dynamics of fetal reprogramming, nor does it provide any value for clinical decision making in terms of optimal timing of delivery [21]. The placental or umbilical cord tissues are likely the tissue types that are the most sensitive to deprivation of oxygen and/or nutrients, and therefore provide an opportunity to assess reprogramming at its earliest stage [32,33,37]. However, these tissue types do not necessarily reflect the growth and development of the fetal body, and their assessment may not be feasible until after the fetus is delivered.…”