Transcriptional and Epigenomic Markers of the Arterial-Venous and Micro/Macro-Vascular Endothelial Heterogeneity within the Umbilical-Placental Bed

Abstract

Umbilical and placental vessels and endothelial cells (EC) are common models to study placental function and vascular programming. Arterio-venous differences are present in the umbilical endothelium; however, the heterogeneity of small placental vessels and the expression of potential micro- vs. macro-vascular (MMV) markers are poorly described. Here, we performed a meta-analysis of transcriptomic and DNA methylation data from placental and umbilical EC. Expression and methylation profiles were compared using hierarchical clustering, dimensionality reduction (i.e., tSNE, MDS, and PHATE), and enrichment analysis to determine the occurrence of arterio-venous (AVH) and micro-macro heterogeneity (MMH). CpG sites correlated with gene expression of transcriptional markers of MMH and AVH were selected by Lasso regression and used for EC discrimination. General transcriptional profile resulted in clear segregation of EC by their specific origin. MM and AVH grouping were also observed when microvascular markers were applied. Altogether, this meta-analysis provides cogent evidence regarding the transcriptional and epigenomic profiles that differentiate among EC, proposing novel markers to define phenotypes based on MM levels.

Epigenetic regulation by hypoxia, N‐acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos

“…Conversely, consistent with findings reported in human (Krause, Costello et al., 2013), rat, mice and guinea‐pig (Herrera et al., 2017a; Krause et al., 2019) pregnancy, the NOS3 promoter in chicken arteries had a low density of CpG sites, in which both mean and site‐specific DNA methylation were decreased in embryos incubated under hypoxic conditions and restored by NAC treatment, correlating with changes in eNOS transcript levels. Studies focused on eNOS regulation show that basal eNOS expression is tightly and inversely regulated by NOS3 DNA methylation (Krause, 2021; Krause, Costello et al., 2013), an effect that has been confirmed by transcriptomic and genome‐wide data (Arenas et al., 2022). Combined, therefore, the data suggest that embryonic or fetal hypoxia drives epigenetic changes in key vascular genes, with a remarkable effect on NOS3 shared across diverse mammalian and non‐mammalian species.…”

Transcriptional Profiling of Human Endothelial Cells Unveils PIEZO1 and Mechanosensitive Gene Regulation by Prooxidant and Inflammatory Inputs

“…Several studies have demonstrated that TNF-α stimulation contributes to endothelial-mesenchymal transition [32] and a proadhesive phenotype [7,15]. Notably, the transcriptional profile associated with TNF-α stimulation was comparable among different endothelial cell types, despite their considerable phenotypic differences [16,17,33], suggesting that this mechanism may affect, in a concerted manner, the endothelial function.…”

“…Transcriptomic datasets were selected as previously described [16,17], applying PRISMA EQUATOR guidelines for the meta-analysis studies (http://www.equator-network.org/ reporting-guidelines/prisma, accessed on 30 June 2021). Using "Endothelial cells", "HU-VEC", "TNF-α", and "Affymetrix" as keywords, we explored GEO (Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/, accessed on 30 October 2021; and OmicsDI, http://www.omicsdi.org, accessed on 30 October 2021).…”

Flow in fetoplacental-like microvessels in vitro enhances perfusion, barrier function, and matrix stability

“…Although fetal and from the placenta ( 75 ), HUVECs are not chorionic endothelial cells. Other studies highlighted significant transcriptomic distinctions between placental macro- and microvasculature, as well as between placental and umbilical endothelium ( 76 ). Despite the use of HUVECs herein, our model incorporates placental-derived stromal cells in a 3D microenvironment, enabling the development of fetoplacental-like microvessels.…”