Human fetoplacental arterial and venous endothelial cells are differentially programmed by gestational diabetes mellitus, resulting in cell-specific barrier function changes

Abstract

Aims/hypothesisAn adverse intrauterine environment can result in permanent changes in the physiology of the offspring and predispose to diseases in adulthood. One such exposure, gestational diabetes mellitus (GDM), has been linked to development of metabolic disorders and cardiovascular disease in offspring. Epigenetic variation, including DNA methylation, is recognised as a leading mechanism underpinning fetal programming and we hypothesised that this plays a key role in fetoplacental endothelial dysfunction following exposure to GDM. Thus, we conducted a pilot epigenetic study to analyse concordant DNA methylation and gene expression changes in GDM-exposed fetoplacental endothelial cells.MethodsGenome-wide methylation analysis of primary fetoplacental arterial endothelial cells (AEC) and venous endothelial cells (VEC) from healthy pregnancies and GDM-complicated pregnancies in parallel with transcriptome analysis identified methylation and expression changes. Most-affected pathways and functions were identified by Ingenuity Pathway Analysis and validated using functional assays.ResultsTranscriptome and methylation analyses identified variation in gene expression linked to GDM-associated DNA methylation in 408 genes in AEC and 159 genes in VEC, implying a direct functional link. Pathway analysis found that genes altered by exposure to GDM clustered to functions associated with ‘cell morphology’ and ‘cellular movement’ in healthy AEC and VEC. Further functional analysis demonstrated that GDM-exposed cells had altered actin organisation and barrier function.Conclusions/interpretationOur data indicate that exposure to GDM programs atypical morphology and barrier function in fetoplacental endothelial cells by DNA methylation and gene expression change. The effects differ between AEC and VEC, indicating a stringent cell-specific sensitivity to adverse exposures associated with developmental programming in utero.Data availabilityDNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4699-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Identification and validation of the miRNA–mRNA regulatory network in fetoplacental arterial endothelial cells of gestational diabetes mellitus

“…Previous research has only focused on the effects of miRNAs or mRNAs in GDM on the heart development of offspring, without a comprehensive analysis of the miRNA-mRNA axis [28][29][30]. Strutz J [13] and Cvitic S [14] analyzed the changes in the expression of miRNAs and mRNAs in dAECs of GDM and concluded that these changes would increase the risk of longterm cardiovascular disease in the offspring. However, the study did not further clarify and verify whether these miRNAs and mRNAs were involved in the development of the heart during the embryonic stage.…”

Nutrition and Metabolic Adaptations in Physiological and Complicated Pregnancy: Focus on Obesity and Gestational Diabetes

“…Placentas from mothers with HIP are frequently larger, with an increased placental weight and placental-weight to birth-weight ratio irrespective of glycemic control (25). Epigenetic studies of Genome-wide methylation analysis highlighted that metabolic disturbances associated to Gestational Diabetes (GDM) may also affect DNA methylation and gene expression profile, particularly at arterial (AEC) and venous endothelial cells (VEC) level, with respect to cell morphology, cellular movement, and those inducing actin organisation and barrier functions (26).…”

Epigenetic Changes in Gestational Diabetes Mellitus

“…The exposure to GDM programs atypical barrier function and morphology in fetoplacental endothelial cells by methylation of DNA and gene expression change. The effects were different in AEC and VEC and indicated a stringent cell-specific sensitivity to affected exposure-linked developmental programming in utero [ 63 ].…”