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Sex-Stratified Transcriptomic Analysis of Cord-Blood Endothelial Colony-Forming Cells from Pregnancies Complicated by Gestational Diabetes

Year: 2026

Type: article

Abstract: Gestational diabetes mellitus (GDM) and maternal obesity are intrauterine metabolic exposures associated with altered fetal development and increased cardiovascular risk later in life. Increasing evidence suggests that fetal responses to these exposures are sex-dependent; however, the regulatory mechanisms underlying sex-specific vascular programming remain poorly understood. Using purified neonatal endothelial colony-forming cells (ECFCs), a progenitor population of fetal vasculature, we performed a sex-stratified transcriptomic analysis of pregnant mothers classified as lean, overweight, or GDM. Differential expression, pathway enrichment, transcription factor activity inference, kinase network reconstruction, and connectivity mapping were integrated to characterize sex-dependent regulatory responses to maternal metabolic dysfunction. Male and female ECFCs exhibited markedly divergent transcriptomic responses to GDM. Correlation between male and female fold-change estimates was negligible ( r = −0.01), and the female-specific signal was not detectable when sex was modeled as a covariate rather than as a stratifying variable. Female GDM-exposed ECFCs demonstrated coordinated enrichment of cell-cycle- and DNA replication-associated pathways together with recurrent prioritization of E2F-family regulators across multiple analytical approaches. In contrast, the male response was comparatively limited and was associated with distinct transcriptional changes, including AKT3 -associated pathways. Notably, E2F1 transcript abundance remained relatively stable despite coordinated expression changes among E2F-associated target genes. Independent endothelial transcriptomic datasets, drawn from previously published findings rather than independent reanalysis, provided complementary biological context rather than direct validation, consistent with enrichment of E2F-associated programs in GDM-exposed ECFCs and greater transcriptional responsiveness in female endothelial cells reported elsewhere. These findings indicate that fetal sex is a major determinant of the endothelial progenitor response to maternal metabolic dysfunction and that biologically relevant signals may be obscured in pooled analyses. Our results support the existence of sex-dependent regulatory programs associated with fetal vascular responses to GDM and identify an E2F1-associated regulatory framework as a candidate mechanism warranting further investigation.

Source: Computational and Structural Biotechnology Journal

DOI: 10.34133/csbj.0252

Authors: Muyiwa S. Adegbaju, Oluseyi Babayeju, Olanrewaju B. Morenikeji, Olusola Ojurongbe, Bolaji N. Thomas

Institutions: Rochester Institute of Technology, Newcastle University, Virginia State University, Ladoke Akintola University of Technology

Language: English

Topic: Gestational Diabetes Research and Management

Subfield: Obstetrics and Gynecology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,230