The E2F1 regulon orchestrates a proliferative emergency and vascular programming in fetal endothelial progenitors exposed to GDM: a sex-stratified systems medicine approach

Authors

Adegbaju, M. S., Babayeju, O., Morenikeji, O. B., Ojurongbe, O., Thomas, B.

Abstract

Maternal Gestational Diabetes Mellitus (GDM) and obesity are major drivers of the Developmental Origins of Health and Disease (DOHaD), predisposing offspring to premature cardiovascular disease. However, the specific molecular pathways that program this sex-specific vascular risk remain poorly defined due to the cellular complexity of the placenta. We sought to identify the primary regulatory engines of fetal vascular programming in a sex-stratified neonatal cohort. We analyzed purified neonatal Endothelial Colony Forming Cells (ECFCs) - the fundamental progenitors of the fetal vasculature - from pregnancies complicated by GDM and pre-pregnancy obesity. Using a sex-stratified regulatory inference framework, we decoupled the priming effects of obesity from the acute transcriptomic insult of GDM. Our findings reveal a profound functional asymmetry in fetal vascular adaptation. While male progenitors maintain metabolic resilience through AKT3-mediated buffering, the female fetal-placental interface undergoes a systemic proliferative emergency. This maladaptive state is driven by a massive unshackling of the E2F1-regulon (NES = 16.86), triggered by a maternal-fetal surge in CDK/MAPK signaling. This female-specific program prioritizes unscheduled cell-cycle progression at the metabolic expense of angiogenic maturation and innate immune surveillance. GDM imposes a sex-specific epigenetic scar on female fetal endothelial progenitors, characterized by a quantity-over-quality trade-off in vascular development. This identification of the E2F1-pathway as a driver of fetal vascular exhaustion provides a mechanistic basis for the increased cardiovascular vulnerability in female offspring and identifies the cell cycle as a potential therapeutic target for mitigating the long-term sequelae of GDM.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 02 Jul 2026.

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