Feto-placental endothelial cells of female neonates are more susceptible to gestational diabetes-induced changes

Fetal sex influences gene expression in the healthy feto-placental endothelium, potentially contributing to sex-dependent developmental programming and disease risk. Gestational diabetes mellitus (GDM) alters maternal–fetal homeostasis and placental vascular function. Building on previous findings of sex-biased gene expression in healthy feto-placental endothelial cells (fpEC), we investigated whether these biases persist or change following GDM exposure. We first identified sex-biased gene expression in fpEC from GDM pregnancies, then analyzed GDM-induced changes separately in male and female fpEC. Gene ontology enrichment was performed using the PANTHER database. Proliferation and network formation were assessed by BrdU incorporation assay and Matrigel assay, respectively. Female fpEC exhibited a greater transcriptional response to GDM, with more differentially expressed genes than male cells. Functionally, GDM reduced proliferation and increased network formation in female fpEC, while male cells were comparatively unaltered. In healthy conditions, male and female fpEC showed clear transcriptomic and functional dimorphism, which was abolished by GDM. Interestingly, GDM amplified sex-biased gene expression despite convergence in cellular behavior. These findings highlight fetal sex as a key modifier of the placental endothelial response to GDM and support its relevance in sex-specific pregnancy outcomes.