Vascular dysfunction at the crossroads of gestational diabetes mellitus and cancer.

Gestational diabetes mellitus (GDM) and cancer develop in distinct clinical and biological contexts; however, both conditions expose tissues to chronic metabolic stress, hypoxia, inflammation, and vascular remodelling. In this review, we advance the hypothesis that GDM and cancer share conserved endothelial adaptive response mechanisms, particularly within the placental and tumour-associated vasculature, without implying malignant transformation or direct oncogenic causation. Common alterations in nitric oxide signalling, mitochondrial metabolic programming, intracellular pH regulation, and redox homeostasis are highlighted. A central shared feature is dysregulation of purinergic signalling, whereby increased extracellular adenosine, driven by altered nucleoside transport and ectonucleotidase activity, including CD73, acts as an immunometabolic modulator. Engagement of A2A and A2B adenosine receptors on endothelial and immune cells suppress effector immune activation, favour myeloid immunoregulatory phenotypes, and promote vascular adaptation in tumours, while contributing to inflammatory persistence and endothelial dysfunction in GDM. These effects intersect with preserved signalling networks, including PI3K/AKT/mTOR, AMPK, MAPK/ERK, NF-κB, and hypoxia-inducible pathways, which regulate endothelial plasticity and survival across both diseases. We further propose that epigenetic stabilisation of these shared signalling states, mediated by DNA methylation, histone modifications, microRNA networks, and dysregulation of imprinted loci such as the insulin-like growth factor 2 gene, may extend the impact of gestational metabolic stress beyond pregnancy. Rather than conferring oncogenic risk per se, these mechanisms likely reflect common adaptive vascular programs reused across pathological settings. This comparative pattern can identify shared immunometabolic signalling nodes and provides a basis for understanding how gestational metabolic environments shape long-term vascular health.