Fetal programming under hyperglycemic stress: The vascular system at risk

Maternal hyperglycemia, arising from pregestational or gestational diabetes, affects approximately 19% of pregnancies worldwide. Beyond its immediate obstetric and neonatal consequences, it may leave a durable imprint on vascular development. Within the framework of the Developmental Origins of Health and Disease (DOHaD) hypothesis, this review synthesizes current evidence linking an intrauterine hyperglycemic environment to persistent vascular dysfunction in the offspring. The analysis first focuses on the utero-fetoplacental interface, where impaired spiral artery remodeling, abnormal placental angiogenesis, and weakened endothelial barrier integrity may disturb maternal-fetal exchange and expose developing tissues to early stress. Clinical and experimental data indicate that these disturbances are followed by long-term alterations in vascular structure and reactivity, including a shift toward a pro-constrictor phenotype, endothelial dysfunction, reduced nitric oxide bioavailability, oxidative stress, altered cyclooxygenase-2-derived prostanoid signaling, and enhanced neurovascular sympathetic influences. Structural remodeling, particularly in resistance arteries, may further increase peripheral vascular resistance and favor the later development of hypertension. The review also considers how epigenetic changes, including DNA methylation and histone modifications, may contribute to a persistent molecular memory of fetal hyperglycemic exposure. By integrating evidence from placental biology, vascular reactivity, arterial remodeling, and early cardiovascular phenotypes, this review outlines how maternal hyperglycemia may shape offspring cardiovascular risk through sustained alterations in vascular structure and function.