Sex differences in the developmental programming of cardiovascular and renal risk across the lifespan

Cardiovascular (CV) disease remains the leading cause of death worldwide, with metabolic disorders nearly doubling CV risk mortality. Although adult lifestyle factors contribute to disease development, increasing evidence supports a critical role for developmental programming in shaping the long-term cardiac health. The developmental origins of health and disease concept, first proposed by Barker, associates low birth weight with increased CV risk in adulthood. Subsequent studies demonstrated that maternal health, including undernutrition, smoking, preeclampsia (PE), autoimmune diseases, and polyendocrine metabolic ovarian syndrome (PMOS), is associated with impaired fetal growth and increased susceptibility to CV, renal, and metabolic disease in offspring. Conversely, high birth weight, associated with maternal or parental obesity, is linked to elevated risk of obesity, type 2 diabetes, renal susceptibility, and heart failure later in life. Preclinical models of developmental insults identify key mechanistic pathways, including activation of the renin-angiotensin system, sympathetic nervous system, oxidative stress, and immune dysregulation, with additional sex-specific differences in susceptibility to adverse outcomes after injury. Despite advances, preventive strategies targeting the preconception and gestational periods remain limited. This review highlights mechanisms linking impaired fetal growth induced via developmental exposure to PE, PMOS, maternal obesity, and parental obesity to long-term cardiometabolic and renal risk and discusses emerging therapeutic approaches.