Chien‐Ning Hsu, You‐Lin Tain
Nitric oxide (NO) functions as a master integrative regulator of cardiovascular-kidney-metabolic (CKM) homeostasis, yet it displays a profound Janus face, defined by concentration- and context-dependent roles in both health and disease. This narrative review examines NO signaling from a life-course perspective, beginning with fetal programming, during which the NO-asymmetric dimethylarginine (ADMA) axis orchestrates placental development and nephron endowment. Perturbations during this critical window-such as maternal ADMA elevation-can imprint a maladaptive trajectory toward adult-onset hypertension and chronic kidney disease. In adulthood, this initially silent dysregulation of NO signaling is amplified by Western dietary patterns and environmental pollutants, culminating in the clinical manifestation of the CKM triad. This pathological transition is driven by eNOS uncoupling and ADMA accumulation, which shift redox balance toward peroxynitrite formation and precipitate mitochondrial bioenergetic failure. Moreover, while constitutive NO production is essential for vascular homeostasis, pathological induction of inducible NOS generates excessive NO fluxes that promote insulin resistance and tissue injury. With advancing age, a progressive loss of NO resilience further exacerbates multi-organ vulnerability. To mitigate the cumulative burden of CKM disease, this review highlights developmental reprogramming strategies-such as perinatal L-citrulline supplementation and ADMA-lowering interventions-as interventions to restore physiological NO signaling. Integrating such early-life strategies with contemporary pharmacological therapies offers a coherent framework for maintaining NO bioavailability and extending health span across the life course.