Vascular Endothelial NAMPT‐Mediated NAD⁺ Biosynthesis Regulates Angiogenesis and Cardiometabolic Functions in Male Mice

Aging is associated with metabolic dysfunction and cardiovascular abnormalities. Defective nicotinamide adenine dinucleotide (NAD + ) biosynthesis correlates with aging and aging‐associated complications. However, the precise molecular mechanisms linking aging‐associated NAD + deficiency to cardiometabolic dysfunction remain unclear. Herein, we examined whether nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD + biosynthesis, influences vascular endothelial function and whole‐body metabolic and hemodynamic homeostasis during aging. Vascular endothelial cell–specific Nampt knockout (VeNKO) mice fed a regular chow diet exhibited no cardiometabolic abnormalities, whereas male VeNKO mice fed a high‐fat diet exhibited reduced angiogenesis, resulting in impaired subcutaneous adipogenesis, impaired glucose metabolism, and hemodynamic disturbances. Mechanistically, NAMPT loss attenuated NAD + ‐dependent deacetylase sirtuin‐1 (SIRT1) and endothelial nitric oxide synthase (eNOS) signaling, impairing angiogenesis. Aged mice exhibited endothelial NAD + depletion driven by an imbalance between NAMPT‐mediated NAD + biosynthesis and consumption, leading to impaired eNOS signaling and associated angiogenic and cardiometabolic dysfunction, similar to that observed in VeNKO mice. Nicotinamide mononucleotide administration replenished vascular endothelial NAD + levels, improved angiogenesis, restored subcutaneous adipose tissue volume, and ameliorated aging‐associated cardiometabolic dysfunction. Collectively, our findings provide mechanistic and therapeutic insights into vascular endothelial NAMPT–NAD + –SIRT1–eNOS signaling related to aging‐associated cardiometabolic disorders.