Vascular Endothelial <scp>NAMPT</scp> ‐Mediated <scp>NAD</scp> ⁺ 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.