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.