PS-BPB01-2: VASCULAR ENDOTHELIAL NAMPT-MEDIATED NAD+ BIOSYNTHESIS REGULATES WHOLE-BODY BLOOD PRESSURE AND INSULIN RESISTANCE

Abstract

Obesity is associated with dysregulation in blood pressure control and whole-body glucose metabolism, but the precise underlying mechanism(s) remain unclear. Here, we generated and characterized mice with vascular endothelial-cell specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism. We found that vascular endothelial cell-specific Nampt knockout (VeNKO) mice exhibited 1) higher blood pressure (systolic blood pressure; flox/flox mice: 111 ± 2.6 mmHg, VeNKO mice: 134 ± 4.0 mmHg, p < 0.05) with cardiac hypertrophy (flox/flox mice: 5.0 mg/g-body weight, VeNKO mice: 6.1 mg/g-body weight, p < 0.05) and 2) insulin resistance with abnormal fat distribution, under high-fat diet feeding. These deleterious alterations were partially rescued by administering nicotinamide mononucleotide (NMN), a key NAD+ intermediate. Taken together, our findings demonstrate that vascular endothelial NAMPT-mediated NAD+ biosynthesis is involved in the regulation of blood pressure and whole-body glucose metabolism. Our study provides mechanistic and therapeutic insights into vascular endothelia NAD+ biology related to obesity-associated hypertension and insulin resistance.