NAMPT Impairs Vascular Permeability in Periodontitis by Influencing FASN-mediated Lipogenesis

Vascular abnormalities promote tissue inflammation and bone loss. Although vascular abnormalities in periodontitis have been studied, underlying pathogenic mechanisms remain unclear. This study aimed to investigate key molecules regulating endothelial cell permeability and explore their role in the progression of periodontitis. Single-cell RNA sequencing revealed leukocyte transendothelial migration in periodontitis is associated with endothelial cells. Moreover, increased vascular permeability was observed in both human and mouse periodontitis tissues. Nicotinamide phosphoribosyltransferase (NAMPT) protein expression was significantly upregulated in endothelial cells within periodontitis tissues, with levels increasing as the disease progressed. NAMPT gain-of-function decreased VE-cadherin expression and membrane potential, increased HUVEC permeability, and promoted leukocyte trans-endothelial migration. Mechanically, NAMPT elevated levels of triglycerides and free fatty acids, leading to lipid droplet accumulation in HUVEC. Fatty acid synthase (FASN), an enzyme that catalyzes the biosynthesis of fatty acids, is also raised with NAMPT. NAMPT promoted NADPH pool which is utilized in FASN-mediated lipogenesis. FASN inhibitor orlistat reversed lipogenesis and endothelial permeability induced by NAMPT. Furthermore, orlistat administration reduced periodontal vascular permeability and further reversed bone resorption in periodontitis mice. This study demonstrated that increased NAMPT in periodontitis promotes endothelial permeability by modulating FASN-mediated lipogenesis, thereby contributing to bone loss in periodontitis.