Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway

Aims—Perivascular adipose tissue (PVAT) is recognized for its vaso-active effects, however it’s unclear how Metabolic Syndrome impact thoracic-aorta (t)PVAT and the subsequent effect on functional and structural aortic stiffness. Methods & Results—Thoracic aorta and tPVAT were removed from 16–17 week old lean (LZR, n=16) and obese Zucker (OZR, n=16) rats. OZR presented with aortic endothelial dysfunction, assessed by wire-myography, and increased aortic stiffness, assessed by elastic modulus. OZR-tPVAT exudate further exacerbated the endothelial dysfunction reducing nitric oxide and endothelial dependent relaxation (p \u3c0.05). Additionally, OZR-tPVAT exudate had increased MMP9 activity (p\u3c0.05) and further increased elastic modulus of the aorta following 72- hours of coculture (p\u3c0.05). We found the observed aortic dysfunction caused by OZR-tPVAT was mediated through increased production and release of TNFα (p\u3c0.01), which was dependent on tPVAT NADPH-oxidase 2 (NOX2) activity. OZR-tPVAT ROS and subsequent aortic dysfunction was inhibited by TNFα neutralization and/ or inhibition of NOX2. Additionally, we found OZRtPVAT had reduced activity of the 20S proteasome’s active sites (p\u3c0.05) and reduced superoxide dismutase activity (p\u3c0.01). Conclusion—Metabolic syndrome causes tPVAT dysfunction through interplay between TNFα and NOX2 leading to tPVAT mediated aortic stiffness by activation of aortic ROS and increased MMP9 activity