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

Perivascular adipose tissue (PVAT) is recognized for its vasoactive effects, but it is unclear how metabolic syndrome impacts thoracic aorta (t)PVAT and the subsequent effect on functional and structural aortic stiffness. Thoracic aorta and tPVAT were removed from 16- to 17-week-old lean (LZR, n=16) and obese Zucker rats (OZR, n=16). The OZR presented with aortic endothelial dysfunction, assessed by wire myography, and increased aortic stiffness, assessed by elastic modulus. The OZR tPVAT exudate further exacerbated the endothelial dysfunction, reducing nitric oxide and endothelium-dependent relaxation (P<0.05). Additionally, OZR tPVAT exudate had increased MMP9 activity (P<0.05) and further increased the elastic modulus of the aorta after 72h of co-culture (P<0.05). We found that the observed aortic dysfunction caused by OZR tPVAT was mediated through increased production and release of tumour necrosis factor- (TNF; P<0.01), which was dependent on tPVAT NADPH-oxidase 2 (NOX2) activity. The OZR tPVAT release of reactive oxygen species and subsequent aortic dysfunction were inhibited by TNF neutralization and/or inhibition of NOX2. Additionally, we found that OZR tPVAT had reduced activity of the active sites of the 20S proteasome (P<0.05) and reduced superoxide dismutase activity (P<0.01). In conclusion, metabolic syndrome causes tPVAT dysfunction through an interplay between TNF and NOX2 that leads to tPVAT-mediated aortic stiffness by activation of aortic reactive oxygen species and increased MMP9 activity.