Perivascular Adipose Tissue Derived TNF α Neutralization Recovers Aortic Function in Metabolic Syndrome
Authors: DeVallance Evan , Branyan Kayla , Lemaster Kent , Brooks Steve , Asano Shinichi , Skinner Roy , Frisbee Jefferson C , Chantler Paul D 
Published: November 2023

Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular impairment and disease. The aorta is important in cardiac health as it provides direct resistance against the heart. Resistance may increase due to inflammation, ROS, decreased nitric oxide (NO), and reduced reactivity. Perivascular adipose tissue (PVAT) is a specific population of adipose, which lays in direct contact with the vasculature. PVAT is known to plays an active roll in vascular function and structure through the release of vasoactive substances. In normal healthy conditions PVAT has an anti‐contractile effect on the vessels. In disease states this effect may be lost which may be attributed to the immune cells that have infiltrated the PVAT. In MetS expression and production of inflammatory cytokines like TNF α increase. TNF α signaling can reduce NO bioavailability, induce reactive oxygen species (ROS) production, increase inflammatory cytokines, and increase immune‐attractive proteins. The purpose of the study was to 1) determine if TNF α neutralization in MetS blunts PVAT impairment of aortic endothelium dependent dilation and hyperconstriction, and 2) to determine how TNF α treatment improves NO bioavailability in MetS. Obese Zucker rats (OZR) were used as an animal model of MetS compared to lean Zucker rats (LZR). Aortas removed and cleaned, cut into 3 mm rings, and hung on a wire myograph for dose response curves to methacholine (MCh) and phenylephrine (PE). The remaining 2 mm aortic rings were used for NO release measured by a DAF‐FM diacetate assay under the following conditions: basal and MCh 1×10−5 M (with out PVAT, PVAT, and PVAT + TNF α neutralizing antibody (NAb)). TNF α expression in PVAT is increased 74 fold in OZR compared to LZR (p<0.05). NO bioavailability was decreased in OZR following treatment with PVAT exudate (12.6±0.7 AU to 10.9±0.5 AU p<0.05) while NO was increased in LZR treated with PVAT exudate (18.5±1.0 AU to 21.6±1.7 AU, p<0.05). Treatment of PVAT exudate with TNF α NAb prior to treating aortic rings eliminated PVAT derived blunting of NO release in OZRs (10.9±0.5 AU up to 16±0.9 AU, p<0.05). Similarly, in cross over experiments LZR aortic rings treated with OZR PVAT exudate decreased NO (MCh −5 18.5±1.0 AU, OZR PVAT exudate 12.6±1.5, p<0.05) while OZR PVAT exudate treated with TNF α neutralizing NAb was comparable to LZR control levels (MCh −5 18.5±1.0 AU, OZR PVAT exudate + TNF α neutralizing NAb 17.4±1.5). The impaired relaxation to MCh in OZR was made worse by incubation with PVAT, and recovered by simultaneous treatment with TNF α NAb (Max dilation: PVAT 64±2%, PVAT+ TNF α NAb 74±3% p<0.05). OZR constriction was increased in the presence of PVAT (p<0.05), which was resolved with simultaneous treatment with TNF α neutralizing NAb. TNF α NAb also reduced PVAT's increase in constriction to PE (Max constriction as % of KCl constriction: PVAT 116±6%, PVAT+ TNF α NAb 92±3%, p<0.05) In conclusion these data highlight the role of PVAT derived TNF α in arterial dysfunction associated with MetS. This emphasizes the need to understand PVAT function to fully grasp the impact of metabolic disease on the cardiovascular system.

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