Metabolic Syndrome Perivascular Adipose Tissue Impairment of Aortic Reactivity Post Stroke, Improved by NOX2 Inhibition
Authors: DeVallance Evan , Branyan Kayla , Lemaster Kent , Skinner Roy , Brooks Steve , Frisbee Jefferson , Chantler Paul 
Published: November 2023

Metabolic Syndrome (MetS) has increased reactive oxygen species (ROS) and inflammation leading to an increased risk of stroke. However, overall cardiovascular function may play an important part during recovery and the chance for secondary events with stroke. Central vessels like the aorta are important in cardiac health as it provides direct resistance against the heart, and is important in pressure amplification, which could impair resistance vessels. Perivascular adipose tissue (PVAT) lays in direct contact with the aorta and is known to play an active roll in its function. Increased production of inflammatory cytokines and ROS are seen in the PVAT of MetS and can be attributed to the infiltrated immune cell. There is a large increase of circulating immune cells following stroke. The local inflammation attracts other immune cells to infiltrate the PVAT leading to an even great population. ROS production from NADPH oxidase 2 (NOX2) in immune cells could reduce NO causing further vascular impairments. Therapeutics aimed at reducing ROS in the PVAT may lead to improved vascular function and better outcomes. GP91 is a strong specific inhibitor of the NOX2 isoform. If PVAT impairment of aortic function following stroke is driven by ROS generated from infiltrated immune cells GP91 treatment may recovery function. The purpose of the current study was to show GP91 eliminated PVAT impairment of aortic reactivity and NO bioavailability. Obese Zucker rats (OZR) underwent transient middle cerebral artery occlusion (tMCAO) for 60 minutes followed by 15 days recovery both with and without GP91 treatment. Aortas were cut into 3mm rings hung on a wire myograph. PVAT incubated in physiological solution at 37°C with and without GP91. Methacholine (MCh) dose response curves were run under these conditions: untreated, PVAT, and GP91 treated PVAT. 2mm aortic rings were used in a DAF‐FM diacatate assay to measure NO under basal conditions, or stimulated with MCh: no PVAT, PVAT exudate, and GP91 treated PVAT exudate. Chronic treatment with GP91 improved aortic reactivity with a max dilation of 77% compared to control 67% and OZR tMCAO 63% (p<0.05). Chronic treatment also improved max dilation in the presence of PVAT to 75% dilation compared to control 58% and OZR tMCAO 51% (p<0.05). If OZR tMCAO PVAT was incubated with GP91 prior to MCh max dilation, it improved to 66% compared to 51%. Improved reactivity is in response to greater NO release in GP91 treated stroke group: 15.2±0.6AU compared to OZR control 13.8±0.7AU and OZR tMCAO 9.4±0.7AU (p<0.05). Chronic GP91 treatment also blocked PVAT reduction of NO 15.4±1AU, control 11.1±0.7AU, and OZR tMCAO 8.4±0.8AU (p<0.05). Acute treatment of OZR tMCAO PVAT with GP91 eliminated the PVAT associated decrease in NO release in a subset of animals: 13.3± 0.5AU, + PVAT: 9.4±0.5AU, + PVAT treated with GP91 13.1±0.3AU (p<0.05). In conclusion inhibition of NOX2 post stroke in MetS improves aortic reactivity through increased NO bioavailability partially through blunting PVAT's detrimental impact.

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