Exercise Training Prophylactically Abrogates Chronic Stress‐Induced Cerebrovascular Dysfunction in Lean and Obese Zucker Rats
Authors: Brooks Steven D , Branyan Kayla , DeVallance Evan , Sheets Whitney J , Skinner Roy , Bryner Randall , Olfert Mark , Chantler Paul D , Frisbee Jefferson C 
Published: November 2023

Chronic stress/depression is a major risk factor for cardiovascular disease (CVD) and impaired vascular function. In animals with comorbid metabolic syndrome, we have previously shown that chronic stress/depression will cause the near‐total loss of vascular reactivity in cerebral blood vessels, significantly impairing regulation of cerebral blood flow. The purpose of this study was twofold: first, to further elucidate mechanical and anatomical effects of chronic stress in the cerebrovasculature of lean and obese Zucker rats (LZR, OZR), and secondly, to determine the efficacy of exercise training as a prophylactic method for abrogating the onset of stress‐induced vasculopathy in LZR and OZR. Eight weeks of an unpredictable chronic mild stress (UCMS) protocol was imposed on 9 week old male LZR and OZR to induce depressive behaviors. Half of all animals also underwent 8 weeks of daily treadmill exercise concurrent to the UCMS protocol. After sacrifice, the brains were removed and the middle cerebral artery (MCA) was isolated and cannulated in an ex vivo microvessel preparation. Vascular reactivity was assessed to acetylcholine (ACh) on naïve vessels, and again following acute incubation with TEMPOL. The brains were frozen in Tissue Freezing Medium, sectioned, and analyzed for microvessel density (MVD). Plasma samples were analyzed by ELIZA or Meso Scale Diagnostics for biomarkers of inflammation and stress. Vascular reactivity was impaired in MCAs from both UCMS‐LZR and OZR compared to non‐stressed control. OZR‐UCMS demonstrated an almost total loss of reactivity to ACh, which was rescued marginally by TEMPOL. Both LZR‐UCMS and OZR control animals showed elevated levels of inflammatory biomarkers and corticosterone compared to LZR control, and OZR also had a significant decrease in cortical MVD. A smaller, but significant, decrease in MVD was also observed in LZR‐UCMS, while an ever larger drop in cortical MVD was seen in OZR‐UCMS. Exercise training was able to completely reverse the effects of UCMS in both LZR and OZR; LZR‐UCMS‐Exercise was comparable to LZR control, while OZR‐UCMS‐Exercise showed improved reactivity beyond OZR control. Interestingly, TEMPOL treatment of vessels from exercised animals resulted in no significant further improvements in reactivity. Plasma inflammatory biomarkers were significantly decreased in exercise trained animals, and the decreases in cortical MVD were prevented as well, with OZR exercise animals actually showing an increase over control. These results suggest that exercise training can protect the cerebrovasculature from the detrimental effects of chronic stress/depression, likely due to the anti‐oxidant and anti‐inflammatory benefits of exercise. Enhanced clearance of ROS and improved NO bioavailability helps improve vascular function and prevent rarefaction of cortical microvessels, indicating that these pathways may be promising avenues for treating stress‐related cerebrovascular disease.Support or Funding InformationAmerican Heart Association Predoctoral Fellowship NIH COBRE grant