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Exercise Training Improves Cerebrovascular Oxidative Stress Regulation and Insulin Stimulated Vasodilation in Juvenile and Mature Pigs



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Background: Selective insulin resistance in the cerebrovasculature, characterized by augmented vasoconstriction in response to insulin, may relate to enhanced sensitivity to endothelin-1 (ET1) or increased oxidative stress, culminating in attenuated nitric oxide (NO) signalling. Regular exercise has been shown to enhance vascular responses to insulin, but the mechanisms remain unclear. This study tested the hypothesis that exercise training improves oxidative stress regulation and cerebrovascular insulin-stimulated vasodilation in juvenile and mature pigs. Methods: Twenty juvenile (n=10F/10M; 3±1 months; mass=11±3 kg) and 17 mature (n=9F/7M; 14±1 months; mass=83±9 kg) Ossabaw miniature-pigs were divided into sedentary or exercise training groups. Pigs in the exercise training groups completed high intensity interval training three times per week for eight weeks. All animals were group housed with access to 1 kg of feed per pig per day, as well as sugar water (~5 L per pig of 10% solution). At euthanasia, cerebral arteries were dissected for pressure myography experiments. Vascular diameter was tracked continuously and vasomotor responses to insulin (1e-9-1e-6 M) and ET1 (1e-12-1e-7 M) were studied under three conditions: 1) untreated (vehicle); 2) superoxide dismutase (SOD) mimetic (TEMPOL; 1e-4 M) and 3) NAD(P)H Oxidase (NOX) inhibition (Apocynin; 1e-4 M). Physiologic maximum and cumulative change in diameter (AUC) for all groups were compared using a two-way ANOVA (independent variables: age and exercise training). Results: Whereas sedentary pigs displayed insulin-stimulated vasoconstriction, exercise trained pigs exhibited insulin-stimulated vasodilation. Indices of insulin-stimulated vasodilation were significantly greater in exercise trained vs. sedentary controls (main effect: P<0.001). Pretreatment with the SOD mimetic or NOX inhibitor abolished between group differences (P≥0.85). Indices of ET1-induced vasoconstriction were not significantly different between groups under any experimental condition (P≥0.11). Conclusion: That insulin-stimulated vasoconstriction was reversible with a SOD mimetic or NOX inhibition in sedentary pigs implicates impaired oxidative stress regulation in the manifestation of selective insulin resistance. Exercise training coincided with improved oxidative stress regulation conjunctional with augmented insulin-stimulated cerebral vasodilation. Given vasoreactivity to ET1 was similar between groups, greater insulin-stimulated vasodilation in exercise trained pigs was likely the result of enhanced oxidative stress regulation yielding improvements in NO signalling.



Pial arteries, exercise, vascular insulin signalling, blood flow control, brain, HIIT



Master of Science (M.Sc.)


Veterinary Biomedical Sciences


Veterinary Biomedical Sciences


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