Exercise training improves cerebral endothelial function in juvenile and mature Ossabaw miniature‐pigs

Background Chronic hyperglycemia promotes excessive production of endothelial reactive oxygen species (ROS), which may impair nitric oxide (NO) signaling, a hallmark of vascular disfunction. How maturation and exercise training influence this process in the cerebrovasculature has yet to be explored. The purpose of this study was to examine the role of ROS on endothelial‐dependent cerebral dilation at different stages of maturation in sedentary and exercise trained hyperglycemic pigs. It was hypothesized that mature pigs would display reduced endothelial NO‐dependent dilation coinciding with augmented NAD(P)H Oxidase (NOX; involved in ROS production) activity and reduced superoxide dismutase (SOD; involved in ROS clearance) activity compared with juvenile pigs. Furthermore, compared with sedentary (SED) pigs, pigs that completed high‐intensity interval training (HIIT) would exhibit enhanced endothelial NO‐dependent dilation coupled with decreased NOX and increased SOD signaling. Methods Twenty juvenile (n=10F/10M; 3±1 mo.) and 17 mature (n=9F/7M; 14±1 mo.) Ossabaw miniature‐pigs were divided into SED or HIIT groups. The HIIT consisted of 3 sessions per week (5X3 min intervals interspersed with 1 min recovery periods performed on a motorized treadmill) for 8 weeks. Animals were group housed with access to 1 kg of feed/pig/day and ad libitum access to a 10% sugar water solution. At the end of the intervention pigs were euthanized, and cerebral arteries were harvested for arterial myography experiments. To examine endothelial NO‐dependent relaxation, vasomotor responses to bradykinin (BK; 3e‐15M to 1e‐6M) were studied in the presence or absence of NO synthase inhibition (L‐NAME; 3e‐4 M). Further, to examine the role of ROS signaling, vasodilatory responses to BK were studied under the following conditions: 1) NOX inhibition (Apocynin; 1e‐4 M) and 2) SOD mimetic (TEMPOL; 1e‐4 M). Results At the end of the trial all groups were considered hyperglycemic (mean plasma glucose> 8.5 mmol/L), and plasma glucose values were lower in mature (8.8±1.6 mmol//L) vs. juvenile pigs (10.3±2.2 mmol/L; main effect; P<0.05). Regarding cerebral vasomotor control, BK‐induced dilation was greater in HIIT vs. SED groups (main effect; P<0.01), owing to enhanced NO signaling (main effect; P=0.05). Treatment with a NOX inhibitor increased BK‐induced dilation in juvenile (P=0.05) and mature SED pigs (P=0.01). Treatment with a SOD mimetic did not influence dilation in juvenile SED pigs (P=0.87), and increases in BK‐induced dilation in mature SED pigs approached significance (P=0.07). Conclusion These results show that despite being hyperglycemic, HIIT improved endothelial‐dependent cerebral dilation in juvenile and mature pigs likely owing to enhanced NO bioavailability, secondary to decreased NOX and increased SOD signaling. Maturity was associated with lower levels of hyperglycemia and did not impair cerebral endothelial‐dependent dilation.