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Low birth weight (LBW) offspring have a higher prevalence of long‐term cognitive impairments, possibly the result of altered blood flow control in the brain. Using a pig model, we tested the hypothesis that LBW progeny exhibit abnormal cerebral hemodynamics and vasomotor control during early developmental stages of growth. At birth, littermate pigs were identified as normal (NBW=1.7±0.1 kg) or low birth weight (LBW=1.2±0.2 kg). Measurements were obtained at 28 d (weaning) and 56 d of age (n=8/group, 4M/4F per group) : i) 28‐d old NBW (28‐NBW; body mass=10.0±0.4 kg); ii) 28‐d old LBW (28‐LBW; body mass=8.0±0.4 kg); iii) 56‐d old NBW (56‐NBW; body mass=23.0±1.0 kg); and iv) 56‐d old LBW (56‐LBW; body mass=17.0±0.8 kg). Cerebral blood flow velocity was measured using Transcranial Doppler ultrasound. Thereafter, pigs were euthanatized, their brains were harvested, weighed and their pial arteries were dissected for pressure myography experiments. Briefly, pial artery vasomotor control was studied in response to a Ca2+‐activated potassium (BK) channel α‐subunit agonist NS1619 (elicits vasodilation; 1e‐10‐1e‐4 M) and sympathetic co‐transmitter neuropeptide Y (NPY; potent vasoconstrictor; 1e‐10‐1e‐4 M). Brain mass and body mass were significantly lower in LBW vs. NBW pigs (p<0.01). Mean cerebral blood flow velocities were similar between LBW and NBW pigs (p≥0.20). Peak systolic velocities were greater (main effect of BW, p<0.01) and reductions in end diastolic velocities approached significance in LBW vs. NBW pigs (main effect of BW, p=0.08). Accordingly, the resistive index was greater in LBW vs. NBW pigs (main effect of BW, p<0.01). The maximum vasodilator response to NS1619 was not significantly different between LBW and NBW pigs (p=0.12). However, the overall magnitude of dilation (area under the curve) was lower in LBW vs. NBW pigs (main effect of BW, p<0.05). The maximum vasoconstrictor response to NPY was greater in LBW vs. NBW groups (main effect of BW, p<0.05). Similarly, the overall magnitude of constriction was greater in LBW vs. NBW pigs (main effect of BW, p<0.01). With respect to cerebral hemodynamics and vasomotor control, no main effects of age were observed (p≥0.50). Results from this study show that LBW pigs display alterations in cerebral hemodynamics as well as cerebral vasomotor control that persist for at least 56 days. Impaired BK channel function and enhanced vasoreactivity to sympathetic co‐transmitter NPY may underlie altered cerebrovascular hemodynamics in LBW pigs. Support or Funding Information SHRF Establishment grant (#4522) and NSERC

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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.

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