Oxygen-Glucose Deprivation Impairs Pial Arteriole Reactivity to Phenylephrine: Implications for Mean Arterial Pressure Augmentation in Neonatal Stroke

Background: Neonatal arterial ischemic stroke (NAIS) severely impairs cerebral perfusion leading to focal ischemia and vascular dysfunction. Current management is largely supportive in nature, and no effective treatments that may decrease the severity of neonatal stroke exist. The current study aimed to assess the impact of oxygen-glucose deprivation (OGD, an in vitro model of stroke) on endothelial and vascular smooth muscle cell (VSMC) function as well as reactivity to phenylephrine (PE), a vasopressor agent that is commonly used clinically to increase blood pressure. We hypothesized that OGD would impair both endothelial and VSMC function, leading to pressure-passive vasculature and blunting of responses to PE. Methods: were used in the study. Pressure myography was used to study fourth order pial branches of the MCA from 5–7-day old piglets (N=12) and these pial arteries were pressurized to physiologic levels (60 mmHg). Paired arterioles from the same animal were studied under physiological conditions (Kreb’s buffer with glucose continuously bubbled with blood gas mixture, pH maintained at 7.35-7.34, temp 38.5oC) or OGD conditions (Kreb’s buffer with 2mM glucose and bubbled with O 2 -free blood gas mixture to achieve pO 2 5-10 mmHg) mimicking ischemia. To assess endothelial and VSMC function, we performed cumulative dose-response experiments with acetylcholine (ACh), phenylephrine (PE) and sodium nitroprusside (SNP) under physiological vs. OGD conditions. Biomechanical properties were assessed under fully passive conditions following ~ 6 hours of OGD exposure. Results: OGD blunted PE-induced vasoconstriction at higher doses with the max difference (11.3%) seen at 10-5M (p< 0.01) Similarly, endothelial-dependent vasodilation to ACh was impaired in vessels under OGD conditions, with significant differences beginning at 3x10-7M (p< 0.01). In contrast, there was no statistically significant difference in SNP-induced dilation at any dose. Biomechanical testing revealed that 6h of OGD significantly increased wall tension at physiologic pressures (p< 0.05 at 10–80 mmHg), consistent with vascular stiffening. Wall stress was elevated at 80 mmHg (p=0.012). Cross-sectional area and strain were not significantly altered, indicating reduced compliance without structural enlargement. Conclusions: In an in vitro, piglet model of ischemia (OGD), α-adrenergic signal transduction is impaired while direct NO-mediated is preserved, indicating that whole receptor-level dysfunction exists, and NO-induced VSMC relaxation is still functional. Despite preserved responses of VSMC to NO, endothelial function was impaired, which could limit bioavailability of NO. Finally, biomechanical assessments suggest that arterioles exposed to 6h of ischemia, which could mimic the period of time during which a stroke has not yet been detected clinically, are stiffer and are more likely to behave like passive conduits. Taken together, this ischemia-induced phenotype in which vessel function becomes pressure-passive and vessels are stiffer may support the hypotheses that blood pressure augmentation with PE may be a viable treatment option to reduce the severity of NAIS. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.