Cross-brain Notch1 Concentrations In Response To Hypocapnia And Hypercapnia

Notch1 has been recognized as an essential regulator of peripheral vascular endothelial function, particularly in response to increased vascular wall shear stress, such as during exercise. However, there is limited data on activity of Notch1 in the brain, and whether it is an important regulator of cerebral vascular endothelial function. PURPOSE: To determine if changes in pH mediated shear stress in the cerebral vasculature impacts Notch1 activity. METHODS: 12 (7 male) young (27 ± 3 yrs) healthy (BMI: 23 ± 2 kg/m2) participants performed a single laboratory visit. Cerebral blood flow (CBF) and shear was manipulated by steady state (5 min) hypercapnia (+9 PaCO2) and hypocapnia (-10 PaCO2) using dynamic end-tidal forcing, with a minimum of 10 min rest between conditions. At baseline (BL), hypercapnia, and hypocapnia, simultaneous blood samples were drawn from the radial artery and internal jugular vein, to determine cross brain concentrations of Notch1, measured by an ELISA. CBF was determined by simultaneous duplex ultrasound of the left vertebral and right internal carotid arteries. Cerebral exchange of Notch1 was calculated from the arterial-venous Notch1 difference multiplied by the CBF. RESULTS: All values are mean ± SD. Statistical analysis was performed by Bonferroni corrected two-tailed T-Tests. At BL there was an average net release of Notch1 from the brain by -38 ± 70 ng/min, corresponding with a higher (non-significant, P = 0.058) concentration of Notch1 in the venous (188 ± 185 pg/mL) vs. arterial (138 ± 131 pg/mL) circulation. Compared to BL, there was no change in the cerebral exchange of Notch1 in hypercapnia (-11 ± 73 ng/min, P = 0.453), however, hypocapnia caused a significant flip of cerebral Notch1 uptake (30 ± 64 ng/min, P = 0.035). The net uptake of Notch1 in the brain during hypocapnia was attributable to an elevated arterial (214 ± 185 pg/mL, P = 0.014) and not venous (166 ± 170 pg/mL, P = 0.659) Notch1. CONCLUSION: Notch1 appears to be more responsive in the peripheral vasculature than the brain, as the relatively localized increase in cerebral shear with hypercapnia had no impact. The physiologic relevance of Notch1 (extracellular domain) uptake in the brain remains to be determined but may play an important role for cerebral vascular homeostasis in response to systemic increases in vascular wall shear stress.