Endothelin Receptor Blockade Improves Cerebral Blood Flow-Mediated Dilation in a Mouse Model of Alzheimer's Disease

Introduction: Cerebral blood flow (CBF) is reduced in patients with Alzheimer's disease (AD). Flow-mediated dilation (FMD), which plays a key role in the regulation of blood flow, is attenuated by endothelin-1. We hypothesized that endothelin receptor blockade may improve CBF in AD.Methods: We investigated cerebrovascular reactivity in a mouse model of AD (APP-PS1; 5-6-month-old male subjects). We assessed the in vivo response to normoxic hypercapnia and in vitro FMD in isolated cerebral and mesenteric resistance arteries before and after endothelin receptor blockade (bosentan).Results: Normoxic hypercapnia increased basilar trunk blood flow velocity (+12.3 +/- 2.4%; p = 0.006, n = 6) in wild-type (WT) mice but reduced blood flow in APP-PS1 mice (-11.4 +/- 1.2%; p < 0.0001, n = 8). Bosentan (50 mg/kg, acute intraperitoneal injection) restored cerebrovascular reactivity in APP-PS1 mice (+10.2 +/- 2.2%; p < 0.0001, n = 8) but had no effect in WT. FMD was reduced in the posterior cerebral artery of APP-PS1 compared to WT and was normalized by bosentan (1 mu mol/L, 30 min, or 50 mg/kg/day for 28 days). FMD was similar in the mesenteric artery of APPS-PS1 and WT.Conclusion: APP-PS1 mice exhibited cerebrovascular endothelial dysfunction. Acute and chronic blockade of endothelin receptors restored endothelial vasomotor function, suggesting a promising therapeutic approach to restoring cerebral vasoreactivity in AD.