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

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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). <b><i>Results:</i></b> Normoxic hypercapnia increased basilar trunk blood flow velocity (+12.3 ± 2.4%; <i>p</i> = 0.006, <i>n</i> = 6) in wild-type (WT) mice but reduced blood flow in APP-PS1 mice (−11.4 ± 1.2%; <i>p</i> < 0.0001, <i>n</i> = 8). Bosentan (50 mg/kg, acute intraperitoneal injection) restored cerebrovascular reactivity in APP-PS1 mice (+10.2 ± 2.2%; <i>p</i> < 0.0001, <i>n</i> = 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 μmol/L, 30 min, or 50 mg/kg/day for 28 days). FMD was similar in the mesenteric artery of APPS-PS1 and WT. <b><i>Conclusion:</i></b> 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.