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 μmol/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.

Alzheimer’s disease (AD) is characterized by the deposition of an abnormal protein in the brain. However, there are numerous arguments suggesting that this disease is also associated with a reduction in cerebral blood flow and with abnormalities in the regulation of blood circulation within the brain. In a mouse model that develops symptoms very similar to AD, we have shown both in vivo and in isolated cerebral blood vessels that the endothelial function of cerebral blood vessels is deeply altered. Endothelin is a very potent vasoconstrictor that is normally present in vessels and possibly augmented in AD. A pharmacological inhibitor of endothelin restored normal brain endothelial function in this mouse model, both in vivo and in vitro. Our work confirms the cerebral vascular abnormalities in an experimental model of AD. Blocking endothelin receptors could therefore be a promising therapeutic approach to normalize the reactivity of cerebral vessels in patients with AD.

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