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

IF 1.8 4区医学 Q3 PERIPHERAL VASCULAR DISEASE

Journal of Vascular Research Pub Date : 2023-01-01 Epub Date: 2023-11-17 DOI:10.1159/000534614

Daniel Henrion, Philippe Bonnin, Emilie Vessieres, Anne-Laure Guihlot, Marc Iglarz, Bernard I Lévy

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引用次数: 0

Abstract

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.

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内皮素受体阻断改善阿尔茨海默病小鼠模型中脑血流介导的舒张

阿尔茨海默病(AD)患者的脑血流量(CBF)减少。血流介导扩张(flow -mediated dilation, FMD)在血流调节中起关键作用，可被内皮素-1减弱。我们假设内皮素受体阻断可能改善AD患者的CBF。方法:研究AD小鼠模型的脑血管反应性(APP-PS1;5-6个月大的男性受试者)。我们评估了内皮素受体阻断(波生坦)前后离体脑和肠系膜抵抗动脉对常氧性高碳酸血症和体外FMD的体内反应。结果:常氧高碳酸血症使基底干血流速度增加(+12.3±2.4%);p = 0.006, n = 6)，但APP-PS1小鼠血流量减少(-11.4±1.2%;p & lt;0.0001, n = 8)。波生坦(50 mg/kg，急性腹腔注射)恢复APP-PS1小鼠脑血管反应性(+10.2±2.2%;p & lt;0.0001, n = 8)，但对WT没有影响。与WT相比，APP-PS1脑后动脉FMD减少，波生坦(1 μmol/L, 30 min，或50 mg/kg/天，连续28天)使FMD正常化。结论:APP-PS1小鼠出现了脑血管内皮功能障碍。急性和慢性阻断内皮素受体可恢复内皮血管舒缩功能，提示恢复AD患者脑血管反应性的有希望的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Vascular Research 医学-生理学

CiteScore

3.40

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： The ''Journal of Vascular Research'' publishes original articles and reviews of scientific excellence in vascular and microvascular biology, physiology and pathophysiology. The scope of the journal covers a broad spectrum of vascular and lymphatic research, including vascular structure, vascular function, haemodynamics, mechanics, cell signalling, intercellular communication, growth and differentiation. JVR''s ''Vascular Update'' series regularly presents state-of-the-art reviews on hot topics in vascular biology. Manuscript processing times are, consistent with stringent review, kept as short as possible due to electronic submission. All articles are published online first, ensuring rapid publication. The ''Journal of Vascular Research'' is the official journal of the European Society for Microcirculation. A biennial prize is awarded to the authors of the best paper published in the journal over the previous two years, thus encouraging young scientists working in the exciting field of vascular biology to publish their findings.