VEGF signalling causes stalls in brain capillaries and reduces cerebral blood flow in Alzheimer's mice.
VEGF signalling causes stalls in brain capillaries and reduces cerebral blood flow in Alzheimer's mice.
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DOI：
10.1093/brain/awab387
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发表时间：
2022-05-24
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在多种阿尔茨海默病小鼠模型中，白细胞粘附到大脑微血管内皮导致毛细血管血流停滞的发生率增加，导致脑血流量减少 17%，并加剧短期记忆丧失。在这里，我们报告大脑微血管系统管腔侧的血管内皮生长因子（VEGF）信号在 APP/PS1 小鼠模型的毛细血管停滞现象中发挥着不可或缺的作用。抗小鼠 VEGF-A164 抗体（一种抑制血脑屏障通透性过高的异构体）的给药，在注射一小时内减少了停滞的毛细血管数量，导致平均毛细血管血流量立即增加，但毛细血管直径没有增加。 VEGF-A 抑制还降低了总体内皮一氧化氮合酶蛋白浓度，增加了 occludin 水平，并减少了循环伊文思蓝染料穿过血脑屏障进入脑实质的渗透，表明血脑屏障完整性增加。抗 VEGF-A 治疗后容易发生中性粒细胞粘附的毛细血管的 occludin 浓度也低于流动的毛细血管。综上所述，我们的研究结果表明，APP/PS1 小鼠中的 VEGF-A 信号传导导致异常的内皮一氧化氮合酶 /occludin 相关的血脑屏障通透性，增加毛细血管失速的发生率，并导致脑血流量减少。通过抑制管腔 VEGF 信号传导来减少白细胞粘附可能为改善阿尔茨海默病患者的脑微血管血流提供一种新颖且耐受性良好的策略。白细胞粘附到大脑微血管内皮引起的毛细血管停滞已被证明会减少阿尔茨海默病小鼠模型的脑血流量。阿里等人。报道称，大脑微血管管腔侧的 VEGF 信号传导在这一现象中发挥着不可或缺的作用。
Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow and exacerbates short-term memory loss in multiple mouse models of Alzheimer’s disease. Here, we report that vascular endothelial growth factor (VEGF) signalling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood–brain barrier hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall endothelial nitric oxide synthase protein concentrations, increased occludin levels and decreased the penetration of circulating Evans Blue dye across the blood–brain barrier into the brain parenchyma, suggesting increased blood–brain barrier integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signalling in APP/PS1 mice contributes to aberrant endothelial nitric oxide synthase /occludin-associated blood–brain barrier permeability, increases the incidence of capillary stalls, and leads to reductions in cerebral blood flow. Reducing leucocyte adhesion by inhibiting luminal VEGF signalling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in Alzheimer’s disease patients. Capillary stalling caused by leucocyte adhesion to the brain microvascular endothelium has been shown to reduce cerebral blood flow in Alzheimer’s disease mouse models. Ali et al. report that VEGF signalling at the luminal side of the brain microvasculature plays an integral role in this phenomenon.
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