We recently demonstrated that when mice are exposed to chronic mild hypoxia (CMH, 8% O2), blood vessels in the spinal cord show transient vascular leak that is associated with clustering and activation of microglia around disrupted vessels. Importantly, microglial depletion profoundly increased hypoxia-induced vascular leak, implying that microglia play a critical role maintaining vascular integrity in the hypoxic spinal cord. The goal of the current study was to examine if microglia play a similar vasculo-protective function in the brain. Employing extravascular fibrinogen leak as an index of blood–brain barrier (BBB) disruption, we found that CMH provoked transient vascular leak in cerebral blood vessels that was associated with activation and aggregation of Mac-1-positive microglia around leaky vessels. Interestingly, CMH-induced vascular leak showed regional selectivity, being much more prevalent in the brainstem and olfactory bulb than the cerebral cortex and cerebellum. Pharmacological depletion of microglia with the colony stimulating factor-1 receptor inhibitor PLX5622, had no effect under normoxic conditions, but markedly increased hypoxia-induced cerebrovascular leak in all regions examined. As in the spinal cord, this was associated with endothelial induction of MECA-32, a marker of leaky CNS endothelium, and greater loss of endothelial tight junction proteins. Brain regions displaying the highest levels of hypoxic-induced vascular leak also showed the greatest levels of angiogenic remodeling, suggesting that transient BBB disruption may be an unwanted side-effect of hypoxic-induced angiogenic remodeling. As hypoxia is common to a multitude of human diseases including obstructive sleep apnea, lung disease, and age-related pulmonary, cardiac and cerebrovascular dysfunction, our findings have important translational implications. First, they point to a potential pathogenic role of chronic hypoxia in triggering BBB disruption and subsequent neurological dysfunction, and second, they demonstrate an important protective role for microglia in maintaining vascular integrity in the hypoxic brain.

中文翻译：

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轻度缺氧会引发短暂的血脑屏障破坏：小胶质细胞的基本保护作用


我们最近证明，当小鼠暴露于慢性轻度缺氧（CMH，8% O2）时，脊髓中的血管会出现短暂的血管渗漏，这与受损血管周围小胶质细胞的聚集和激活有关。重要的是，小胶质细胞的耗竭大大增加了缺氧引起的血管渗漏，这意味着小胶质细胞在维持缺氧脊髓中的血管完整性方面发挥着关键作用。当前研究的目的是检查小胶质细胞是否在大脑中发挥类似的血管保护功能。采用血管外纤维蛋白原渗漏作为血脑屏障 (BBB) 破坏的指标，我们发现 CMH 会引起脑血管短暂的血管渗漏，这与渗漏血管周围 Mac-1 阳性小胶质细胞的激活和聚集有关。有趣的是，CMH 诱导的血管渗漏表现出区域选择性，在脑干和嗅球中比大脑皮层和小脑中更为普遍。使用集落刺激因子 1 受体抑制剂 PLX5622 对小胶质细胞进行药理学耗竭，在含氧量正常的条件下没有效果，但在所有检查区域中，缺氧诱导的脑血管漏明显增加。与脊髓一样，这与 MECA-32（中枢神经系统内皮渗漏的标志物）的内皮诱导以及内皮紧密连接蛋白的更大损失有关。显示出最高水平的缺氧诱导的血管渗漏的大脑区域也显示出最高水平的血管生成重塑，这表明短暂的血脑屏障破坏可能是缺氧诱导的血管生成重塑的不良副作用。 由于缺氧是多种人类疾病的常见症状，包括阻塞性睡眠呼吸暂停、肺部疾病以及与年龄相关的肺、心脏和脑血管功能障碍，因此我们的发现具有重要的转化意义。首先，他们指出慢性缺氧在触发血脑屏障破坏和随后的神经功能障碍中具有潜在的致病作用；其次，他们证明了小胶质细胞在维持缺氧大脑中血管完整性方面的重要保护作用。