Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037
Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):26029-26037. doi: 10.1073/pnas.1912178116. Epub 2019 Nov 26.
Hypoxic preconditioning reduces disease severity in a mouse model of multiple sclerosis (MS), in part by enhancing the barrier properties of spinal cord blood vessels. Because other studies have shown that similar levels of hypoxia transiently increase permeability of central nervous system (CNS) blood vessels, the goal of this study was to define the impact of chronic mild hypoxia (CMH, 8% O) on the integrity of spinal cord blood vessels and the responses of neighboring glial cells. Using extravascular fibrinogen as a marker of vascular disruption, we found that CMH triggered transient vascular leak in spinal cord blood vessels, particularly in white matter, which was associated with clustering and activation of Mac-1-positive microglia around disrupted vessels. Microglial depletion with the colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX5622, while having no effect under normoxic conditions, profoundly increased vascular leak in both white and gray matter during CMH, and this was associated with disruption of astrocyte-vascular coupling and enhanced loss of tight junction proteins. Microglial repair of leaky blood vessels was blocked by a peptide that inhibits the interaction between fibrinogen and its Mac-1 integrin receptor. These findings highlight an important role for microglia in maintaining vascular integrity in the hypoxic spinal cord and suggest that a fibrinogen-Mac-1 interaction underpins this response. As relative hypoxia is experienced in many situations including high altitude, lung disease, obstructive sleep apnea, and age-related CNS ischemia/hypoxia, our findings have important implications regarding the critical role of microglia in maintaining vascular integrity in the CNS.
缺氧预处理可降低多发性硬化症（MS）小鼠模型的疾病严重程度，部分原因是增强了脊髓血管的屏障特性。由于其他研究表明，类似程度的缺氧会短暂增加中枢神经系统（CNS）血管的通透性，因此本研究的目的是定义慢性轻度缺氧（CMH，8%O）对脊髓血管完整性的影响以及邻近神经胶质细胞的反应。使用血管外纤维蛋白原作为血管破坏的标志物，我们发现 CMH 可触发脊髓血管的短暂血管渗漏，特别是在白质中，这与围绕受损血管聚集和激活 Mac-1 阳性小胶质细胞有关。用集落刺激因子-1 受体（CSF-1R）抑制剂 PLX5622 耗尽小胶质细胞，在常氧条件下没有作用，但在 CMH 期间，无论是在白质还是灰质中，都可显著增加血管渗漏，这与星形胶质细胞-血管偶联的破坏和紧密连接蛋白的增强丢失有关。抑制纤维蛋白原与其 Mac-1 整合素受体相互作用的肽可阻断小胶质细胞修复渗漏血管。这些发现强调了小胶质细胞在维持缺氧脊髓血管完整性中的重要作用，并表明纤维蛋白原-Mac-1 相互作用是这种反应的基础。由于相对缺氧在许多情况下都会出现，包括高海拔、肺部疾病、阻塞性睡眠呼吸暂停和与年龄相关的 CNS 缺血/缺氧，因此我们的发现对于小胶质细胞在维持 CNS 血管完整性方面的关键作用具有重要意义。
