Un rôle essentiel de la microglie dans le maintien de l'intégrité vasculaire dans la moelle épinière hypoxique [Physiologie]novembre 30, 2019
Sebok K. Halder and Richard Milner
Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved November 5, 2019 (received for review July 15, 2019)
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We show that chronic mild hypoxia (CMH; 8% O2) induces transient vascular leak in spinal cord blood vessels that is associated with microglial clustering. Microglial depletion profoundly increased vascular leak during CMH, and this was associated with astrocyte-vascular uncoupling and loss of tight junction proteins. Microglial repair of blood vessels was blocked by a peptide that inhibits fibrinogen–Mac-1 interactions. These findings highlight a critical 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 during lung disease, sleep apnea, and age-related central nervous system (CNS) ischemia, our findings have important implications regarding the critical role of microglia in maintaining CNS vascular integrity.
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% O2) 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.
Published under the PNAS license.