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Research Article

A critical role for microglia in maintaining vascular integrity in the hypoxic spinal cord

Sebok K. Halder and Richard Milner
PNAS first published November 26, 2019 https://doi.org/10.1073/pnas.1912178116
Sebok K. Halder
aDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037
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Richard Milner
aDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037
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  • For correspondence: rmilner@sdbri.org
  1. 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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Significance

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.

Abstract

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.

  • spinal cord
  • blood vessels
  • microglia
  • hypoxia
  • fibrinogen

Footnotes

  • ↵1To whom correspondence may be addressed. Email: rmilner{at}sdbri.org.
  • ↵2Present address: San Diego Biomedical Research Institute, San Diego, CA 92121.

  • Author contributions: R.M. designed research; S.K.H. performed research; S.K.H. and R.M. analyzed data; and R.M. wrote the paper.

  • The authors declare no competing interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1912178116/-/DCSupplemental.

Published under the PNAS license.

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A critical role for microglia in maintaining vascular integrity in the hypoxic spinal cord
Sebok K. Halder, Richard Milner
Proceedings of the National Academy of Sciences Nov 2019, 201912178; DOI: 10.1073/pnas.1912178116

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A critical role for microglia in maintaining vascular integrity in the hypoxic spinal cord
Sebok K. Halder, Richard Milner
Proceedings of the National Academy of Sciences Nov 2019, 201912178; DOI: 10.1073/pnas.1912178116
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