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Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39.

Zhongxiao Fu1, Mallikarjunarao Ganesana2, Philip Hwang3,4,5

  • 1Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, USA. zf3e@virginia.edu.

Nature Communications
|January 22, 2025
PubMed
Summary

Microglia regulate cerebral blood flow via adenosine triphosphate breakdown. This process, involving CD39, is crucial for neurovascular coupling and restoring normal blood flow.

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Area of Science:

  • Neuroscience
  • Immunology
  • Vascular Biology

Background:

  • Microglia and border-associated macrophages influence cerebral blood flow, but mechanisms are unclear.
  • Understanding glial cell roles in neurovascular coupling is essential for brain health.

Purpose of the Study:

  • To elucidate the role of microglia in regulating cerebral blood flow.
  • To identify molecular mechanisms underlying microglial control of cerebrovascular function.

Main Methods:

  • Utilized a mouse model to assess microglial regulation of cerebral blood flow.
  • Investigated responses to whisker stimulation and intra-cisternal magna injections (ATP, adenosine).
  • Examined the roles of P2RY12 receptor and CD39 ectonucleotidase in microglia.
  • Employed pharmacological inhibition and genetic deletion (CX3CR1-CreER) of CD39.

Main Results:

  • Microglia regulate baseline cerebral blood flow and responses to stimuli like whisker stimulation and ATP injection.
  • Microglial CD39 and P2RY12 are critical for this regulation, converting extracellular ATP to adenosine.
  • CD39 deficiency or inhibition replicated microglial deficiency phenotypes and reduced adenosine levels.
  • Microglia repopulation restored normal cerebral blood flow regulation.

Conclusions:

  • Microglia actively regulate cerebral blood flow through the CD39-mediated breakdown of extracellular ATP.
  • This pathway is vital for neurovascular coupling and cerebrovascular reactivity.
  • Targeting microglial CD39 may offer therapeutic potential for cerebrovascular disorders.