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Updated: May 31, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
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.
Abstract:
Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies. The microglial-dependent regulation of cerebral blood flow requires the adenosine triphosphate-sensing P2RY12 receptor and ectonucleotidase CD39 that initiates the dephosphorylation of extracellular adenosine triphosphate into adenosine in both male and female mice. Pharmacological inhibition or CX3CR1-CreER-mediated deletion of CD39 mimics the cerebral blood flow anomalies in microglia-deficient mice and reduces the upsurges of extracellular adenosine following whisker stimulation. Together, these results suggest that the microglial CD39-initiated breakdown of extracellular adenosine triphosphate co-transmitter is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.
Insights
Microglia regulate cerebral blood flow via adenosine triphosphate breakdown. This process, involving CD39, is crucial for neurovascular coupling and restoring normal blood flow.
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.
