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Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice
Kanchan Bisht1,2, Kenneth A Okojie1,2, Kaushik Sharma1,2
1Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, USA.
Abstract:
Microglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12-/- and PANX1-/- mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.
Insights
Brain microglia interact with capillaries, regulating blood flow and vessel function. Purines released via PANX1 channels activate microglial P2RY12 receptors, impacting neurovascular health.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Microglia, brain immune cells, have poorly understood interactions with brain vasculature.
- Their role in regulating vascular physiology requires further investigation.
Purpose of the Study:
- To characterize capillary-associated microglia (CAMs) and their interactions with brain capillaries.
- To elucidate the molecular mechanisms regulating CAMs and their impact on neurovascular function.
Main Methods:
- Molecular, morphological, and ultrastructural analysis of microglia.
- Spatio-temporal characterization of CAMs versus parenchymal microglia (PCMs).
- Investigation using P2RY12 knockout and PANX1 knockout mouse models.
Main Results:
- Identified ramified CX3CR1+ myeloid cells interacting with brain capillaries as bona fide microglia.
- Demonstrated P2RY12 receptors regulate CAM interactions, controlled by purines from PANX1 channels.
- Microglial depletion caused capillary dilation, increased blood flow, and impaired vasodilation, mimicking knockout models.
Conclusions:
- Capillary-associated microglia play a critical role in regulating cerebral blood flow and vascular tone.
- Purinergic signaling via PANX1 channels and P2RY12 receptors is essential for microglial regulation of neurovascular function.
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