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Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions
Eszter Császár1,2, Nikolett Lénárt1, Csaba Cserép1
1"Momentum" Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary.
Abstract:
Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.
Insights
Microglia, the brain's immune cells, actively regulate cerebral blood flow (CBF) by forming purinergic contacts. Their absence or dysfunction impairs neurovascular coupling and cerebrovascular adaptation to hypoperfusion.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Microglia are the brain's primary immune cells, known for regulating neuronal function.
- Their specific role in regulating cerebral blood flow (CBF) has been largely unknown.
Purpose of the Study:
- To investigate the role of microglia in modulating CBF under physiological and pathological conditions.
- To elucidate the mechanisms by which microglia influence neurovascular coupling and cerebrovascular adaptation.
Main Methods:
- Studies in mice and human brain tissue.
- Investigated microglial P2Y12 receptor (P2Y12R) function.
- Utilized chemogenetics to induce microglial dysfunction.
- Assessed CBF, neurovascular coupling, and cerebrovascular responses to hypercapnia and hypoperfusion.
Main Results:
- Microglia directly modulate CBF through dynamic purinergic contacts with the neurovascular unit.
- Absence or dysfunction of microglia, particularly P2Y12R blockade, impairs neurovascular coupling and ATP sensitivity.
- Microglia regulate hypercapnia-induced vasodilation, brain pH, and adenosine production.
- Microglial dysfunction hinders cerebrovascular adaptation to hypoperfusion.
Conclusions:
- Microglia are critical regulators of CBF in both normal and disease states.
- Microglial P2Y12R signaling is essential for neurovascular coupling and cerebrovascular adaptation.
- These findings highlight a novel role for microglia in brain circulation with implications for neurological diseases.
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