Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions.

Autor:	Császár E; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary.; János Szentágothai Doctoral School of Neurosciences, Schools of PhD Studies, Semmelweis University, Budapest, Hungary., Lénárt N; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary., Cserép C; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary., Környei Z; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary., Fekete R; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary., Pósfai B; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary.; János Szentágothai Doctoral School of Neurosciences, Schools of PhD Studies, Semmelweis University, Budapest, Hungary., Balázsfi D; Lendület Laboratory of Systems Neuroscience, Institute of Experimental Medicine, Budapest, Hungary., Hangya B; Lendület Laboratory of Systems Neuroscience, Institute of Experimental Medicine, Budapest, Hungary., Schwarcz AD; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary., Szabadits E; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary., Szöllősi D; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary., Szigeti K; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary., Máthé D; Hungarian Centre of Excellence for Molecular Medicine, Szeged, Hungary., West BL; Plexxikon Inc., Berkeley, CA., Sviatkó K; Lendület Laboratory of Systems Neuroscience, Institute of Experimental Medicine, Budapest, Hungary., Brás AR; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary.; János Szentágothai Doctoral School of Neurosciences, Schools of PhD Studies, Semmelweis University, Budapest, Hungary., Mariani JC; Institute of Psychiatry and Neurosciences of Paris, INSERM U1266, Université de Paris, Paris, France., Kliewer A; Institute of Psychiatry and Neurosciences of Paris, INSERM U1266, Université de Paris, Paris, France., Lenkei Z; Institute of Psychiatry and Neurosciences of Paris, INSERM U1266, Université de Paris, Paris, France., Hricisák L; Institute of Translational Medicine, Semmelweis University, Budapest, Hungary., Benyó Z; Institute of Translational Medicine, Semmelweis University, Budapest, Hungary., Baranyi M; Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Budapest, Hungary., Sperlágh B; Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Budapest, Hungary., Menyhárt Á; Hungarian Centre of Excellence for Molecular Medicine, University of Szeged, Cerebral Blood Flow and Metabolism Research Group, Szeged, Hungary.; Department of Medical Physics and Informatics, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary., Farkas E; Hungarian Centre of Excellence for Molecular Medicine, University of Szeged, Cerebral Blood Flow and Metabolism Research Group, Szeged, Hungary.; Department of Cell Biology and Molecular Medicine, Albert Szent-Györgyi Medical School, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary., Dénes Á; 'Momentum' Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2022 Mar 07; Vol. 219 (3). Date of Electronic Publication: 2022 Feb 24.
DOI:	10.1084/jem.20211071
Abstrakt:	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. Competing Interests: Disclosures: D. Máthé reported grants from European Union H2020 HCEMM-739593 and from NRDIO, Hungary, TKP-BIOImaging-2020-4.1.1-TKP2020 during the conduct of the study. D. Máthé is CEO and stakeholder of CROmed Ltd. Z. Lenkei reported personal fees from Iconeus outside the submitted work. No other disclosures were reported. (© 2022 Császár et al.)
Databáze:	MEDLINE
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