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

Császár, Eszter and Lénárt, Nikolett and Cserép, Csaba and Környei, Zsuzsanna and Fekete, Rebeka and Pósfai, Balázs and Balázsfi, Diána and Hangya, Balázs and Schwarcz, Dóra Anett and Cserépné Szabadits, Eszter and Szöllősi, Dávid and Szigeti, Krisztián and Máthé, Domokos and Tóthné Sviatkó, Katalin and Brás, Ana Rita and Lenkei, Zsolt and Hricisák, László and Benyó, Zoltán and Baranyi, Mária and Sperlágh, Beáta and Menyhárt, Ákos and Farkas, Eszter and Dénes, Ádám (2022) Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions. JOURNAL OF EXPERIMENTAL MEDICINE, 219 (3). No. e20211071. ISSN 0022-1007

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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.

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