Microglia modulate cerebral blood flow and neurovascular coupling through ectonucleotidase CD39

Fu, Z.; Ganesana, M.; Hwang, P.; Tan, X.; Kinkaid, M. M.; Sun, Y.-Y.; Bian, E.; Weybright, A.; Sol-Church, K.; Eyo, U.; Pridans, C.; Quintana, F. J.; Robson, S. C.; Kumar, P.; Venton, B. J.; Schaefer, A.; Kuan, C.-Y.

doi:10.1101/2024.11.05.622122

bioRxiv · 10.1101/2024.11.05.622122

Microglia modulate cerebral blood flow and neurovascular coupling through ectonucleotidase CD39

Fu, Z.·Ganesana, M.·Hwang, P.·Tan, X.·Kinkaid, M. M.·Sun, Y.-Y.·Bian, E.·Weybright, A.·Sol-Church, K.·Eyo, U.·Pridans, C.·Quintana, F. J.·Robson, S. C.·Kumar, P.·Venton, B. J.·Schaefer, A.·Kuan, C.-Y.

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Abstract

Microglia and the border-associated macrophages (BAMs) contribute to the modulation of cerebral blood flow (CBF), but the mechanisms have remained ill-defined. Here, we show that microglia regulate the CBF baseline and upsurges after whisker stimulation or intracisternal magna injection of adenosine triphosphate (ATP). Genetic or pharmacological depletion of microglia reduces the activity-dependent hyperemia but not the cerebrovascular responses to adenosine stimulation. Notably, microglia repopulation corrects these CBF reactivity deficits. The microglial-dependent regulation of CBF requires the ATP-sensing P2ry12 receptor and the ectonucleotidase CD39 that initiates the breakdown of extracellular ATP. Pharmacological inhibition or microglia-specific deletion of CD39 simulates the CBF anomalies detected in microglia-deficient mice and reduces the rise of extracellular adenosine after whisker stimulation. Together, these results suggest that the microglial CD39-initiated conversion of extracellular ATP to adenosine is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.

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Fu, Z., Ganesana, M., Hwang, P., Tan, X., Kinkaid, M. M., Sun, Y.-Y., Bian, E., Weybright, A., Sol-Church, K., Eyo, U., Pridans, C., Quintana, F. J., Robson, S. C., Kumar, P., Venton, B. J., Schaefer, A., Kuan, C.-Y.. 2024-11-05. Microglia modulate cerebral blood flow and neurovascular coupling through ectonucleotidase CD39. https://doi.org/10.1101/2024.11.05.622122

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