Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39

Microglia and border-associated macrophages are known to be near cerebral blood vessels, yet their exact contribution to neurovascular coupling—the process by which the brain increases blood flow to match neuronal activity—has remained unclear. This paper investigates whether microglia actively modulate cerebral blood flow (CBF) through purinergic signaling, specifically by metabolizing extracellular adenosine triphosphate (ATP).

Researchers used a variety of experimental approaches in mice, including pharmacological depletion of microglia using CSF1R inhibitors, genetic models of microglia deficiency (such as the Csf1r-FIRE mice), and chemogenetic manipulation. Using laser speckle contrast imaging, they monitored CBF responses to physiological stimuli like whisker stimulation. They also performed RNA sequencing to identify differentially expressed genes in microglia-depleted cortex and utilized electrochemical methods to measure local adenosine surges. Finally, they employed cell-specific genetic deletion of CD39 to confirm the causal role of this enzyme in purinergic regulation.

Microglia play a crucial role in maintaining proper CBF regulation. When microglia were depleted, the researchers observed an elevated baseline blood flow but a significant impairment in the blood flow response to whisker stimulation. The study identifies CD39 as the primary microglial enzyme responsible for breaking down activity-dependent extracellular ATP into adenosine. This process is essential because extracellular adenosine acts as a potent vasodilator, facilitating the necessary hyperemia during neuronal activity. The data demonstrate that neither parenchymal microglia depletion nor CD39 deletion significantly affected the peak blood flow itself, but rather blunted the response kinetics and coupling reserve, suggesting that microglia act as a critical control point for neurovascular dynamics.