Activity-Dependent Dilation of Mice Brain Capillaries Requires Pericyte Pannexin1 and A1 Adenosine Receptors

Abstract

Aim

Neuronal activity drives increases in cerebral blood flow to match metabolic demands, with capillary dilation critical for blood–brain exchange. However, the molecular mechanisms coupling neuronal activity to capillary diameter adjustments remain unclear. We examined the contribution of pericyte pannexin1 channels to capillary responses during increased neuronal excitability and investigated the underlying signaling pathway.

Methods

To induce neuronal excitability, we administered picrotoxin, a GABAA receptor antagonist, to acute hippocampal slices and in vivo, which induces epileptiform activity. Pericyte pannexin1 activity and capillary responses were monitored via dye uptake and capillary diameter measurements in slices from wild-type and pannexin1-deficient mice. Pharmacological blockade of adenosine A1 receptors and exogenous adenosine application were used to identify the signaling pathway.

Results

In vivo picrotoxin administration inhibited pericyte pannexin1 channel activity in the hippocampus. Equivalent suppression was observed in picrotoxin-treated acute hippocampal slices, where neuronal excitability led to pericyte pannexin1 inhibition and capillary dilation. Both responses were abolished by tetrodotoxin and absent in pannexin1-deficient mice, confirming dependence on neuronal activity and pannexin1 expression. Pharmacological blockade of adenosine A1 receptors prevented pannexin1 inhibition and the associated vasodilatory response, whereas exogenous adenosine recapitulated these effects, demonstrating that adenosine signaling is required for neuronal activity–dependent modulation of pericyte pannexin1.

Conclusion

We identify a previously uncharacterized adenosine–pannexin1 signaling axis in pericytes linking neuronal excitability to capillary relaxation. This mechanism provides a molecular substrate for activity-dependent capillary regulation and supports a role for pericyte pannexin1 in adenosine-mediated neurovascular responses during states of elevated metabolic demand.