Electro-Metabolic Sensing Through Capillary ATP-Sensitive K+Channels and Adenosine to Control Cerebral Blood Flow

SUMMARY The dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuro/glial-derived compounds that regulate regional and global cerebral perfusion. The membrane potential (V M ) of vascular cells serves as the essential output in this scenario, linking brain activity to vascular function. The ATP-sensitive K + channel (K ATP ) is a key regulator of vascular V M in other beds, but whether brain capillaries possess functional K ATP channels remains unknown. Here, we demonstrate that brain capillary ECs and pericytes express K ATP channels that robustly control V M . We further show that the endogenous mediator adenosine acts through A 2A receptors and the G s /cAMP/PKA pathway to activate capillary K ATP channels. Moreover, K ATP channel stimulation in vivo causes vasodilation and increases cerebral blood flow (CBF). These findings establish the presence of K ATP channels in cECs and pericytes and suggest their significant influence on CBF. HIGHLIGHTS Capillary network cellular components—endothelial cells and pericytes—possess functional K ATP channels. Activation of K ATP channels causes profound hyperpolarization of capillary cell membranes. Capillary K ATP channels are activated by exogenous adenosine via A 2A receptors and cAMP-dependent protein kinase. K ATP channel activation by adenosine or synthetic openers increases cerebral blood flow.