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

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 (VM) of vascular cells serves as the essential output in this scenario, linking brain activity to vascular function. The ATP-sensitive K+ channel (KATP) is a key regulator of vascular VM in other beds, but whether brain capillaries possess functional KATP channels remains unknown. Here, we demonstrate that brain capillary ECs and pericytes express KATP channels that robustly control VM. We further show that the endogenous mediator adenosine acts through A2A receptors and the Gs/cAMP/PKA pathway to activate capillary KATP channels. Moreover, KATP channel stimulation in vivo causes vasodilation and increases cerebral blood flow (CBF). These findings establish the presence of KATP channels in cECs and pericytes and suggest their significant influence on CBF. HIGHLIGHTSO_LICapillary network cellular components--endothelial cells and pericytes--possess functional KATP channels. C_LIO_LIActivation of KATP channels causes profound hyperpolarization of capillary cell membranes. C_LIO_LICapillary KATP channels are activated by exogenous adenosine via A2A receptors and cAMP-dependent protein kinase. C_LIO_LIKATP channel activation by adenosine or synthetic openers increases cerebral blood flow. C_LI