Adenosine signaling activates ATP-sensitive K⁺ channels in endothelial cells and pericytes in CNS capillaries

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 neuron- and glial-derived compounds that enhance regional and global cerebral perfusion. The membrane potential (V_M) of vascular cells serves as the physiological bridge that translates brain activity into vascular function. In other beds, the ATP-sensitive K⁺ (K_ATP) channel regulates V_M in vascular smooth muscle, which is absent in the capillary network. Here, with transgenic mice that expressed a dominant-negative mutant of the pore-forming Kir6.1 subunit specifically in brain cECs or pericytes, we demonstrated that K_ATP channels were present in both cell types and robustly controlled V_M. We further showed that the signaling nucleotide adenosine acted through A_2A receptors and the Gα_s/cAMP/PKA pathway to activate capillary K_ATP channels. Moreover, K_ATP channel stimulation in vivo increased cerebral blood flow (CBF), an effect that was blunted by expression of the dominant-negative Kir6.1 mutant in either capillary cell type. These findings establish an important role for K_ATP channels in cECs and pericytes in the regulation of CBF.