Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch

Abstract

Despite the abundance of capillary thin-strand pericytes and their proximity to neurons and glia, little is known of the contributions of these cells to the control of brain hemodynamics. We demonstrate that the pharmacological activation of thin-strand pericyte K_ATP channels profoundly hyperpolarizes these cells, dilates upstream penetrating arterioles and arteriole-proximate capillaries, and increases capillary blood flow. Focal stimulation of pericytes with a K_ATP channel agonist is sufficient to evoke this response, mediated via K_IR2.1 channel-dependent retrograde propagation of hyperpolarizing signals, whereas genetic inactivation of pericyte K_ATP channels eliminates these effects. Critically, we show that decreasing extracellular glucose to less than 1 mM or inhibiting glucose uptake by blocking GLUT1 transporters in vivo flips a mechanistic energy switch driving rapid K_ATP-mediated pericyte hyperpolarization to increase local blood flow. Together, our findings recast capillary pericytes as metabolic sentinels that respond to local energy deficits by increasing blood flow to neurons to prevent energetic shortfalls.

Keywords: CP: Neuroscience; K(IR) channels; KATP channels; capillaries; cerebral blood flow; endothelial cells; energy; functional hyperemia; glucose; metabolism; neurovascular coupling; pericytes.