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

• Published in: Cell reports (Cambridge) Vol. 41; no. 13; p. 111872
• Main Authors: Hariharan, Ashwini, Robertson, Colin D., Garcia, Daniela C.G., Longden, Thomas A.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 27.12.2022
• Subjects: capillaries; cerebral blood flow; endothelial cells; energy; functional hyperemia; glucose; KATP channels; KIR channels; metabolism; neurovascular coupling; pericytes; endothelial cells; glucose; KATP channels; CP: Neuroscience; pericytes; capillaries; KIR channels; neurovascular coupling; functional hyperemia; cerebral blood flow; metabolism; energy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111872

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 KATP channels profoundly hyperpolarizes these cells, dilates upstream penetrating arterioles and arteriole-proximate capillaries, and increases capillary blood flow. Focal stimulation of pericytes with a KATP channel agonist is sufficient to evoke this response, mediated via KIR2.1 channel-dependent retrograde propagation of hyperpolarizing signals, whereas genetic inactivation of pericyte KATP 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 KATP-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. [Display omitted] •Focal activation of thin-strand pericyte KATP channels dilates the upstream arteriole•Brain capillary thin-strand pericytes monitor local glucose levels•A pericyte KATP channel energy switch couples glucose changes with hyperemia•This pericyte electro-metabolic signaling may protect neuronal health and function Hariharan et al. characterize a KATP channel-dependent energy switch mechanism that imbues brain capillary thin-strand pericytes with the ability to couple subtle changes in local glucose with profound elevations in brain blood flow.