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Brain Capillary Pericytes are Metabolic Sentinels that Control Blood Flow through KATP Channel Activity

Ashwini Hariharan, Colin D. Robertson, Daniela C.G. Garcia, Thomas A. Longden
doi: https://doi.org/10.1101/2022.03.14.484304
Ashwini Hariharan
1Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD, USA
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Colin D. Robertson
2Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD, USA
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Daniela C.G. Garcia
1Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD, USA
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Thomas A. Longden
1Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD, USA
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  • For correspondence: thomas.longden@som.umaryland.edu
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SUMMARY

Capillary pericytes and their processes cover ∼90% of the total length of the brains capillary bed. Despite their abundance, little is known of pericyte function, and their contributions to the control of brain hemodynamics remain unclear. Here, we report that deep capillary pericytes possess a mechanistic ‘energy switch’ that, when activated by a decrease in glucose, elicits robust KATP channel activation to increase blood flow and protect energy substrate availability. We demonstrate that pharmacological activation of KATP channels profoundly hyperpolarizes capillary pericytes and leads to dilation of upstream penetrating arterioles and arteriole-proximate capillaries covered with contractile pericytes, leading to an increase in local capillary blood flow. Stimulation of a single capillary pericyte with a KATP channel agonist is sufficient to evoke this response, which is mediated via KIR channel-dependent retrograde propagation of hyperpolarizing electrical signals. Genetic inactivation of pericyte KATP channels via expression of a dominant-negative version of KIR6.1 eliminates these effects. Critically, we show that lowering extracellular glucose below 1 mM evokes dramatic KATP channel-mediated pericyte hyperpolarization. Inhibiting glucose uptake by blocking GLUT1 transporters in vivo also activates this energy switch to increase pericyte KATP channel activity, dilate arterioles and increase blood flow. Together, our findings recast capillary pericytes as metabolic sentinels that respond to local energy deficits by robustly increasing blood flow to protect metabolic substrate delivery to neurons and prevent energetic shortfalls.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 17, 2022.
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Brain Capillary Pericytes are Metabolic Sentinels that Control Blood Flow through KATP Channel Activity
Ashwini Hariharan, Colin D. Robertson, Daniela C.G. Garcia, Thomas A. Longden
bioRxiv 2022.03.14.484304; doi: https://doi.org/10.1101/2022.03.14.484304
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Brain Capillary Pericytes are Metabolic Sentinels that Control Blood Flow through KATP Channel Activity
Ashwini Hariharan, Colin D. Robertson, Daniela C.G. Garcia, Thomas A. Longden
bioRxiv 2022.03.14.484304; doi: https://doi.org/10.1101/2022.03.14.484304

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