# Pericytes as metabolic sentinels in the control of brain blood flow in health and Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $386,250

## Abstract

Neurons lack energy stores and thus their ongoing function is dependent on the delivery of energy
substrates in the blood. Precise control of brain blood flow is therefore essential for neuronal
health. However, the mechanisms through which blood flow through the brain is regulated remain
unclear. Furthering our understanding of this process is critical, as it is increasingly appreciated
that disruption of brain blood flow is one of the earliest pathological events in Alzheimer’s disease,
and may be a key contributory factor to disease progression. Thus, advancing our understanding
of the mechanisms of blood flow control in normal physiology, and their disruption in the context
of Alzheimer’s disease, may reveal novel and much needed targets for therapeutic intervention.
Pericytes are mural cells that reside on brain capillaries, interposed between endothelial cells and
astrocytic endfeet. It is thought that these cells contribute to the control of brain blood flow but
mechanistic details are lacking. Based on the preliminary data in this proposal, we posit that
pericytes are ideally positioned and equipped to act as metabolic sentinels in the control of brain
blood flow. Specifically, we show for the first time that acutely isolated brain pericytes possess
functional KATP channels, and we demonstrate that these open in response to depletion of glucose
to cause contractile capillary pericyte, and upstream arteriole smooth muscle, relaxation. This
drives capillary and arteriole dilation and an increase in brain blood flow. This has profound
implications for understanding how blood flow is controlled in the brain, as local glucose
concentrations are known to transiently decrease during neuronal activity. Our data offer an
explanation for this phenomenon—during increases in neuronal glucose utilization, pericytes
sense falling local concentrations which triggers KATP-mediated hyperpolarizing electrical signals
that relax both pericytes themselves and upstream arteriolar smooth muscle. This increases blood
flow to compensate for the local decrease in glucose, thereby protecting brain metabolism.
Strikingly, this pericyte metabolism-electrical coupling mechanism is profoundly disrupted in a
mouse model of Alzheimer’s disease, suggesting that loss of this blood flow control mechanism
may contribute to a mismatch between neuronal energy demand and supply, precipitating neuronal
dysfunction and cognitive decline. Using these findings as a springboard, we propose to determine
the molecular composition and metabolic regulation of KATP channels in pericytes throughout the
brain. We will define the precise mechanisms that engage pericyte KATP channels to control blood
flow, and we will determine the mechanisms through which pericyte control of brain blood flow
is disrupted in Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10241247
- **Project number:** 5R01AG066645-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Thomas A Longden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241247

## Citation

> US National Institutes of Health, RePORTER application 10241247, Pericytes as metabolic sentinels in the control of brain blood flow in health and Alzheimer's disease (5R01AG066645-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241247. Licensed CC0.

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