# A pericyte Cl- clamp controls capillary electrical signaling and brain blood flow

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $433,159

## Abstract

Neurons lack substantial energy stores and thus their function is critically dependent on the timely delivery of
energy substrates in the blood. Precise control of brain blood flow is therefore essential for brain health. However,
the exact mechanisms through which cerebral hemodynamics are regulated remain unclear. Furthering our
understanding of this control 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 related disorders and may be a key contributory
factor to disease progression and neurodegeneration. Thus, advancing our understanding of the mechanisms of
brain blood flow control may reveal novel and much needed targets for therapeutic interventions.
Thin-strand pericytes are mural cells that reside on brain capillaries deep within the vascular network, interposed
between capillary endothelial cells and astrocytic endfeet. It is thought that thin-strand pericytes contribute to the
control of brain blood flow but a detailed mechanistic understanding of this process is lacking. Based on the
compelling preliminary data in this proposal, we suggest a novel dimension to thin-strand pericyte control of
electrical signaling throughout the vascular network—from capillaries to arterioles—which plays a central role in
blood flow control. Specifically, we identify for the first time a “pericyte chloride clamp” mechanism that
counterbalances hyperpolarizing electrical signaling to precisely control local blood flow. The activity of thin-
strand pericyte calcium-activated chloride channels is central to this mechanism, and these are controlled by
calcium signals generated by membrane voltage-dependent calcium channels and endoplasmic reticulum
calcium release channels. This signaling module is tethered to neuronal activity through the activity of thin-strand
pericyte metabotropic glutamate receptors, activation of which shuts off the pericyte chloride clamp to augment
hyperpolarizing electrical signaling and increase blood flow to the active network.
Using these exciting findings as a springboard, we propose to define the precise mechanisms through which
calcium-activated chloride channels are controlled in thin-strand pericytes, how these channels contribute to the
control of capillary blood flow by shaping electrical signals, and how neuronal activity toggles the pericyte chloride
clamp on and off to regulate local blood flow on a moment-to-moment basis to satisfy fluctuating neuronal energy
needs. Completion of this work may thus identify novel therapeutic targets in thin-strand pericytes and could lay
the groundwork for much needed treatments aimed at protecting or rescuing blood flow in brain disorders with a
vascular component.

## Key facts

- **NIH application ID:** 10940608
- **Project number:** 1R01NS138179-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Thomas A Longden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,159
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940608

## Citation

> US National Institutes of Health, RePORTER application 10940608, A pericyte Cl- clamp controls capillary electrical signaling and brain blood flow (1R01NS138179-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10940608. Licensed CC0.

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