# Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease

> **NIH NIH R35** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $905,963

## Abstract

PROJECT SUMMARY
Neurons in the brain have limited energy reserves and thus rely on a “just-in-time” delivery strategy in which
active neurons signal to the brain microvasculature to increase regional cerebral blood flow (CBF), resupplying
nutrients and oxygen as well as removing toxic metabolites. Despite extensive study, the mechanisms
underlying the functional linkage between neuronal metabolic demand and vascular supply, termed
neurovascular coupling (NVC), remain poorly understood. Blood flow to the brain is mediated by parenchymal
arterioles and hundreds of miles of capillaries, which enormously extend the territory of perfusion. We recently
presented evidence supporting the concept that brain capillaries act as a neuronal activity-sensing network,
demonstrating that brain capillary endothelial cells (cECs) are capable of initiating an electrical
(hyperpolarizing) signal in response to neuronal activity that propagates upstream to cause dilation of feeding
arterioles and increase blood flow locally at the site of signal initiation. We have established the mechanistic
basis for this electrical signal, showing that neuron- and/or astrocyte-derived potassium (K+) is the critical
mediator and identifying the strong inward rectifier K+ channel, Kir2.1, as the key molecular player. We have
recently discovered that a second fundamental NVC mechanism based on calcium (Ca2+) signaling, with
distinct kinetics and regulatory features, also operates in brain capillaries, and can be initiated by the putative
NVC mediator prostaglandin E2 (PGE2). We have further found that a mechanism initiated by Gq-protein
coupled receptor signaling and mediated by dynamic changes in membrane phosphatidylinositol 4,5-
bisphosphate (PIP2) levels controls the balance between electrical and Ca signaling. Additional preliminary
2+
data support a role for gasotransmission via Ca2+-dependent endothelial nitric oxide signaling and pericyte-
mediated regulation of capillary blood flow in modulating NVC. The immediate goals of this proposal are to
create an integrated view of electrical, Ca2+ and related regulatory signaling mechanisms at molecular,
biophysical, and computational-modeling levels by examining their operation in increasingly complex segments
of the brain vasculature ex vivo, in vivo, and in silico. Ultimately, we propose to weave these research threads
together to create a systems-level view of physiological capillary-to-arteriole/pial artery signaling in the brain,
and test the concept that gradual degradation of this sensory web and the attendant progressive decay of
cerebrovascular function contributes to small vessel diseases of the brain.

## Key facts

- **NIH application ID:** 9843532
- **Project number:** 5R35HL140027-02
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** MARK T NELSON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $905,963
- **Award type:** 5
- **Project period:** 2019-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843532

## Citation

> US National Institutes of Health, RePORTER application 9843532, Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease (5R35HL140027-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9843532. Licensed CC0.

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