# Ion channel dysfunction in small vessel disease of the brain

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $511,532

## Abstract

PROJECT SUMMARY
Cerebral blood flow (CBF) is exquisitely controlled to meet the diverse and ever-changing demands of active
neurons. Blood flow into the brain is mediated by penetrating/parenchymal arterioles and hundreds of miles of
capillaries, which enormously extend the territory of perfusion. Blood delivery to active neurons (functional
hyperemia) is rapidly and precisely controlled through a process termed neurovascular coupling (NVC). We
recently provided compelling evidence that brain capillaries act as a neural activity-sensing network, and
therefore are much more than simple conduits for blood. This concept explains the rapid and coordinated delivery
of blood to active neurons, demonstrating that brain capillary endothelial cells (cECs) are capable of initiating an
electrical (hyperpolarizing) signal in response to neural activity that rapidly propagates upstream to cause dilation
of feeding arterioles and locally increase blood flow. 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 a second
fundamental NVC mechanism based on calcium (Ca2+) signaling, which is initiated by Gq-protein coupled
receptor signaling and is partly mediated by TRPV4 channels. Dynamic changes in membrane
phosphatidylinositol 4,5-bisphosphate (PIP2) levels appear to control the balance between electrical and Ca2+
signaling. A major focus of our laboratory has been on the pathogenesis of Small Vessel Disease (SVD) of the
brain, which is a major cause of stroke and dementia. Using a monogenic model of SVD (CADASIL) and our
mechanistic insights into NVC, we discovered that SVD precipitates early defects in functional hyperemia, which
we propose involve extracellular matrix changes and a loss of PIP2 activation of cEC Kir2.1 channels and
suppression of TRPV4 channels. Importantly, we are able to rescue functional hyperemia in CADASIL through
exogenous application of PIP2, suggesting a broad-spectrum approach for improving CBF control in disease.
We have further found that hypertension, the major driver of sporadic SVDs, also leads to age-dependent
deterioration of this major functional hyperemia mechanism. We propose to elucidate mechanisms for defective
functional hyperemia in CADASIL (Aim 1) and hypertension (Aim 2), including common molecular intersections.
A goal of this proposal is to create an integrated view of the impact of SVD on CBF regulation 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.

## Key facts

- **NIH application ID:** 9912206
- **Project number:** 5R01NS110656-02
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** MARK T NELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $511,532
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912206

## Citation

> US National Institutes of Health, RePORTER application 9912206, Ion channel dysfunction in small vessel disease of the brain (5R01NS110656-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9912206. Licensed CC0.

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