# Pericyte KATP channel hyperactivity in cerebral small vessel disease

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2024 · $40,402

## Abstract

Project Summary
Cerebral Autosomal Dominate Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a
common small vessel disease (SVD) that is characterized by microvascular dysfunction leading to ischemic
stroke and vascular dementia. CADASIL is caused by mutations in the NOTCH3 gene expressed by smooth
muscle cells (SMCs), that are associated with larger vasculature such as arteries/arterioles, and pericytes that
wrap around capillaries. These mutations induce extracellular receptor aggregation and complex formation with
other proteins including matrix metalloproteinase inhibitor, TIMP3. TIMP3 therefore accumulates around the
microcirculation causing impaired cerebral blood flow (CBF) regulation. Downstream of TIMP3 accumulation,
the pathomechanism includes epidermal growth factor receptor (EGFR) inhibition, resulting in decreased
neurovascular coupling (NVC) and ATP production. While this pathomechanism has been investigated in other
vascular cell types (endothelial cells and SMCs), pericytes remain understudied.
Pericytes are an abundant, highly heterogenous population, that includes mesh pericytes which display fast
on/off contractile responses and typically reside on 1-4th order capillaries. Recent studies have revealed a KATP
channel, Kir6.1, is uniquely highly expressed in pericytes compared to other cells in the microvascular domain.
This channel has proven to be highly relevant in CBF regulation where activation of the channel from low ATP,
results in pericyte hyperpolarization, ensuing vasodilation to enhance regional cerebral perfusion to meet energy
demands. Due to the CADASIL’s early presentation of neurovascular dysfunction, this proposal focuses on mesh
pericytes and their impairment.
My preliminary data show that, in CADASIL, mesh pericyte Kir6.1 channels are hyperactive in basal conditions,
indicating dysregulation of channel activity. However further characterization of the channel is needed to
elucidate potential treatment targets. Specifically, how TIMP3 and EGFR signaling influence Kir6.1 channel
activity. This proposal’s first Aim is to characterize Kir6.1 channel properties using a bimodal approach looking
at both function and expression in cerebral mesh pericytes. The goal of the second Aim is to expose the
mechanism underlying Kir6.1 channel dysfunction including TIMP3 exogenous application and genetic
knockdown. This Aim will also employ rescue techniques via EGFR ligand, HB-EGF, to restore Kir6.1 channel
function, which due to its prominent expression in cerebral pericytes may be key to restoring CBF dysregulation
in CADASIL. Completion of this proposal will fill a significant gap in the literature involving cerebral mesh
pericytes and the devastating cerebrovascular disease, CADASIL which currently has no cure and limited
treatment options.

## Key facts

- **NIH application ID:** 10917115
- **Project number:** 5F31HL170645-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Danielle A Jeffrey
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,402
- **Award type:** 5
- **Project period:** 2023-07-16 → 2026-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917115

## Citation

> US National Institutes of Health, RePORTER application 10917115, Pericyte KATP channel hyperactivity in cerebral small vessel disease (5F31HL170645-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10917115. Licensed CC0.

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