# Network signature of low-flow endothelial dysfunction

> **NIH NIH R01** · UNIVERSITY OF SOUTH ALABAMA · 2022 · $385,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The endothelium is a crucial regulator of vascular homeostasis and endothelial dysfunction is a hallmark of
cardiovascular disease. The challenge in searching for new therapies is finding early control points that prevent
the shift to broad pathologic signaling profiles and disrupt the endothelial network. Employing novel imaging and
analysis approaches, we have identified discrete patterns of dynamic Ca2+ signalling along the vascular intima
that underlie vascular function and direct the specificity, sensitivity and intensity of prevailing vascular responses.
These patterns, defined by profiles of dynamic event parameters (frequency, amplitude, duration and spatial
spread), form distinct signatures along the endothelial network. The complex spectrum of endothelial Ca2+ events
(from isolated brief transients to broad multicellular waves) result from positive feedback interaction between
plasma membrane TRP channels (Ca2+ entry) and endoplasmic reticulum IP3Rs (Ca2+ release). Small
conductance Ca2+-activated K+ channels (KCa) play a key role in this signaling by exerting Ca2+-dependent
hyperpolarization and amplifying Ca2+ influx through TRP channels (particularly fluid shear stress (FSS)-
activated TRPV4 channels). In flow-deprived distal arteries from patients with peripheral artery disease, the
endothelium exhibits a distinctive truncated Ca2+ signature characterized by spatially restricted small amplitude
transients. This anomalous Ca2+ profile appears early in a low-flow carotid ligation mouse model, giving rise to
endothelial dysfunction and vascular remodelling. These low-flow adaptations involve progressive loss of
endothelial KCa2.3 channels and suggest an early loss of cooperative KCa/TRPV4 action. We hypothesize that
disruption of TRPV4-KCa2.3 signaling under conditions of low FSS causes a progressive, highly
restricted endothelial Ca2+ signature that promotes endothelial dysfunction and vascular remodeling.
Aim 1 will characterize the role of TRPV4-KCa2.3 signaling in physiologic Ca2+ signatures along the arterial
endothelium. We will conduct confocal imaging (with novel high-content analysis) and employ endothelium-
specific knockout mice (ecKCa2.3-/- and ecTRPV4-/-) as well as human peripheral arteries to elucidate cooperative
channel impacts under differential FSS. Aim 2 will determine whether low/oscillatory FSS causes truncation of
the TRPV4-KCa2.3-dependent endothelial Ca2+ signature that leads to endothelial dysfunction and vascular
remodeling. We will employ a partial ligation mouse model to assess the magnitude and time course of TRPV4-
KCa2.3-specific impacts on Ca2+ signaling, vasoreactivity and vascular wall thickening. Aim 3 will determine
whether preservation of endothelial TRPV4-KCa2.3 Ca2+ signaling ameliorates development of functional and
structural vascular changes resulting from chronic low flow. We will also assess whether interventions to preserve
the Ca2+ signature directly abate patholog...

## Key facts

- **NIH application ID:** 10475161
- **Project number:** 5R01HL155288-02
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** MARK STEPHEN TAYLOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475161

## Citation

> US National Institutes of Health, RePORTER application 10475161, Network signature of low-flow endothelial dysfunction (5R01HL155288-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475161. Licensed CC0.

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