# Cellular Reductive State Regulates Arteriogenesis

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2020 · $365,000

## Abstract

PROJECT ABSTRACT
The incidence of tissue ischemia resulting from progressive vascular occlusion is on the rise, and leads to
several cardiovascular pathologies characterized by arterial blockage such as peripheral artery disease.
Revascularization of tissue is time sensitive and essential to restore adequate blood flow. Decreases in
antioxidant capacity such as decreases in the reduced form of glutathione (GSH) concentrations and
corresponding increases in oxidant stress are hallmarks of disease progression and endothelial cell
dysfunction. Decreases in glutathione are thought to correspond with a linear increase in disease severity that
is a poorly understood relationship. The current proposal seeks to: (a) determine the influence of changing
GSH:GSSG levels on protein glutathionylation driving vascular endothelial growth factor receptor 2 (VEGFR2)
signaling in arteriogenesis, (b) determine the role of glutathionylation in oxidative and shear stress induced
endothelial cell NF-κB signaling, (c) study in vivo arteriogenesis in murine models that have mutations in the
GSH synthesis pathway, and are undergoing ligations to mimic acute and chronic peripheral artery disease,
and (d) restore defective arteriogenesis progression by stimulating a more reductive cellular environment to
improve endothelial cell function. We will test the central hypothesis that a critical balance between the
reductive and oxidative cellular environments drives optimal VEGFR2 signaling to mediate arteriogenic
remodeling in response to increased shear and oxidant stress. The proposed aims will utilize in vitro
cultures of endothelial cells isolated from our glutathione synthesis mutant murine animals to generate data
focusing on glutathionylation of proteins driving VEGFR2 specific signaling. The proposed aims also include
our in vivo mouse models of arterial blockage as clinically relevant models of vascular remodeling. Specific
Aim 1 will focus on determining the role of glutathionylation in VEGFR2 activation during endothelial cell
arteriogenic signaling. Specific Aim 2 will assess the role of low level oxidant stress and its control over
glutathionylation driving arteriogenic signaling. We will utilize in vitro cultures of endothelial cells isolated from
our glutathione synthesis mutant murine animals to study signaling in aims 1 and 2. Specific Aim 3 will assess
the role of the oxidative/reductive balance in arteriogenesis remodeling in vivo. Here we will use our in vivo
mouse models of arterial blockage.
Successful completion of this project will provide new insights into the mechanism by which glutathione
regulates arteriogenesis in a physiologic range of GSH:GSSG following arterial ligation. Such information could
be the basis for new intervention therapies developed to precisely control arteriogenesis following artery
blockage. Enhancing the vascular remodeling potential of tissue through manipulation of glutathione and
protein glutathionylation may represent a cri...

## Key facts

- **NIH application ID:** 9855067
- **Project number:** 5R01HL139755-02
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Christopher Bruce Pattillo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,000
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855067

## Citation

> US National Institutes of Health, RePORTER application 9855067, Cellular Reductive State Regulates Arteriogenesis (5R01HL139755-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9855067. Licensed CC0.

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