# Matrix signaling in endothelial cell dysfunction

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2020 · $362,500

## Abstract

The arterial microenvironment at atherosclerosis-prone sites primes the endothelium for activation by a variety
of systemic atherogenic factors, in part through enhanced endothelial NF-B expression at sites of disturbed
flow. Additionally, disturbed flow patterns are permissive for subendothelial matrix remodeling, and work from
my group and others have shown that fibronectin deposition enhances the endothelial proinflammatory
response to both disturbed flow and oxidized LDL. Current research into the mechanisms of fibronectin
deposition at atheroprone sites focus on altered fibronectin expression. However, our preliminary data show
that oxidized LDL elicits robust fibronectin deposition driven by dynamic talin1-dependent integrin activation
without altered fibronectin expression, suggesting a novel model for atherogenic matrix remodeling.
In the previous grant period, we demonstrated that integrin-specific signaling differentially mediates flow and
oxidized LDL induced NF-B signaling and proinflammatory gene expression, and our published and
preliminary data show that inhibiting or deleting endothelial fibronectin-binding integrins reduces early
atherogenic inflammation in vivo. Despite the importance of integrin-mediated NF-B activation in multiple
systems, the signaling pathways linking integrins to NF-B activation remain relatively unknown. The IB
kinase IKK activates canonical NF-B signaling, and both flow and oxLDL stimulate IKK-dependent NF-B
activation. Nonproteolytic ubiquitination (K63-linked and Met1-linked ubiquitin chains) drives the formation of
signaling microdomains that classically couple IKK to its upstream activators through the recruitment of
ubiquitin-binding proteins, such as obligatory IKK-binding partner IKK. Our preliminary data demonstrate
robust K63 ubiquitination in integrin adhesion complexes associated with IKK targeting, and blunting K63
ubiquitination prevents oxLDL-induced NF-B activation. In addition, we show that endothelial cells lacking
fibronectin-binding integrins display reduced responsiveness to proinflammatory stimuli, suggesting that
integrin signaling contributes to endothelial priming associated with the atheroprone phenotype. The research
outlined in this proposal will test the hypothesis that dynamic integrin activation in endothelial cells drives
fibronectin deposition and integrin-specific signaling to promote endothelial activation. We will accomplish this
by examining the mechanisms regulating talin1-dependent integrin activation and fibronectin deposition in vitro
and in vivo using the endothelial talin1 L325R transgenic mice deficient for integrin activation (Aim 1). We will
delineate the mechanisms regulating integrin-dependent nonproteolytic ubiquitination in IKK/NF-B activation
and characterize how fibronectin-binding integrins prime the endothelial cells for activation (Aim 2). Lastly, we
will utilize inducible endothelial-specific deletion models to determine whether endoth...

## Key facts

- **NIH application ID:** 9851911
- **Project number:** 5R01HL098435-09
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Anthony Wayne Orr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,500
- **Award type:** 5
- **Project period:** 2010-08-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851911

## Citation

> US National Institutes of Health, RePORTER application 9851911, Matrix signaling in endothelial cell dysfunction (5R01HL098435-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851911. Licensed CC0.

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