# Homeostatic regulation of endothelial mechanotransduction

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $282,183

## Abstract

The vascular endothelium's principal responsibility is to support the inflammatory and metabolic 
needs of each of the body's organ systems. As such, these cells are highly sensitive to 
environmental cues and must be able to respond in a precise manner. The regulation of these 
responses likely occurs via numerous competing pathways. Of particular importance are the fluid 
shear stress forces imparted by blood flow. The mechanosensitive transcription factors KLF2 and 
KLF4 compete with other mechanosensitive transcription factors such as NF-kB and SMAD2/3 to 
suppress inflammation and vessel remodeling. Defects in the coupling between these competing 
pathways can cause vascular malformations. Klf2/4 are transcriptionally regulated by a MAPK-complex 
consisting of the kinases MEKK2/3, MEK5, and ERK5, and the scaffold protein p62. Importantly, the 
p62-MAPK-Klf2/4 axis is activated by high shear but suppressed by low shear to permit low 
shear-induced inflammation and remodeling. Besides the MAPKs, p62 also interacts with mitochondrial 
proteins and polyubiquitinated proteins. As mitochondrial remodeling and proteotoxic stress 
responses have been implicated in both shear responses and p62 signaling, this project will explore 
the possibility that shear-dependent changes to mitochondrial or ubiquitin homeostasis acts as a 
key regulator of p62-MAPK signaling. In aim 1 we will test shear-dependent changes to mitochondrial 
function and the role of mitochondria in regulating 
p62-MAPK-Klf2/4 signaling. In aim 2 we characterize shear-dependent changes to the ubiquitinome, 
determine its role in regulating p62-MAPK-Klf2/4 signaling, and the role of ubiquitin homeostasis 
regulating crosstalk between mechanotransduction pathways. The results obtained in this project 
will provide insight into the regulation of homeostatic mechanotransduction pathways and may reveal 
genetic and environmental drivers of KLF2-4-associated pathologies.

## Key facts

- **NIH application ID:** 10880525
- **Project number:** 5P20GM139763-04
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Brian Gene Coon
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $282,183
- **Award type:** 5
- **Project period:** 2021-02-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880525

## Citation

> US National Institutes of Health, RePORTER application 10880525, Homeostatic regulation of endothelial mechanotransduction (5P20GM139763-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10880525. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*