# Paracrine TNF signaling impairs endothelial TRPV4 microdomains in obesity

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $697,430

## Abstract

ABSTRACT
Endothelial calcium signaling mechanisms regulate vascular function and blood pressure. In obesity, impaired
endothelial calcium signaling results in the loss of endothelium-mediated dilation and elevation of blood pressure.
The goal of this application is to identify targetable abnormalities in endothelial calcium signaling mechanisms in
obesity. Our recent studies show that TRPV4 channels, a crucial calcium entry pathway in endothelial cells,
lower blood pressure under normal conditions. Moreover, increased formation of peroxynitrite, a reactive nitrogen
species, reduces the activity of endothelial TRPV4 channels and elevates blood pressure in obesity. Tumor
necrosis factor (TNF), an inflammatory cytokine, is a well-known promoter of cellular peroxynitrite formation. Our
preliminary data show that TNF is selectively upregulated in the vascular smooth muscle cells in obesity.
Therefore, we will determine the role of smooth muscle cell TNF and endothelial cell TNF receptor I (TNFRI) in
increasing endothelial peroxynitrite levels and impairing endothelial calcium signaling in diet-induced obesity.
We will use newly developed cell-specific knockout mice for TNF and TNFRI in combination with peroxynitrite
and TRPV4 channel measurements in small arteries. Also, mineralocorticoid receptor (MR) activation has been
linked with increased TNF levels and endothelial dysfunction. Therefore, we will delineate how vascular MR-
induced TNF production impairs endothelial calcium signaling and elevates blood pressure in obesity. We will
use smooth muscle cell-specific MR knockout mice to determine the role of smooth muscle MR in increasing
TNF production and impairing endothelial function in obesity. Finally, we will determine the contribution of smooth
muscle TRPV4 channels and related pathways in increasing TNF production in obesity. Studies in skeletal
muscle arteries of obese patients will establish the clinical relevance of our findings on vascular MR-TNF-TNFRI
signaling axis in obesity. Collectively, these fundamental and clinically relevant studies will fill major gaps in our
understanding of endothelial calcium signaling abnormalities in obesity and identify potential therapeutic targets
for rescuing endothelial function.

## Key facts

- **NIH application ID:** 10890409
- **Project number:** 2R01HL142808-06
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Swapnil K. Sonkusare
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $697,430
- **Award type:** 2
- **Project period:** 2019-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890409

## Citation

> US National Institutes of Health, RePORTER application 10890409, Paracrine TNF signaling impairs endothelial TRPV4 microdomains in obesity (2R01HL142808-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10890409. Licensed CC0.

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