# Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $503,275

## Abstract

Abstract
Pulmonary arterial hypertension (PAH) is a disease of pulmonary vasculature with a high mortality rate of up to
45% three years after diagnosis. PAH is often associated with the loss of endothelium-dependent vasodilation,
which has long been thought to be a major contributor to development of PAH. However, the underlying
mechanisms for the loss of endothelium-dependent vasodilation in PAH remain unclear, particularly in the native
endothelium from small pulmonary arteries (PAs) that control pulmonary arterial pressure. We recently showed
that endothelial TRPV4 (transient receptor potential vanilloid 4) channels are key regulators of endothelium-
dependent vasodilation in PAs. In this application, we provide novel preliminary data that endothelial TRPV4
channels regulate resting pulmonary arterial pressure (PAP), and are impaired in PAH. Moreover, we show that
scaffolding protein caveolin-1 provides a signaling platform for protein kinase C (PKC)-dependent regulation of
TRPV4 channels, a mechanism that is defective in PAH. Interestingly, two different peroxynitrite scavengers
restored endothelial TRPV4 channel activity in PAH, suggesting that peroxynitrite may be a key contributor to
dysfunction of TRPV4 channel function. Additionally, exogenous peroxynitrite also impaired caveolin-1·PKC
regulation of endothelial TRPV4 channel function. We, therefore, hypothesize that peroxynitrite-induced
impairment in caveolin-1·PKC regulation of TRPV4 channel function contributes to the loss of endothelium-
dependent vasodilation in PAH. In Specific Aim 1, we will use PAs from endothelium-specific TRPV4 and
caveolin-1 knockout mice and human lungs to define a novel caveolin-1·PKC·TRPV4 vasodilator signaling
complex that controls endothelial regulation of PAP. In Specific Aim 2, we will test the hypothesis that elevated
peroxynitrite levels disrupt caveolin-1·PKC·TRPV4 vasodilator signaling complex in PAH. We will also determine
whether lowering peroxynitrite levels in PAH reduces PAP in a TRPV4-dependent manner. These studies will
establish that abnormalities in endothelial TRPV4 channels in small PAs contribute to PAH, and lay the
foundation for novel therapeutic strategies to rescue endothelial TRPV4 channel function.

## Key facts

- **NIH application ID:** 9913574
- **Project number:** 5R01HL146914-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Swapnil K. Sonkusare
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $503,275
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913574

## Citation

> US National Institutes of Health, RePORTER application 9913574, Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries (5R01HL146914-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9913574. Licensed CC0.

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