# Lymphatic Endothelial Piezo1-TRPV4 Channel Signaling in Obesity

> **NIH NIH K99** · UNIVERSITY OF VIRGINIA · 2024 · $89,880

## Abstract

Obesity is a serious health concern in the US and is a significant risk factor for many causes of mortality, including
stroke and cardiovascular disease. Significant evidence points to an important pathogenic link between lymph
barrier dysfunction and obesity. Lymphatic endothelial cells (LECs) are crucial regulators of lymphatic barrier
function. Impaired LEC barrier can cause lymph leakage and lead to adipose tissue accumulation in obesity,
although
few pathways have been identified that regulate the barrier function of lymphatic vessels. Growing
evidence supports a crucial role for LEC Ca2+ signaling pathways in regulating the function of collecting lymphatic
vessels, which collect lymph from peripheral tissues. In this regard, transient receptor potential vanilloid 4
(TRPV4) ion channels serve as a Ca2+ influx pathway in LECs. In preliminary studies, I determine the first
recordings of TRPV4 channel activity in the intact LECs (TRPV4LEC) from mesenteric collecting lymphatic vessels
(MCLVs) of mice. In addition, I show that LEC barrier is disrupted in MCLVs from LEC-specific Trpv4 knockout
(Trpv4LECKO) mice, and Trpv4LECKO mice gain more weight after high-fat diet (HFD) feeding. I also observed that
HFD feeding impairs the activity of LEC TRPV4 (TRPV4LEC) channels in control mice. In addition, my preliminary
studies show that stimulation of mechanosensitive cation channel, Piezo1, increases the activity of TRPV4LEC
channels, supporting a Piezo1LEC–TRPV4LEC signaling axis. Moreover, Piezo1LEC–TRPV4LEC signaling axis is
impaired after HFD feeding, raising the possibility that impaired Piezo1LEC–TRPV4LEC signaling may lead to leaky
MCLVs in obesity. Therefore, I hypothesize that 1) Piezo1LEC–TRPV4LEC signaling regulates body weight;
and 2) disrupted Piezo1LEC–TRPV4LEC signaling impairs LEC barrier function, contributing to weight gain
in obesity.
I will test these hypotheses by executing the following specific aims: In Aim 1, I will determine whether
LEC-specific TRPV4 deletion results in leaky collecting lymph vessels and increased body weight; in Aim 2, I will
determine whether a loss of Piezo1LEC–TRPV4LEC signaling leads to leaky collecting lymph vessels and increased
body weight; in Aim 3, I will determine whether impaired Piezo1LEC–TRPV4LEC signaling contributes to weight
gain in obesemice. The proposed studies will identify a novel LEC Ca2+ signaling mechanism that maintains the
barrier function of collecting lymphatic vessels and regulates body weight.
This application will contribute to Dr. Yen-Lin Chen’s career development as he transitions from a postdoctoral
fellow to an independent researcher. Dr. Sonkusare, a world-renowned physiologist in studying ion channels and
Ca2+ signaling, will support this proposal and mentor Dr. Chen’s scientific and career development, and transition
to independence during this award. To strengthen Dr. Chen’s training, the proposed plan additionally enlists a
mentoring team, including Drs. Scallan, Isakson...

## Key facts

- **NIH application ID:** 10785360
- **Project number:** 1K99DK138271-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Yen-Lin Chen
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $89,880
- **Award type:** 1
- **Project period:** 2024-02-14 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10785360

## Citation

> US National Institutes of Health, RePORTER application 10785360, Lymphatic Endothelial Piezo1-TRPV4 Channel Signaling in Obesity (1K99DK138271-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10785360. Licensed CC0.

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