# Pathways Regulating Lymphatic Vessel Permeability and Valve Formation

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2023 · $429,240

## Abstract

Lymphedema is a lifelong disease characterized by tissue swelling, fibrosis, and increased risk of infections for
millions of people in the US and is caused by impaired lymph flow. While congenital gene mutations can cause
lymphedema, breast cancer surgery to remove lymph nodes is the most common cause in developed
countries. Analyses of lymphatic vessels in human patients have revealed retrograde lymph flow and leaky
lymphatic vessels, indicating valve dysfunction. An effective treatment for lymphedema is currently lacking, but
targeted therapies to restore lymphatic valve function and prevent leakage would ideally enhance lymph flow in
these patients. However, surprisingly little is known about the molecules or mechanisms regulating lymphatic
vessel permeability because no methods existed to quantify lymphatic permeability. To address this gap, our
lab recently developed the only approach to quantify the permeability of lymphatic vessels from knockout mice.
The current proposal has combined this new physiological approach with inducible, tissue-specific knockout
and transgenic mice to investigate lymphatic endothelial junction protein signaling. Our results suggest a new
paradigm – that a single junction protein is capable of regulating both valve development and lymphatic vessel
permeability. The central hypothesis of this proposal is that constant signaling through the junction protein, VE-
cadherin, maintains normal valve structure and lymphatic barrier function. Our findings show that VE-cadherin
is required for lifelong valve maintenance by providing persistent cell signals in response to shear stress, and
the same pathway prevents excessive lymphatic permeability (i.e. leakage). The central hypothesis will be
tested by the following two aims investigating the role of lymphatic junction proteins: Aim 1 will test whether
VE-cadherin regulates lymphatic valve formation and maintenance by transducing shear stress into
intracellular signals (i.e. mechanotransduction), and Aim 2 will determine whether the same
mechanotransduction signaling events regulate lymphatic permeability in the valve and non-valve areas of
lymphatic collecting vessels. The completion of these aims will lead to new strategies to target VE-cadherin
signaling to prevent the development of lymphedema in at-risk patients.

## Key facts

- **NIH application ID:** 10599157
- **Project number:** 5R01HL142905-05
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Joshua Paul SCALLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $429,240
- **Award type:** 5
- **Project period:** 2019-05-24 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599157

## Citation

> US National Institutes of Health, RePORTER application 10599157, Pathways Regulating Lymphatic Vessel Permeability and Valve Formation (5R01HL142905-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10599157. Licensed CC0.

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