# VEGFR Signaling Controls Lymphatic Junctions

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2022 · $660,910

## Abstract

Congenital lymphedema is caused by inherited gene mutations that impair the functioning of the lymphatic
vasculature and lead to swelling of the limbs, disfigurement, cellulitis, and increased susceptibility to MRSA
infections of the skin and sepsis. Congenital lymphedema is also a comorbidity of lymphatic malformations and
other common syndromes (e.g. Noonan). The most common gene mutation that causes congenital
lymphedema is a heterozygous inactivating mutation in the VEGFR3 gene that causes Milroy’s disease. While
VEGFR3 has been widely studied as the main receptor that induces lymphangiogenesis, virtually nothing is
known about how VEGFR3 regulates physiological functions of the lymphatic vasculature. Thus, the
pathogenesis of Milroy’s disease remains unknown, prohibiting the development of drug therapies. Patients
with congenital mutations in VEGFR3 have lower leg lymphedema and upon lymphoscintigraphy imaging it is
revealed that their lymphatic vessels are unable to absorb any tracer from the interstitium. Here, we have
developed a mouse model in which the VEGFR3 gene can be deleted specifically from the lymphatic
vasculature to understand its physiological functions. Our preliminary data show that loss of VEGFR3
negatively affects the ability of lymphatic capillaries to remodel their continuous cell-cell junctions, reminiscent
of zippers, into discontinuous wide-open junctions called buttons. Junctional remodeling in the lymphatic
capillaries is a relatively new biological process that is poorly understood but relies on the adherens junction
protein, VE-cadherin, in which our laboratory has expertise. Importantly, the button junctions are thought to
enable fluid absorption from the interstitium. Our preliminary data identify VEGFR3 as a novel regulator of
lymphatic capillary junction remodeling to form button junctions. We will combine this mouse model with cell
culture and physiological approaches to investigate the role of VEGFR3 in the lymphatic vasculature in the
following specific aims. In Aim 1, we will assess the ability of lymphatic capillaries to remodel their junctions in
the absence of VEGFR3 at various timepoints after birth. We will also investigate whether VEGFR3 is required
not only for button junction formation, but also for the lifelong maintenance of these special junctions. Lymph
flow will be assessed in vivo to determine how the loss of button junctions affects physiological interstitial fluid
absorption. In Aim 2, we will investigate the downstream cell signals that regulate button junction formation and
identify the signaling pathways involved using a variety of approaches. The completion of these aims will
identify a new signaling pathway by which VEGFR3 controls lymphatic junction remodeling to enable interstitial
fluid absorption by the lymphatic capillaries. This work will significantly impact patients with congenital
lymphedema by providing mechanistic insight into the pathogenesis of the disease, opening the doo...

## Key facts

- **NIH application ID:** 10502986
- **Project number:** 1R01HL164825-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Joshua Paul SCALLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $660,910
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10502986

## Citation

> US National Institutes of Health, RePORTER application 10502986, VEGFR Signaling Controls Lymphatic Junctions (1R01HL164825-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10502986. Licensed CC0.

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