# Notch Signaling in the Adult Lymphatic Vasculature

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $559,718

## Abstract

SUMMARY
 Notch signaling is a fundamental regulator of lymphatic growth, function and vessel homeostasis. Lymphatic
dysfunction is associated with many acquired human diseases, including liver fibrosis, psoriasis, metabolic
diseases, and cancer. The postnatal lymphatic endothelium dynamically expresses both Notch1 and Notch4, as
well as the Notch ligands, Jag1 and Dll4. Numerous therapies that target Notch pathway components are in
clinical development or trials. Thus, it is essential to understand the role of the distinct receptors and ligands of
the Notch pathway in the adult lymphatic vasculature.
 Downstream of Dll4- and Jag1-activation, we found that Notch1 and Notch4 have overlapping and distinct
transcriptional profiles in lymphatic endothelial cells (LECs), suggesting a dynamic role for Notch in LECs. Our
studies of Notch4-/- mice indicate that Notch4 regulates dermal lymphatic vascular patterning, while it is
necessary specifically in adult females for the regeneration and maintenance of dermal lymphatics. Using in vitro
studies, we show that Notch4 regulates proliferation, and VECADHERIN expression posttranslationally, which
in turn may affect LEC growth, responses to flow and barrier function. Postnatal deletion of LEC Notch4 using a
novel transgenic model led to reduced dermal capillary lymphatics and LEC proliferation and altered
VECADHERIN expression. Analysis of male N4LECKO mice revealed increased hepatic portal lymphatics
associated with multiple hallmarks of pathological liver disease and fibrosis.
 We hypothesize that Dll4 and Jag1 dynamically signal via Notch1 and Notch4 in capillary lymphatics
to maintain lymphatic vessel homeostasis and regeneration in the adult. To address these hypotheses, we
propose to 1) transcriptionally profile lymphatic endothelial Notch1 and Notch4 signaling downstream of Dll4 and
Jag1 activation using in vitro and in vivo approaches, 2) determine the mechanisms by which Notch4 functions
in the dermal lymphatic endothelium of the adult mice, and 3) determine the role of lymphatic endothelial Notch4
in the liver and a mouse model of dietary-induced non-alcoholic steatohepatitis (NASH). The goal is to
understand LEC Notch4 functions in lymphatic vascular maintenance and homeostasis and how its loss
contributes to pathogenic phenotypes in the skin and liver.

## Key facts

- **NIH application ID:** 10803353
- **Project number:** 1R01HL164718-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Carrie J Shawber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $559,718
- **Award type:** 1
- **Project period:** 2023-12-07 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803353

## Citation

> US National Institutes of Health, RePORTER application 10803353, Notch Signaling in the Adult Lymphatic Vasculature (1R01HL164718-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10803353. Licensed CC0.

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