# Lymphatics in the liver

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $589,312

## Abstract

SUMMARY
 The lymphatic system maintains tissue fluid homeostasis and regulates local inflammatory
responses.1,2 The liver lymphatic system remains poorly understood. The goal of this proposed research is to
advance our understanding of the mechanisms of hepatic lymphangiogenesis (the formation of new lymphatic
vessels) and the role of lymphatic vessels in liver pathophysiology.
 Vascular endothelial growth factor C (VEGF-C) is the major inducer of lymphangiogenesis. Our
preliminary studies have shown that enhanced hepatic lymphangiogenesis by VEGF-C overexpression
reduces liver fibrosis, suggesting a therapeutic potential. Additional data show that Schwann cells of hepatic
sympathetic nerves play a central role in hepatic lymphangiogenesis as a source of VEGF-C and as a recruiter
of macrophages, which may contribute to hepatic lymphangiogenesis by producing fibronectin-1 (FN1), a
substrate for integrins essential for VEGF-C/VEGF receptor 3 (VEGFR3) signaling. We thus hypothesize that
lymphatic ablation should increase inflammation and promote disease progression, and lymphangiogenesis
driven by Schwann cells and macrophages through VEGF-C signaling should alleviate inflammation and inhibit
disease progression. To test these hypotheses, we propose the following Specific Aims:
1. Determine the Schwann cell-driven mechanisms that promote hepatic lymphangiogenesis.
2. Determine Kupffer cells/macrophages-driven mechanisms that promote hepatic lymphangiogenesis.
3. Determine the role of lymphangiogenesis in the development of liver fibrosis.
 The proposed research will elucidate the regulation of lymphatic vessels visually and mechanistically
and their functional importance in liver fibrosis/cirrhosis. Further, the potential of VEGF-C overexpression and
subsequent induction of lymphangiogenesis for the prevention and treatment of liver fibrosis/cirrhosis as well
as portal hypertension and ascites will be evaluated. Furthermore, this research will significantly contribute to
the advancement of the study of the liver by exploring relatively underexamined areas of the hepatic lymphatic
system and nervous system.

## Key facts

- **NIH application ID:** 10657334
- **Project number:** 5R01DK121511-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YASUKO IWAKIRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $589,312
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10657334

## Citation

> US National Institutes of Health, RePORTER application 10657334, Lymphatics in the liver (5R01DK121511-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10657334. Licensed CC0.

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