# Mechanisms of Lymphatic Regression and Recurrent Lymphangiogenesis

> **NIH NIH R15** · SOUTH DAKOTA STATE UNIVERSITY · 2020 · $432,463

## Abstract

Project Summary/Abstract
Injury-induced inflammation progresses along one of two trajectories: wound healing or chronic inflammation.
Lymphatic vessel (LV) remodeling contributes to both processes by regulating fluid homeostasis and immune
cell traffic to draining lymph nodes. Lymphatic endothelial cells (LECs) respond to acute inflammation by
forming new LVs through lymphangiogenesis (LA). These newly-synthesized LVs then regress as inflammation
resolves, supporting wound healing. Dysregulation of wound healing impairs LV regression and leads to
recurrent LA and chronic inflammation. The mechanisms that govern sustained LV regression vs. activation of
recurrent LA are unknown. Our long-term goal is to develop strategies targeting LV remodeling to promote
wound healing and prevent or reverse chronic inflammation. The overall objective of this proposal is to define
the cellular events of LV regression during wound healing and to identify the cellular events and signals that
reactivate regressed LV fragments for recurrent LA. Our preliminary data indicate that macrophages critically
coordinate lymphatic remodeling. We hypothesize that differentially polarized macrophages perform distinct
functions in regression and recurrent LA, first supporting fragmentation by engulfment of apoptotic LECs and
later elaborating LA factors to reactivate LECs and degrading collagen to support fragment migration and
anastomosis. We will test this hypothesis with two specific aims: (1) Define the mechanisms by which
macrophage presence and polarization regulate LEC fate in regression and reactivation in recurrent LA; and
(2) Identify signals governing the transition from LV regression to recurrent LA. The first aim will employ a
novel dual-color transgenic mouse model to track the interactions and fates of eGFP+ macrophages and
tdTomato+ LECs by intravital microscopy. The second aim will use an innovative in vivo approach to identify
and validate candidate protein regulators of recurrent LA, pairing protein cytokine arrays with the corneal
micropocket model. This will expand basic knowledge of LEC and macrophage functional phenotypes and
inform therapeutic development for lymphatic dysfunction, macrophage modulation, and chronic inflammation.

## Key facts

- **NIH application ID:** 10114873
- **Project number:** 1R15GM140458-01
- **Recipient organization:** SOUTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Darci M. Fink
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,463
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114873

## Citation

> US National Institutes of Health, RePORTER application 10114873, Mechanisms of Lymphatic Regression and Recurrent Lymphangiogenesis (1R15GM140458-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10114873. Licensed CC0.

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