# A Critical Role for Hypoxia-Inducible Factors in Lymphedema

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2021 · $612,344

## Abstract

PROJECT SUMMARY / ABSTRACT
Lymphedema is a chronic and debilitating condition currently without approved medical therapies. Lymphatic
drainage insufficiency, caused by inflammation and lymphatic endothelial cell (LEC) dysfunction, is the main
factor promoting the progression of lymphedema. LEC-derived hypoxia-inducible factor (HIF)-2α is required for
proper lymphatic development and homeostasis; the decline of LEC HIF-2α, observed in lymphedema, may be
directly involved with disease progression. In experimental models, reducing HIF-2α expression aggravates
lymphatic drainage insufficiency and exacerbates accumulating interstitial fluid. Anti-inflammatory ketoprofen
therapy was recently shown to be effective in lymphedema, and treated patients show increased LEC HIF-2α
expression in their skin biopsies. The studies proposed in this grant are designed to address fundamental
questions about why LEC HIF-2α is decreased in lymphedema and how this reduction influences lymphatic
drainage. The grant hypothesis is that suppressed LEC HIF-2α expression, caused by inflammatory mediators,
impairs lymphatic drainage by promoting LEC phenotypic transformation and abnormal cellular energetics.
Specific Aim 1 is to explore the mechanisms by which inflammation inhibits LEC HIF-2α expression and map
HIF-2α-regulated gene networks in LECs. Aim 2 will investigate how LEC HIF-2α reduction may cause LEC
phenotypic transformation, promote lymphatic vascular remodeling, and aggravate lymphatic drainage
insufficiency. Aim 3 will study how LEC HIF-2α reduction affects lymphatic structure and function by promoting
abnormal cellular metabolism. Collectively, the proposed studies are expected to advance the understanding of
the role that HIF-2α plays in lymphedema with the rationale that the knowledge gained can facilitate much-
needed therapeutic development.

## Key facts

- **NIH application ID:** 10297663
- **Project number:** 1R01HL150583-01A1
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** Xinguo Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $612,344
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297663

## Citation

> US National Institutes of Health, RePORTER application 10297663, A Critical Role for Hypoxia-Inducible Factors in Lymphedema (1R01HL150583-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10297663. Licensed CC0.

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