# Metabolic mechanisms controlling lymphatic vessel formation

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2022 · $437,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Lymphatic vessels play critical roles in regulating tissue fluid drainage, dietary fat absorption, and reverse
cholesterol transport. Fulfilling these important physiological functions requires proper development of the
lymphatic vasculature, which is mainly driven by vascular endothelial growth factor C (VEGF-C). VEGF-C
signaling also stimulates pathological lymphangiogenesis in tumors and organ transplantation, which may, in
turn, promote cancer metastasis and allograft rejection respectively. Therefore, elucidating the mechanisms by
which VEGF-C signaling drives lymphangiogenesis will not only enhance the fundamental understanding of
physiological processes regulated by lymphatics, but also facilitate the development of novel anti-
lymphangiogenic strategies for disease treatments. We previously discovered that lymphatic endothelial cells
(LECs), even when grown in an oxygen-rich environment, preferentially convert glucose to lactate. This unique
metabolic feature is termed the Warburg effect. Despite this finding, it remains unclear whether and how the
Warburg effect is regulated by VEGF-C signaling for promoting developmental and pathological
lymphangiogenesis. Lactate dehydrogenase A (LDHA) catalyzes the reduction of pyruvate to lactate and the
regeneration of oxidized nicotinamide adenine dinucleotide (NAD+) from its reduced form NADH. Our preliminary
studies suggest that LDHA mediates the Warburg effect in LECs. We also found that genetic ablation of Ldha in
mice impairs LEC proliferation and migration during lymphatic vascular development. Moreover, VEGF-C
enhances LDHA transcription and lactate generation in LECs. These data collectively support our central
hypothesis that LDHA couples VEGF-C signaling with cellular metabolism to drive lymphangiogenesis, which
will be tested through two Specific Aims. Aim 1 will use genetic mouse models and cultured LECs to determine
the molecular mechanisms by which VEGF-C signaling induces LDHA expression during lymphatic vessel
formation. Aim 2 will combine several advanced analytical tools to elucidate the mechanisms by which LDHA
controls cellular metabolism to promote lymphangiogenesis. Taken together, our proposed studies will identify
LDHA as a novel mechanistic link between VEGF-C signaling and metabolic processes critical for lymphatic
vessel formation. Our work may also suggest an innovative strategy, i.e., targeting the Warburg effect via LDHA
inhibition, for suppressing VEGF-C-induced pathological lymphangiogenesis.

## Key facts

- **NIH application ID:** 10423646
- **Project number:** 1R01HL162985-01
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** PENGCHUN YU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $437,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10423646

## Citation

> US National Institutes of Health, RePORTER application 10423646, Metabolic mechanisms controlling lymphatic vessel formation (1R01HL162985-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10423646. Licensed CC0.

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