APOA1 Binding Protein Promotes Lymphatic Cell Fate and Lymphangiogenesis by Relieving Caveolae-Mediated Inhibition of VEGFR3 Signaling

Authors

Jun-Dae Kim
Surbhi Chaudhary
Weiqing Chen
Jonathan Astin
Philip S Crosier
Pengchun Yu
John P Cooke
Henry J Pownall
Hugo J Bellen
Nhat-Tu Le
Daniel L Kiss
Guangyu Wang
Stanley G Rockson
Hong Chen
Longhou Fang

Language

English

Publication Date

10-21-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-60611-w

PMID

41120256

PMCID

PMC12540785

PubMedCentral® Posted Date

10-21-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The lymphatic system maintains tissue fluid balance, and its dysfunction can result in lymphedema. Although cholesterol is essential for cellular function, its role in lymphatic development has remained unknown. Here, we identify APOA1 binding protein (AIBP) as a key regulator that promotes lymphatic endothelial cell fate specification and lymphangiogenesis. Mechanistically, AIBP reduces plasma membrane cholesterol content, thereby enhancing VEGFR3 signaling by disrupting caveolae—small plasma membrane invaginations formed by the scaffolding protein caveolin-1 (CAV-1)—and relieving CAV-1–mediated inhibition. In zebrafish and mice, AIBP loss impairs VEGFR3 signaling and lymphatic development, defects that can be rescued by CAV-1 deletion or by a VEGFR3 mutant (VEGFR3AAA) lacking CAV-1 binding. Administration of recombinant AIBP augments VEGFC-induced lymphangiogenesis and accelerates the resolution of secondary lymphedema in adult mice. These findings define the AIBP–CAV-1 axis as a regulator of VEGFR3 signaling and lymphatic growth, offering potential therapeutic opportunities for treating lymphatic dysfunction.

Keywords

Animals, Lymphangiogenesis, Vascular Endothelial Growth Factor Receptor-3, Zebrafish, Mice, Signal Transduction, Caveolae, Caveolin 1, Humans, Endothelial Cells, Apolipoprotein A-I, Cholesterol, Vascular Endothelial Growth Factor C, Lymphedema, Lymphatic Vessels, Mice, Knockout, Mice, Inbred C57BL, Lymphangiogenesis, Lipid signalling, Growth factor signalling

Published Open-Access

yes

Recommended Citation

Kim, Jun-Dae; Chaudhary, Surbhi; Chen, Weiqing; et al., "APOA1 Binding Protein Promotes Lymphatic Cell Fate and Lymphangiogenesis by Relieving Caveolae-Mediated Inhibition of VEGFR3 Signaling" (2025). Faculty and Staff Publications. 5020.
https://digitalcommons.library.tmc.edu/baylor_docs/5020