VEGFR2 is required for VEGF-C-VEGFR3-PI3Kα-mediated sprouting lymphangiogenesis.

Authors

Hans Schoofs, Yan Zhang, Henrik Ortsäter, Mariya Lytvyn, Rui Benedito, Taija Mäkinen

Published in

Nature communications. Volume 17. Issue 1. May 15, 2026. Epub May 15, 2026.

Abstract

Lymphatic vessels are essential for tissue homoeostasis and their growth is regulated by vascular endothelial growth factor C (VEGF-C) signalling through VEGFR3. However, how VEGF-C balances lymphatic endothelial cells (LECs) proliferation versus sprouting to ensure functional vessel formation has remained unclear. Using high-fidelity conditional genetics and receptor-specific ligands, we uncover a requirement for the alternative receptor VEGFR2 in VEGF-C-VEGFR3-driven lymphatic vessel sprouting. While activation of VEGFR2 alone fails to induce lymphangiogenesis, VEGFR2 loss abolishes LEC sprouting, but not proliferation, in response to VEGF-C. In contrast, deletion of the VEGFR3 downstream effector PI3Kα completely abrogates lymphangiogenesis. VEGFR2 is activated and found in proximity to VEGFR3 in LECs in vivo, with PI3Kα controlling their relative cell-surface availability and VEGF-C increasing VEGFR2 relative to VEGFR3, thereby priming LECs for sprouting. This receptor coordination balances VEGF-C-driven proliferative and sprouting responses, coupling LEC expansion to vessel growth, ensuring the formation of functional lymphatic networks.

PMID:
42140900
Bibliographic data and abstract were imported from PubMed on 14 Jun 2026.

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