Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis

Yingdi Wang, Masanori Nakayama, Mara E. Pitulescu, Tim S. Schmidt, Magdalena L. Bochenek, Akira Sakakibara, Susanne Adams, Alice Davy, Urban Deutsch, Urs Lüthi, Alcide Barberis, Laura E. Benjamin, Taija Mäkinen, Catherine D. Nobes, Ralf H. Adams

Research output: Contribution to journalArticlepeer-review

783 Citations (Scopus)

Abstract

In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions. Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.

Original languageEnglish
Pages (from-to)483-486
Number of pages4
JournalNature
Volume465
Issue number7297
DOIs
Publication statusPublished - May 27 2010
Externally publishedYes

ASJC Scopus subject areas

  • General

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