Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis

Y Wang, M Nakayama, M.E Pitulescu, T.S Schmidt, M.L Bochenek, A Sakakibara, S Adams, A Davy, U Deutsch, U Lüthi, A Barberis, L.E Benjamin, T Mäkinen, C.D Nobes, R.H Adams

Research output: Contribution to journalArticle (Academic Journal)peer-review

651 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 protrusions1, 2, 3. 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.
Translated title of the contributionEphrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis
Original languageEnglish
Pages (from-to)483 - 489
Number of pages7
JournalNature
Volume465
Issue number7297
DOIs
Publication statusPublished - May 2010

Bibliographical note

Other: First published online 5th May 2010

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