Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.
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.
Wang
Yingdi
Y
Vascular Development Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, UK.
Nakayama
Masanori
M
Pitulescu
Mara E
ME
Schmidt
Tim S
TS
Bochenek
Magdalena L
ML
Sakakibara
Akira
A
Adams
Susanne
S
Davy
Alice
A
Deutsch
Urban
U
Lüthi
Urs
U
Barberis
Alcide
A
Benjamin
Laura E
LE
Mäkinen
Taija
T
Nobes
Catherine D
CD
Adams
Ralf H
RH
D000818:Animals; D002478:Cells, Cultured; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism; D004705:Endocytosis; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D036388:Ephrin-B2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics; D042601:Lymphatic Vessels; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D036224:Receptor, EphB4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D015027:Zebrafish; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
D036388:Ephrin-B2; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D042582:Vascular Endothelial Growth Factor C; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4; D040321:Vascular Endothelial Growth Factor Receptor-3; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
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