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  Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis

Sawamiphak, S., Seidel, S., Essmann, C. L., Wilkinson, G. A., Pitulescu, M. E., Acker, T., et al. (2010). Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature, 465(7297), 487-91. doi:10.1038/nature08995.

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Sawamiphak, S., Author
Seidel, S., Author
Essmann, C. L., Author
Wilkinson, G. A., Author
Pitulescu, M. E., Author
Acker, T., Author
Acker-Palmer, Amparo1, Author              
Affiliations:
1Neurovascular interface Group, Max Planck Institute for Brain Research, Max Planck Society, ou_2461707              

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Free keywords: Animals Astrocytoma/*blood supply/*metabolism/pathology Brain/blood supply Cells, Cultured Endocytosis Endothelial Cells/cytology/metabolism Ephrin-B2/deficiency/genetics/*metabolism Mice Mice, Inbred C57BL Neoplasm Transplantation *Neovascularization, Pathologic Neovascularization, Physiologic Pseudopodia/metabolism Retina Retinal Vessels/cytology/physiology Signal Transduction Vascular Endothelial Growth Factor Receptor-2/*metabolism
 Abstract: The formation and guidance of specialized endothelial tip cells is essential for both developmental and pathological angiogenesis. Notch-1 signalling regulates the generation of tip cells, which respond to gradients of vascular endothelial growth factor (VEGF-A). The molecular cues and signalling pathways that control the guidance of tip cells are poorly understood. Bidirectional signalling by Eph receptors and ephrin ligands represents one of the most important guidance cues involved in axon path finding. Here we show that ephrin-B2 reverse signalling involving PDZ interactions regulates endothelial tip cell guidance to control angiogenic sprouting and branching in physiological and pathological angiogenesis. In vivo, ephrin-B2 PDZ-signalling-deficient mice (ephrin-B2DeltaV) exhibit a reduced number of tip cells with fewer filopodial extensions at the vascular front in the mouse retina. In pathological settings, impaired PDZ signalling decreases tumour vascularization and growth. Mechanistically, we show that ephrin-B2 controls VEGF receptor (VEGFR)-2 internalization and signalling. Importantly, internalization of VEGFR2 is necessary for activation and downstream signalling of the receptor and is required for VEGF-induced tip cell filopodial extension. Together, our results suggest that ephrin-B2 at the tip cell filopodia regulates the proper spatial activation of VEGFR2 endocytosis and signalling to direct filopodial extension. Blocking ephrin-B2 reverse signalling may be an attractive alternative or combinatorial anti-angiogenic therapy strategy to disrupt VEGFR2 function in tumour angiogenesis.

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 Dates: 2010-05-07
 Publication Status: Published in print
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 Identifiers: Other: 20445540
DOI: 10.1038/nature08995
ISSN: 1476-4687 (Electronic)0028-0836 (Linking)
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Title: Nature
Source Genre: Journal
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Pages: - Volume / Issue: 465 (7297) Sequence Number: - Start / End Page: 487 - 91 Identifier: -