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Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis

Item Type:Article
Title:Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis
Creators Name:Sawamiphak, S. and Seidel, S. and Essmann, C.L. and Wilkinson, G.A. and Pitulescu, M.E. and Acker, T. and Acker-Palmer, A.
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.
Keywords:Astrocytoma, Brain, Cultured Cells, Endocytosis, Endothelial Cells, Ephrin-B2, Inbred C57BL Mice, Neoplasm Transplantation, Pathologic Neovascularization, Physiologic Neovascularization, Pseudopodia, Retina, Retinal Vessels, Signal Transduction, Vascular Endothelial Growth Factor Receptor-2, Animals, Mice
Publisher:Nature Publishing Group
Page Range:487-491
Date:27 May 2010
Official Publication:https://doi.org/10.1038/nature08995
PubMed:View item in PubMed

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