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Blood, 1 November 2006, Vol. 108, No. 9, pp. 2914-2922.
Prepublished online as a Blood First Edition Paper on July 13, 2006; DOI 10.1182/blood-2006-05-023341.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
EphB2 and EphB4 receptors forward signaling promotes SDF-1induced endothelial cell chemotaxis and branching remodeling
Ombretta Salvucci,
Maria de la Luz Sierra,
Jose A. Martina,
Peter J. McCormick, and
Giovanna Tosato
From the Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, and the Laboratory of Cell Biology, National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD.
The complex molecular mechanisms that drive endothelial cell movement and the formation of new vessels are poorly understood and require further investigation. Eph receptor tyrosine kinases and their membrane-anchored ephrin ligands regulate cell movements mostly by cellcell contact, whereas the G-proteincoupled receptor CXCR4 and its unique SDF-1 chemokine ligand regulate cell movement mostly through soluble gradients. By using biochemical and functional approaches, we investigated how ephrinB and SDF-1 orchestrate endothelial cell movement and morphogenesis into capillary-like structures. We describe how endogenous EphB2 and EphB4 signaling are required for the formation of extracellular matrixdependent capillary-like structures in primary human endothelial cells. We further demonstrate that EphB2 and EphB4 activation enhance SDF-1induced signaling and chemotaxis that are also required for extracellular matrixdependent endothelial cell clustering. These results support a model in which SDF-1 gradients first promote endothelial cell clustering and then EphB2 and EphB4 critically contribute to subsequent cell movement and alignment into cord-like structures. This study reveals a requirement for endogenous Eph signaling in endothelial cell morphogenic processes, uncovers a novel link between EphB forward signaling and SDF-1induced signaling, and demonstrates a mechanism for cooperative regulation of endothelial cell movement.

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