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Letter
Nature Medicine 14, 448 - 453 (2008)
Published online: 16 March 2008 | Corrected online: 18 April 2008 | doi:10.1038/nm1742
There is a Corrigendum (May 2008) associated with this Letter.
Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability
Christopher A Jones1,2,9, Nyall R London1,2,9, Haoyu Chen3, Kye Won Park1,2,8, Dominique Sauvaget4, Rebecca A Stockton5, Joshua D Wythe1,2, Wonhee Suh2,8, Frederic Larrieu-Lahargue2, Yoh-suke Mukouyama6, Per Lindblom4,8, Pankaj Seth7, Antonio Frias2, Naoyuki Nishiya5,8, Mark H Ginsberg5, Holger Gerhardt4, Kang Zhang2,3 & Dean Y Li1,2
Abstract
The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures1. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system2, 3; however, their role in the mammalian vasculature remains ill defined4, 5, 6, 7, 8. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165–induced migration, tube formation and permeability in vitro and VEGF-165–stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.
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