Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability

Christopher A. Jones, Nyall R. London, Haoyu Chen, Kye Won Park, Dominique Sauvaget, Rebecca A. Stockton, Joshua D. Wythe, Wonhee Suh, Frederic Larrieu-Lahargue, Yoh Suke Mukouyama, Per Lindblom, Pankaj Seth, Antonio Frias, Naoyuki Nishiya, Mark H. Ginsberg, Holger Gerhardt, Kang Zhang, Dean Y. Li

Research output: Contribution to journalArticle

273 Scopus citations

Abstract

The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. 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.

Original languageEnglish (US)
Pages (from-to)448-453
Number of pages6
JournalNature medicine
Volume14
Issue number4
DOIs
StatePublished - Apr 1 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Jones, C. A., London, N. R., Chen, H., Park, K. W., Sauvaget, D., Stockton, R. A., Wythe, J. D., Suh, W., Larrieu-Lahargue, F., Mukouyama, Y. S., Lindblom, P., Seth, P., Frias, A., Nishiya, N., Ginsberg, M. H., Gerhardt, H., Zhang, K., & Li, D. Y. (2008). Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nature medicine, 14(4), 448-453. https://doi.org/10.1038/nm1742