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

A Corrigendum to this article was published on 01 May 2008

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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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Figure 1: Robo4 expression is endothelial specific and stalk-cell centric.
Figure 2: Robo4 signaling inhibits VEGF-165–induced migration, tube formation, permeability and SFK activation.
Figure 3: Slit2 blocks oxygen-induced retinopathy in a Robo4-dependent manner.
Figure 4: Robo4 signaling inhibits pathologic angiogenesis.

Change history

  • 18 April 2008

    Nat. Med. 14, 448–453 (2008); published online 16 March 2008; corrected after print 18 April 2008. In the version of this article initially published, the affiliation of Rebecca A. Stockton was incorrect. Her correct affiliation is affiliation 5: the Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093-0726, USA. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank K. Thomas and J. Wythe for critical reading of the manuscript, L. Sorensen-Brunhart and W. Zhu for technical assistance and D. Lim for expert graphical assistance. This work was funded by grants from the US National Cancer Institute Multidisciplinary Cancer Research Training Program (N.R.L.); Cancer Research–UK (H.G.); the National Eye Institute (K.Z.); National Heart, Lung and Blood Institute (M.H.G. and D.Y.L.); and National Institute of Arthritis and Musculoskeletal and Skin Diseases (M.H.G.), the H.A. and Edna Benning Foundation, the Juvenile Diabetes Research Foundation, the American Heart Association, the Burroughs Wellcome Fund and the Flight Attendants Medical Research Institute (D.Y.L.).

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Correspondence to Kang Zhang or Dean Y Li.

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C.A.J., N.R.L., H.C., K.W.P., J.D.W., W.S., F.L.-L., A.F., K.Z. and D.Y.L. are or were previously employed by the University of Utah, which has filed intellectual property surrounding the therapeutic uses of targeting Robo4 and with the intent to license this body of intellectual property for commercialization.

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Supplementary Figs. 1–10 and Supplementary Table 1 (PDF 7932 kb)

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Jones, C., London, N., Chen, H. et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat Med 14, 448–453 (2008). https://doi.org/10.1038/nm1742

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