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 system^{2, 3}; however, their role in the mammalian vasculature remains ill defined^{4, 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.

1. Departments of Oncological Sciences and Medicine, University of Utah, 15 North 2030 East, Salt Lake City, Utah 84112, USA.
2. Program in Human Molecular Biology and Genetics, University of Utah, 15 North 2030 East, Salt Lake City, Utah 84112, USA.
3. Department of Ophthalmology, University of Utah, 15 North 2030 East, Salt Lake City, Utah 84112, USA.
4. Vascular Biology Laboratory, London Research Institute–Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
5. Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093-0726, USA.
6. Stem Cell and Neuro-Vascular Development and Patterning Section, Laboratory of Developmental Biology, Genetics and Development Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, 10 Center Dr., Bethesda, Maryland 20892, USA.
7. Renal Division and Center for Study of the Tumor Microenvironment, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 300 Brookline Ave., Boston, Massachusetts 02215, USA.
8. Present addresses: Department of Pathology and Laboratory Medicine, University of California Los Angeles, 675 Charles E. Young Dr. South, Los Angeles, California 90095, USA (K.W.P); Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-Ku, Seoul 135-710, Korea (W.S.); Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University, School of Pharmaceutical Sciences, 2-1-1 Nishitokuda, Yahaba, Shiwa-Gun, Iwate, 028-3694, Japan (N.N.); Molecular Toxicology, Safety Assessment, AstraZeneca R&D, SE-151 85 Södertälje, Sweden (P.L.).
9. These authors contributed equally to this work.

Correspondence to: Dean Y Li^1,2 e-mail: Dean.Li@hmbg.utah.edu

Correspondence to: Kang Zhang^2,3 e-mail: Kang.Zhang@hmbg.utah.edu

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