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

Item Type:Article
Title:Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability
Creators Name:Jones, C.A. and London, N.R. and Chen, H. and Park, K.W. and Sauvaget, D. and Stockton, R.A. and Wythe, J.D. and Suh, W. and Larrieu-Lahargue, F. and Mukouyama, Y.S. and Lindblom, P. and Seth, P. and Frias, A. and Nishiya, N. and Ginsberg, M.H. and Gerhardt, H. and Zhang, K. and Li, D.Y.
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.
Keywords:Capillary Permeability, Choroid, Intercellular Signaling Peptides and Proteins, Knockout Mice, Nerve Tissue Proteins, Pathologic Neovascularization, ReceptorsImmunologic, Recombinant Proteins, Retinal Vessels, Signal Transduction, Transgenic Mice, Vascular Endothelial Growth Factor A, Vascular Endothelium, Animals, Mice
Source:Nature Medicine
ISSN:1078-8956
Publisher:Nature Publishing Group (U.S.A.)
Volume:14
Number:4
Page Range:448-453
Date:April 2008
Additional Information:Erratum in: Nat Med 14(5):585.
Official Publication:https://doi.org/10.1038/nm1742
PubMed:View item in PubMed

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