title: Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability.
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.
authors.affiliation: Department of Oncological Sciences, University of Utah, 15 North 2030 East, Salt Lake City, Utah 84112, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Jones
authors.forename: Nyall R
authors.initials: NR
authors.lastname: London
authors.forename: Haoyu
authors.initials: H
authors.lastname: Chen
authors.forename: Kye Won
authors.initials: KW
authors.lastname: Park
authors.forename: Dominique
authors.initials: D
authors.lastname: Sauvaget
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Stockton
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Wythe
authors.forename: Wonhee
authors.initials: W
authors.lastname: Suh
authors.forename: Frederic
authors.initials: F
authors.lastname: Larrieu-Lahargue
authors.forename: Yoh-Suke
authors.initials: YS
authors.lastname: Mukouyama
authors.forename: Per
authors.initials: P
authors.lastname: Lindblom
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.forename: Antonio
authors.initials: A
authors.lastname: Frias
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nishiya
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002829:Choroid / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C467484:VEGFA protein, human