Robo4 Stabilizes the Vascular Network by Inhibiting Pathologic Angiogenesis and Endothelial Hyperpermeability

Nat Med. 2008 Apr;14(4):448-53. doi: 10.1038/nm1742. Epub 2008 Mar 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillary Permeability* / drug effects
  • Choroid / blood supply
  • Choroid / drug effects
  • Choroid / pathology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neovascularization, Pathologic* / prevention & control
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / pharmacology
  • Nerve Tissue Proteins / physiology*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / physiology*
  • Recombinant Proteins / pharmacology
  • Retinal Vessels / drug effects
  • Retinal Vessels / pathology
  • Retinal Vessels / physiopathology
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • Recombinant Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • roundabout protein
  • Slit homolog 2 protein