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

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.

Pubmed ID: 18345009

Authors

  • Jones CA
  • London NR
  • Chen H
  • Park KW
  • Sauvaget D
  • Stockton RA
  • Wythe JD
  • Suh W
  • Larrieu-Lahargue F
  • Mukouyama YS
  • Lindblom P
  • Seth P
  • Frias A
  • Nishiya N
  • Ginsberg MH
  • Gerhardt H
  • Zhang K
  • Li DY

Journal

Nature medicine

Publication Data

April 8, 2008

Associated Grants

  • Agency: NHLBI NIH HHS, Id: R01 HL065648
  • Agency: NHLBI NIH HHS, Id: R01 HL068873
  • Agency: NHLBI NIH HHS, Id: R01 HL068873-05
  • Agency: NHLBI NIH HHS, Id: R01 HL068873-06
  • Agency: NHLBI NIH HHS, Id: R01 HL077671
  • Agency: NHLBI NIH HHS, Id: R01 HL077671-03
  • Agency: NHLBI NIH HHS, Id: R01 HL077671-04
  • Agency: NHLBI NIH HHS, Id: R01 HL084516
  • Agency: NHLBI NIH HHS, Id: R01 HL084516-01A1
  • Agency: NHLBI NIH HHS, Id: R01 HL084516-02
  • Agency: Intramural NIH HHS, Id: Z01 HL005702-02
  • Agency: Cancer Research UK, Id:

Mesh Terms

  • Animals
  • Capillary Permeability
  • Choroid
  • Endothelium, Vascular
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neovascularization, Pathologic
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • Recombinant Proteins
  • Retinal Vessels
  • Signal Transduction
  • Vascular Endothelial Growth Factor A