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

Christopher A. Jones, Nyall R. London, Haoyu Chen, Kye Won Park, Dominique Sauvaget, Rebecca A. Stockton, Joshua D. Wythe, Wonhee Suh, Frederic Larrieu-Lahargue, Yoh Suke Mukouyama, Per Lindblom, Pankaj Seth, Antonio Frias, Naoyuki Nishiya, Mark H. Ginsberg, Holger Gerhardt, Kang Zhang, Dean Y. Li

Research output: Contribution to journalArticle

259 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)448-453
Number of pages6
JournalNature Medicine
Volume14
Issue number4
DOIs
StatePublished - Apr 2008
Externally publishedYes

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Pathologic Neovascularization
Blood Vessels
Chemical activation
src-Family Kinases
Neurology
Choroid Diseases
Retinal Vessels
Pathologic Processes
Vascular Diseases
Nervous System
Axons
Permeability
Proteins
human VEGFA protein
roundabout protein

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Jones, C. A., London, N. R., Chen, H., Park, K. W., Sauvaget, D., Stockton, R. A., ... Li, D. Y. (2008). Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nature Medicine, 14(4), 448-453. https://doi.org/10.1038/nm1742

Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. / Jones, Christopher A.; London, Nyall R.; Chen, Haoyu; Park, Kye Won; Sauvaget, Dominique; Stockton, Rebecca A.; Wythe, Joshua D.; Suh, Wonhee; Larrieu-Lahargue, Frederic; Mukouyama, Yoh Suke; Lindblom, Per; Seth, Pankaj; Frias, Antonio; Nishiya, Naoyuki; Ginsberg, Mark H.; Gerhardt, Holger; Zhang, Kang; Li, Dean Y.

In: Nature Medicine, Vol. 14, No. 4, 04.2008, p. 448-453.

Research output: Contribution to journalArticle

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 2008, 'Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability', Nature Medicine, vol. 14, no. 4, pp. 448-453. https://doi.org/10.1038/nm1742
Jones, Christopher A. ; London, Nyall R. ; Chen, Haoyu ; Park, Kye Won ; Sauvaget, Dominique ; Stockton, Rebecca A. ; Wythe, Joshua D. ; Suh, Wonhee ; Larrieu-Lahargue, Frederic ; Mukouyama, Yoh Suke ; Lindblom, Per ; Seth, Pankaj ; Frias, Antonio ; Nishiya, Naoyuki ; Ginsberg, Mark H. ; Gerhardt, Holger ; Zhang, Kang ; Li, Dean Y. / Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. In: Nature Medicine. 2008 ; Vol. 14, No. 4. pp. 448-453.
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