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The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization

Author

Listed:
  • Feng Zhang

    (Cardiovascular Research Center, Yale University School of Medicine)

  • Claudia Prahst

    (Cardiovascular Research Center, Yale University School of Medicine)

  • Thomas Mathivet

    (INSERM U970, Paris Center for Cardiovascular Research (PARCC))

  • Laurence Pibouin-Fragner

    (INSERM U970, Paris Center for Cardiovascular Research (PARCC))

  • Jiasheng Zhang

    (Cardiovascular Research Center, Yale University School of Medicine)

  • Gael Genet

    (Cardiovascular Research Center, Yale University School of Medicine)

  • Raymond Tong

    (Genentech Inc.)

  • Alexandre Dubrac

    (Cardiovascular Research Center, Yale University School of Medicine)

  • Anne Eichmann

    (Cardiovascular Research Center, Yale University School of Medicine
    INSERM U970, Paris Center for Cardiovascular Research (PARCC)
    Yale University School of Medicine)

Abstract

Vascular permeability and neovascularization are implicated in many diseases including retinopathies and diabetic wound healing. Robo4 is an endothelial-specific transmembrane receptor that stabilizes the vasculature, as shown in Robo4−/− mice that develop hyperpermeability, but how Robo4 signals remained unclear. Here we show that Robo4 deletion enhances permeability and revascularization in oxygen-induced retinopathy (OIR) and accelerates cutaneous wound healing. To determine Robo4 signalling pathways, we generated transgenic mice expressing a truncated Robo4 lacking the cytoplasmic domain (Robo4ΔCD). Robo4ΔCD expression is sufficient to prevent permeability, and inhibits OIR revascularization and wound healing in Robo4−/− mice. Mechanistically, Robo4 does not affect Slit2 signalling, but Robo4 and Robo4ΔCD counteract Vegfr2-Y949 (Y951 in human VEGFR2) phosphorylation by signalling through the endothelial UNC5B receptor. We conclude that Robo4 inhibits angiogenesis and vessel permeability independently of its cytoplasmic domain, while activating VEGFR2-Y951 via ROBO4 inhibition might accelerate tissue revascularization in retinopathy of prematurity and in diabetic patients.

Suggested Citation

  • Feng Zhang & Claudia Prahst & Thomas Mathivet & Laurence Pibouin-Fragner & Jiasheng Zhang & Gael Genet & Raymond Tong & Alexandre Dubrac & Anne Eichmann, 2016. "The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13517
    DOI: 10.1038/ncomms13517
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    Cited by:

    1. Kevin Boyé & Luiz Henrique Geraldo & Jessica Furtado & Laurence Pibouin-Fragner & Mathilde Poulet & Doyeun Kim & Bryce Nelson & Yunling Xu & Laurent Jacob & Nawal Maissa & Dritan Agalliu & Lena Claess, 2022. "Endothelial Unc5B controls blood-brain barrier integrity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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