The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization

Feng Zhang, Claudia Prahst, Thomas Mathivet, Laurence Pibouin-Fragner, Jiasheng Zhang, Gael Genet, Raymond Tong, Alexandre Dubrac and Anne Eichmann ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13517

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