Format

Send to

Choose Destination
Nat Commun. 2016 Nov 24;7:13517. doi: 10.1038/ncomms13517.

The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization.

Author information

1
Cardiovascular Research Center, Yale University School of Medicine, Department of Internal Medecine Cardiology, New Haven, Connecticut 06510-3221, USA.
2
INSERM U970, Paris Center for Cardiovascular Research (PARCC), 75015 Paris, France.
3
Genentech Inc., Molecular Oncology Division, South San Francisco, California 94030, USA.
4
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510-3221, USA.

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.

PMID:
27882935
PMCID:
PMC5123080
DOI:
10.1038/ncomms13517
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center