| First Author | Zhang F | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 13517 | PubMed ID | 27882935 |
| Mgi Jnum | J:243065 | Mgi Id | MGI:5907557 |
| Doi | 10.1038/ncomms13517 | Citation | Zhang F, et al. (2016) The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization. Nat Commun 7:13517 |
| abstractText | 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 (Robo4DeltaCD). Robo4DeltaCD 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 Robo4DeltaCD 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. |
