Format

Send to

Choose Destination
Nat Med. 2015 May;21(5):483-91. doi: 10.1038/nm.3849. Epub 2015 Apr 20.

Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization.

Author information

1
1] INSERM UMR S968, Institut de la Vision, Paris, France. [2] Université Pierre et Marie Curie, Sorbonne Universités, Paris, France. [3] UMR 7210, CNRS, Paris, France.
2
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.
3
Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, France.
4
Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
5
1] Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, France. [3] Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Abstract

Ocular neovascular diseases are a leading cause of blindness. Vascular endothelial growth factor (VEGF) blockade improves vision, but not all individuals respond to anti-VEGF treatment, making additional means to prevent neovascularization necessary. Slit-family proteins (Slits) are ligands of Roundabout (Robo) receptors that repel developing axons in the nervous system. Robo1 expression is altered in ocular neovascular diseases, and previous in vitro studies have reported both pro- and anti-angiogenic effects of Slits. However, genetic evidence supporting a role for Slits in ocular neovascularization is lacking. Here we generated conditional knockout mice deficient in various Slit and Robo proteins and found that Slit2 potently and selectively promoted angiogenesis via Robo1 and Robo2 in mouse postnatal retina and in a model of ocular neovascular disease. Mechanistically, Slit2 acting through Robo1 and Robo2 promoted the migration of endothelial cells. These receptors are required for both Slit2- and VEGF-induced Rac1 activation and lamellipodia formation. Thus, Slit2 blockade could potentially be used therapeutically to inhibit angiogenesis in individuals with ocular neovascular disease.

PMID:
25894826
PMCID:
PMC4819398
DOI:
10.1038/nm.3849
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

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