title: Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization.
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.
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rama
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dubrac
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mathivet
authors.affiliation: 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.
authors.forename: Róisín-Ana
authors.initials: RA
authors.lastname: Ní Chárthaigh
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Gael
authors.initials: G
authors.lastname: Genet
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, France.
authors.forename: Brunella
authors.initials: B
authors.lastname: Cristofaro
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Pibouin-Fragner
authors.affiliation: Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.affiliation: 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.
authors.forename: Alain
authors.identifier: 0000000175773794
authors.initials: A
authors.lastname: Chédotal
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D012160:Retina / Q000196:embryology / Q000378:metabolism; D015861:Retinal Neovascularization; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D042461:Vascular Endothelial Growth Factor A; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C498890:ROBO2 protein, human; C498888:Robo2 protein, mouse