title: Semaphorin-3C signals through Neuropilin-1 and PlexinD1 receptors to inhibit pathological angiogenesis.
abstract: Retinopathy of prematurity causes visual impairment due to destructive neoangiogenesis after degeneration of the retinal microvasculature. This study was aimed at analyzing whether local delivery of Semaphorin-3C (Sema3C) suppresses pathological retinal angiogenesis. Sema3C exerted potent inhibiting effects in cellular models of angiogenesis. In an endothelial cell xenotransplantation assay, Sema3C acted primarily on immature microvessels by inducing endothelial cell apoptosis. Intravitreal administration of recombinant Sema3C disrupted endothelial tip cell formation and cell-cell contacts, which led to decreased vascular bed expansion and vessel branching in the growing retinal vasculature of newborn mice, while not affecting mature vessels in the adult retina. Sema3C administration strongly inhibited the formation of pathological pre-retinal vascular tufts during oxygen-induced retinopathy. Mechanistically, Sema3C signaled through the receptors Neuropilin-1 and PlexinD1, which were strongly expressed on vascular tufts, induced VE-cadherin internalization, and abrogated vascular endothelial growth factor (VEGF)-induced activation of the kinases AKT, FAK, and p38MAPK. This disrupted endothelial cell junctions, focal adhesions, and cytoskeleton assembly resulted in decreased cell migration and survival. Thus, this study identified Sema3C as a potent and selective inhibitor of pathological retinal angiogenesis.
authors.affiliation: Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM) Heidelberg University, Mannheim, Germany.
authors.forename: Wan-Jen
authors.initials: WJ
authors.lastname: Yang
authors.affiliation: Vascular Oncology and Metastasis (A190), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
authors.affiliation: Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Tetzlaff
authors.affiliation: Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM) Heidelberg University, Mannheim, Germany Vascular Oncology and Metastasis (A190), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM) Heidelberg University, Mannheim, Germany Department of Medicine I and Clinical Chemistry, Heidelberg University, Heidelberg, Germany a.fischer@dkfz-heidelberg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D017690:Cell Transplantation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology*; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D014183:Transplantation, Heterologous
chemical_list: D020533:Angiogenesis Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C473552:Plxnd1 protein, mouse; D039961:Semaphorins; D039942:Neuropilin-1
keywords: Sema3C; angiogenesis; retinopathy of prematurity; semaphorin