title: The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization.
abstract: Hypoxia causes increased expression of several proteins that have the potential to promote neovascularization. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia in the retina and plays a central role in the development of several types of ocular neovascularization, but the effects of other hypoxia-regulated proteins are less clear. Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, have hypoxia response elements in the promoter regions of their genes and are increased in hypoxic liver and heart. In this study, we found that SDF-1 and CXCR4 are increased in hypoxic retina, with SDF-1 localized in glial cells primarily near the surface of the retina and CXCR4 localized in bone marrow-derived cells. Glial cells also expressed CXCR4, which suggested the possibility of autocrine stimulation, but influx of bone marrow-derived cells is the major source of increased levels of CXCR4. High levels of VEGF in the retina in the absence of hypoxia also increased levels of Cxcr4 and Sdf1 mRNA. CXCR4 antagonists reduced influx of bone marrow-derived cells into ischemic retina and strongly suppressed retinal neovascularization, VEGF-induced subretinal neovascularization, and choroidal neovascularization. These data suggest that SDF-1 and CXCR4 contribute to the involvement of bone marrow-derived cells and collaborate with VEGF in the development of several types of ocular neovascularization. They provide new targets for therapeutic intervention that may help to bolster and supplement effects obtained with VEGF antagonists.
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-9277, USA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Lima e Silva
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Sean F
authors.initials: SF
authors.lastname: Hackett
authors.forename: Shu
authors.initials: S
authors.lastname: Kachi
authors.forename: Hideo
authors.initials: H
authors.lastname: Akiyama
authors.forename: Katsuji
authors.initials: K
authors.lastname: Kiuchi
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yokoi
authors.forename: Maria C
authors.initials: MC
authors.lastname: Hatara
authors.forename: Thomas
authors.initials: T
authors.lastname: Lauer
authors.forename: Sadia
authors.initials: S
authors.lastname: Aslam
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Gong
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Xiao
authors.forename: Naw Htee
authors.initials: NH
authors.lastname: Khu
authors.forename: Catherine
authors.initials: C
authors.lastname: Thut
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001854:Bone Marrow Cells; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D016510:Corneal Neovascularization; D006801:Humans; D000860:Hypoxia; D007511:Ischemia / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000033:anatomy & histology* / Q000473:pathology / Q000502:physiology*; D015861:Retinal Neovascularization; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C525448:1-pyridin-2-yl-N-(4-(1,4,7-triazacyclotetradecan-4-ylmethyl)benzyl)methanamine; D000943:Antigens, Differentiation; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D009842:Oligopeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011725:Pyridines; D019718:Receptors, CXCR4; C504129:TC14012; D042461:Vascular Endothelial Growth Factor A; C036763:monocyte-macrophage differentiation antigen; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse