title: Hyperoxia therapy of pre-proliferative ischemic retinopathy in a mouse model.
abstract: OBJECTIVE
  To investigate the therapeutic use and mechanisms of action of normobaric hyperoxia to promote revascularization and to prevent neovascularization in a mouse model of oxygen-induced ischemic retinopathy.
  
  
  METHODS
  Hyperoxia treatment (HT, 40%-75% oxygen) was initiated on postnatal day (P) 14 during the pre-proliferative phase of ischemic retinopathy. Immunohistochemistry, ELISA, and quantitative PCR were used to assess effects on retinal vascular repair and pathologic angiogenesis in relation to glial cell injury, VEGF protein, and mRNA levels of key mediators of pathologic angiogenesis. Effects of intravitreal injections of VEGF and the VEGF inhibitor VEGFR1/Fc fusion protein were also studied.
  
  
  RESULTS
  Administration of HT during the ischemic pre-proliferative phase of retinopathy effectively accelerated the process of revascularization while preventing the development of vitreous neovascularization. HT enhanced the formation of specialized endothelial tip cells at the edges of the repairing capillary networks and blocked the overexpression of several molecular mediators of angiogenesis, inflammation, and extracellular proteolysis. HT markedly reduced the reactive expression of GFAP in Müller cells and improved the morphology of astrocytes in the avascular region of the retina. Exogenous VEGF administered into the vitreous on P14 was not sufficient to cause vitreous neovascularization in the HT mice. Injection of the VEGF antagonist VEGFR1/Fc blocked both pathologic and physiological angiogenesis and did not rescue astrocytes.
  
  
  CONCLUSIONS
  HT may be clinically useful to facilitate vascular repair while blocking neovascularization in the pre-proliferative stage of ischemic retinopathy by correcting a broad range of biochemical and cellular abnormalities.
authors.affiliation: Vascular Biology Center, Georgia Health Sciences University, Augusta, Georgia 30912-2500, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.forename: Harumasa
authors.initials: H
authors.lastname: Yokota
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xu
authors.forename: Subhadra P
authors.initials: SP
authors.lastname: Narayanan
authors.forename: Lauren
authors.initials: L
authors.lastname: Yancey
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Yoshida
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Marcus
authors.forename: Robert W
authors.initials: RW
authors.lastname: Caldwell
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.forename: Steven E
authors.initials: SE
authors.lastname: Brooks
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D058449:Intravitreal Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism; D010100:Oxygen / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D015861:Retinal Neovascularization / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000502:physiology*; D012178:Retinopathy of Prematurity / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000008:administration & dosage
chemical_list: D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D010100:Oxygen