title: A murine model for retinopathy of prematurity identifies endothelial cell proliferation as a potential mechanism for plus disease.
abstract: OBJECTIVE
  To characterize the features and possible mechanism of plus disease in the mouse oxygen-induced retinopathy (OIR) model for retinopathy of prematurity.
  
  
  METHODS
  Wild-type and Adam (A Disintegrin And Metalloproteinase) knockout mice were exposed to 75% oxygen from postnatal day 7 to 12 (P7 to P12) (hyperoxia), then returned to normal air (relative hypoxia). Live fundus imaging and fluorescein angiography at P17 were compared to immunofluorescence analysis of flat-mounted retinas. Two hallmarks of plus disease, arterial tortuosity and venous dilation, were analyzed on fixed retinas (P12-P17). The length of tortuous vessels was compared to a straight line between two points; the diameter of retinal vessels was determined using ImageJ software, and bromo-deoxyuridine (BrdU) labeling was used to visualize proliferation of retinal vascular cells.
  
  
  RESULTS
  Mice developed retinal arterial tortuosity and venous dilation after exposure to OIR, which was visible in live fundus images and fixed whole-mounted retinas. Vein dilation, arterial tortuosity, and BrdU incorporation gradually increased over time. Moreover, Adam8(-/-) and Adam9(-/-) mice and mice lacking Adam10 in endothelial cells were partially protected from plus disease compared to controls.
  
  
  CONCLUSIONS
  The mouse OIR model can be used to study the pathogenesis of plus disease and identify potential therapeutic targets. The severity of plus disease increases over time following OIR and correlates with increased proliferation of endothelial cells, suggesting that proliferation of vascular cells may be a mechanism underlying the development of plus disease. Moreover, our findings suggest that ADAMs 8, 9, and 10 could be targets for treatment of plus disease.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Guaiquil
authors.forename: Nina J
authors.initials: NJ
authors.lastname: Hewing
authors.forename: Michael F
authors.initials: MF
authors.lastname: Chiang
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rosenblatt
authors.forename: R V Paul
authors.initials: RV
authors.lastname: Chan
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000068258:Bevacizumab; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D058449:Intravitreal Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000633:toxicity; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D010100:Oxygen
keywords: oxygen-induced retinopathy; plus disease; retinopathy of prematurity