TY - JOUR
T1 - A murine model for retinopathy of prematurity identifies endothelial cell proliferation as a potential mechanism for plus disease
AU - Guaiquil, Victor H.
AU - Hewing, Nina J.
AU - Chiang, Michael F.
AU - Rosenblatt, Mark I.
AU - Chan, R. V.Paul
AU - Blobel, Carl P.
PY - 2013
Y1 - 2013
N2 - PURPOSE. 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. 2013 The Association for Research in Vision and Ophthalmology, Inc.
AB - PURPOSE. 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. 2013 The Association for Research in Vision and Ophthalmology, Inc.
KW - Oxygen-induced retinopathy
KW - Plus disease
KW - Retinopathy of prematurity
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U2 - 10.1167/iovs.12-11492
DO - 10.1167/iovs.12-11492
M3 - Article
C2 - 23833070
AN - SCOPUS:84881520969
SN - 0146-0404
VL - 54
SP - 5294
EP - 5302
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 8
ER -