A Murine Model for Retinopathy of Prematurity Identifies Endothelial Cell Proliferation as a Potential Mechanism for Plus Disease

Abstract

Citation: Guaiquil VH, Hewing NJ, Chiang MF, Rosenblatt MI, Chan RVP, Blobel CP. A murine model for retinopathy of prematurity identifies endothelial cell proliferation as a potential mechanism for plus disease. Invest Ophthalmol Vis Sci. 2013;54:5294-5302. DOI:10.1167/ iovs.12-11492 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 À/À and Adam9 À/À 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.

Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF‐1α‐VEGF pathway in oxygen‐induced retinopathy mice

“…However, it is the hyperoxic condition that leads to the appearance of avascular areas in the retinas of OIR. As the mice in control group have not undergone a hyperoxic period, there is no obvious avascular area in the retinas of normal mice …”

“…As the mice in control group have not undergone a hyperoxic period, there is no obvious avascular area in the retinas of normal mice. 55 Microglia cells are resident immunocompetent cells in central nerve system (CNS), 15,50 and retina is the extension of the CNS. Under the physiologic condition, local microglia have a vital role in organized blood vessel formation.…”

Oxygen-Induced Retinopathy and Choroidopathy: In Vivo Longitudinal Observation of Vascular Changes Using OCTA

“…The venous dilation and the arterial tortuosity were observed in the OIR eyes at P15, which support the previous studies. 11,32 The vascular development in superficial and deep plexuses of the OIR retina was also investigated. The vessel densities measured by OCTA revealed that there was no significant change in the development of superficial vascular plexus between the control and the OIR groups.…”

The Eyes Absent Proteins in Developmental and Pathological Angiogenesis

“…22 To determine whether EYA inhibitors had an effect on proliferation, we measured incorporation of the nucleotide analog BrdU. Low levels of BrdU incorporation were detected in control vehicle-treated OIR retinas in the proliferative phase (measured here at P14), with a 60% decrease in either the BZ-or BBR-treated retinas ( Figure 4D).…”