Targeting VEGF in canine oxygen-induced retinopathy – a model for human retinopathy of prematurity

Abstract

Development of the dog superficial retinal vasculature is similar to the mechanism of human retinal vasculature development; they both develop by vasculogenesis, differentiation, and assembly of vascular precursors called angioblasts. Canine oxygen-induced retinopathy (OIR) was first developed by Arnall Patz in an effort to experimentally determine the effects of hyperoxia on the development of the retinal vasculature. The canine OIR model has many characteristics in common with human retinopathy of prematurity. Exposure of 1-day-old dogs to hyperoxia for 4 days causes a vaso-obliteration throughout the retina. Vasoproliferation, after the animals have returned to room air, is robust. The initial small preretinal neovascular formations anastomose to form large preretinal membranes that eventually cause tractional retinal folds. The end-stage pathology of the canine model is similar to stage IV human retinopathy of prematurity. Therefore, canine OIR is an excellent forum to evaluate the response to drugs targeting VEGF and its receptors. Evaluation of an antibody to VEGF-R2 and the VEGF-Trap demonstrated that doses should be titered down so that preretinal neovascularization is inhibited but retinal revascularization is able to proceed, vascularizing peripheral retina and preventing it from being a source of VEGF.

Keywords:

• angioblasts
• blood vessels
• endothelial cells
• oxygen
• retinopathy
• retina
• vascular endothelial cell growth factor

Acknowledgments

This study was supported by NIH grants RO1-EY09357 (GAL) and EY001765 (Wilmer Ophthalmological Institute CORE grant) and unrestricted funds from Research to Prevent Blindness (unrestricted funds to Wilmer). The Johns Hopkins School of Medicine Institutional Animal Care and Use Committee provided Ethics approval and also approved the use of dogs for this study in accordance with the guidelines of the Association for Research in Vision and Ophthalmology on use of laboratory animals.

Disclosure

The authors report no other conflict of interest in this work.