The development of the rat model of retinopathy of prematurity

Abstract

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting premature infants. ROP is characterized by pathological ocular angiogenesis or retinal neovascularization (NV). Models of ROP have yielded much of what is currently known about physiological and pathological blood vessel growth in the retina. The rat provides a particularly attractive and cost effective model of ROP. The rat model of ROP consistently produces a robust pattern of NV, similar to that seen in humans. This model has been used to study gross aspects of angiogenesis. More recently, it has been used to identify and therapeutically target specific genes and molecular mechanisms involved in the angiogenic cascade. As angiogenesis occurs as a complication of many diseases, knowledge gained from these studies has the potential to impact nonocular angiogenic conditions. This article provides historical perspective on the development and use of the rat model of ROP. Key findings generated through the use of this model are also summarized.

Fig. 1

This schematic illustrates the oxygen exposure protocol used by Penn et al. to compare the initial 40/80% treatment paradigm and the current 50/10% treatment regimen. The litters were placed in incubators within 4 h after birth and the oxygen level was adjusted every 24 h thereafter. After 14 days of variable oxygen, the rats were returned to room air to allow NV to occur. Rats were killed on day 18 and NV severity was assessed [45]

Fig. 2

FITC-dextran infused rat retinas at P20. Exposing rats to the 50/10% model retards the development of the retinal vasculature. Room air-raised rats (a) exhibit normal retinal vascular development. 50/10% rats (b) demonstrate reduced vascular development, which leads to the development of NV. Image reproduced with permission from Springer Publishing Co. [74]

Fig. 3

This figure demonstrates that ΔFiO₂ is related to NV susceptibility. The top graph illustrates that the ΔFiO₂ must be at least 0.2 for NV to develop. All animals with ΔFiO₂ ≥ 0.3 developed NV. The bottom graph illustrates the importance of the extent of hypoxia during hypoxic episodes. For NV to develop, hypoxic episodes must be ≤12.5% oxygen. Image reproduced with permission from Investigative Ophthalmology and Visual Sciences [75]

Fig. 4

Retinal NV produced by the 50/10% rat model mimics human pathology. Retinal NV occurs at the boundary between the vascular central retina and the avascular peripheral retina, at the advancing edge of new vessel growth. Image reproduced with permission from Investigative Ophthalmology and Visual Sciences [75]