hyperglycemia, PDGF-B-deficient mice developed aggravated retinopathy, including high numbers of acellular capillaries and the formation of microaneurysms (149).

Oxygen-Induced Retinopathy

Probably the most utilized animal model of preretinal neovascularization is the oxygen-induced retinopathy (OIR) model (150). In this model, exposure of neonatal animals to elevated concentrations of oxygen impairs development of the normal retinal vasculature and causes regression of many existing vessels. After removal from the high oxygen environment, the lack of retinal blood vessels results in profound retinal ischemia and neovascularization. The neovascularization in this model differs from diabetic retinopathy in that the neovascularization in the OIR model occurs acutely in a retina that is not fully differentiated, as compared to the progressive capillary obliteration that develops in the fully differentiated retina in diabetes.

Sympathectomy

Several retinal lesions consistent with diabetic retinopathy also have been detected after sympathectomy in rats (151). Experimental elimination of sympathetic innervation to the eye resulted in increases in expression of basement membrane proteins, capillary basement membrane thickness, and glial fibrillary acidic protein (GFAP) staining, and reduced number of capillary pericytes (151, 152). There was a significant reduction in photoreceptor numbers due to apoptosis and changes of choroidal vascularity in the sympathectomized eye (153).

Retinal Ischemia–Reperfusion

Ischemia and reperfusion injury to the retina has been known for many years to cause degeneration of retinal neurons. Subsequent to the neuronal injury, however, retinal capillaries also begin to degenerate, a fact that was only recently demonstrated (154). The capillary degeneration is morphologically similar to that which develops in diabetes, but occurs over a period of only days (instead of months to years in diabetes). Aminoguanidine, a nonspecific inhibitor of iNOS, inhibited the degeneration of both neuronal and vascular cells of the retina. This study raises a possibility that damage to the neural retina contributes to capillary degeneration, and perhaps does so also in diabetes.

AREN’T THERE ANY “GOOD” MODELS OF DIABETIC

RETINOPATHY?

Some have claimed that there are no “good” or “appropriate” animal models of diabetic retinopathy because diabetic animal models have failed to reproduce the advanced (neovascular) stages of diabetic retinopathy. The statement that animal models have not developed the advanced lesions of diabetic retinopathy seems accurate, but is that because the animals do not live long enough, or because the animals lack some critical biochemical feature that would allow the neovascular response? Moreover, some diabetic

150 Kern

or galactosemic animals have been demonstrated to develop intraretinal vessel structures that are characteristic of endothelial proliferation or intraretinal neovascularization after prolonged study (15, 115, 155).

A critical component of diabetic retinopathy that is commonly overlooked is duration of diabetes. Vaso-obliteration and subsequent retinal ischemia are believed to be major causes of neovascularization in the retina, and one likely reason that the diabetic models have not developed preretinal neovascularization is that much less retinal vaso-obliteration develops during the short duration of diabetes that the animal models are studied (as compared to the more extensive vaso-obliteration that develops over many years in diabetic patients). Efforts to reduce the length of research studies, usually by using models that develop complications “faster,” likely will not provide much insight into how the early stages of diabetic retinopathy progress to the neovascular stages in humans, and why animals seem not to duplicate this. On the other hand, identifying causes of capillary obliteration in diabetes, and using models where those processes are especially accelerated are likely to provide a perspective that is directly relevant to understanding and developing therapies to inhibit the progression of diabetic retinopathy.

SUMMARY

Animal models of diabetic retinopathy have provided a wealth of information pertaining to biochemical, physiological, and histopathologic abnormalities that contribute to the development of diabetic retinopathy, and additional insight from the models can be expected to continue. Nevertheless, the advantages and deficiencies of the various models need to be recognized in order to utilize them to their fullest potential. The early stages of diabetic retinopathy have been found to develop in essentially all species studied who have had diabetes for sufficiently long durations. It does seem that animal models develop at least the early stages of the retinopathy faster than what occurs in diabetic humans (rodents < dogs and cats < humans and nonhuman primates). Rats and genetically modified mice are likely to remain the most utilized models to study the pathogenesis of the retinopathy and in efforts to develop pharmacological therapies to inhibit it. There remains considerable value, however, in the use also of larger animals as models of diabetic retinopathy, since the rate at which the retinopathy develops, the life span of the animals, and the size of eye are more comparable in large animals to that of humans. Only primates have the macula, an important site of damage in diabetic retinopathy.

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