148 Kern

experimental galactosemia has been shown to cause diabetic-like retinal lesions also in rats (30, 37, 50, 120–123) and mice (52, 124). The galactose-retinopathy model was utilized extensively for studies of the role of aldose reductase in the pathogenesis of dia- betic-like retinopathy (12, 30, 111–123), but numerous other biochemical sequelae of hyperglycemia including nonenzymatic glycation, protein kinase C activity, and oxidative stress (125–133) also occur in galactosemia. The galactose-fed model has been used also in studies of the role of leukostasis and interleukin-1β in the development of retinopathy (52, 94), and the abilities of aminoguanidine, antioxidants, minocycline, and antisense against fibronectin and other basement membrane components to inhibit the retinopathy (37, 50, 94, 134, 135).

Experimental galactosemia can be an easy model of diabetic-like pathology, and the animals require less nursing care than experimental diabetes. Not to be overlooked, however, is the expense of the galactose diet, which can be costly if animals are large or numerous. Moreover, the pathogenesis of galactose-induced retinopathy seems to differ from that of diabetic retinopathy in some manner, since aminoguanidine inhibits the retinal microvascular disease in diabetic rats (19, 50, 82, 83) but not in galactose-fed rats (50, 136), and caspases activated in diabetic mice differ from those induced in galactose-fed mice (137).

Nondiabetic Models in Which Growth Factors are Altered

VEGF overexpression

Vascular endothelial growth factor 165 was injected into the eyes of normal cynomolgus monkeys, and as a result, capillaries became nonperfused, dilated, and tortuous (138). Preretinal neovascularization was observed throughout peripheral retina, but not in the posterior pole. Arterioles demonstrated endothelial cell hyperplasia and microaneurysmal dilations. Overexpression of VEGF in retinal photoreceptors results in neovascularization, demonstrating the role of the growth factor in the neovascular response (139–144). This neovascular response, however, differs from that in diabetic retinopathy in that the abnormal blood vessel growth is toward the photoreceptors (the source of overexpressed VEGF), rather than toward the inner retina and vitreous.

IGF overexpression

Nondiabetic mice overexpressing IGF-1 in the retina developed several vascular alterations characteristic of diabetic retinopathy, including nonproliferative lesions (pericyte loss, thickened capillary basement membrane, intraretinal microvascular abnormalities), proliferative retinopathy, and retinal detachment (145). Likewise, injection of a single dose of hrIGF-1 into the vitreous cavity of pigs resulted in an angiopathy that included increased endothelial density, basement membrane thickening, vascular leakage, and microaneurysms (146).

PDGF-B-deficient mice

PDGF (platelet-derived growth factor-B) has major effects on pericyte activation, survival, and growth (147). Mice with a genetic ablation of PDGF-B exhibit several vascular phenotypes characteristic of diabetic retinopathy, including a reduction in the number of pericytes and increase in the numbers of acellular capillaries (148). In chronic