Our results also have clinical implications. Tissue hypoxia and/or neural loss occurs in retinal diseases, such as diabetic retinopathy, ROP, retinal detachment, age-related macular degeneration, glaucoma, and tumor growth, and adversely affects quality of life.
69 70 71 Although oxygen deprivation is an early stimulus for neovascularization and cell injury, the molecular signals for the pathologic development of new vessels and neuronal cell death are not fully defined. Induction of angiogenic factors and extracellular matrix degradation stimulate angiogenesis and cell injury.
72 73 Whereas VEGF and MMP-2 and -9 are important in choroidal and retinal neovascularization, and in RGC death,
27 53 74 prevention of angiogenesis and retinal cell death are associated with increases of antiangiogenic and neurotrophic factors—one being PEDF, the principal antiangiogenic and neurotrophic protein of the eye.
1 2 3 Evidence that supports a role of MMPs in modulating the activities of PEDF in the eye is increasing.
53 In diabetic retinopathy and ROP animal models, the ischemic retina has upregulated MMP-2 and -9 and lower levels of PEDF compared with physiological conditions.
15 18 53 MMP-2 and PEDF are present in the interphotoreceptor matrix, and while the interphotoreceptor matrix MMP-2 (gelatinase A) increases with age-related macular degeneration, there is a decrease in retinal PEDF levels associated with this disease.
25 75 Inhibitors of MMPs decrease retinal neovascularization in ROP mouse models
66 and are being clinically tested as novel therapies for age-related macular degeneration, predicting an increase in PEDF.
76 The fact that in MMP-9-null mice the RGCs do not die when injured by ischemia
28 would point to an increase in PEDF levels in the RGC layer due to lack of PEDF degradation by the ablated MMP-9. A decrease in retinal angiogenesis is identified in MMP-2-null mice,
77 consistent with the involvement of MMP-2 in degrading PEDF in retinal neovascularization. In double MMP-2- and -9-null mice,
27 and in wild-type mice treated with gelatinase specific inhibitors, choroidal neovascularization is inhibited, again consistent with decreased degradation of the antiangiogenic PEDF. Evidence also exits for photoreceptor cell death induced by hypoxia at early developmental stages
78 and suggests that MMPs induced by hypoxia degrade PEDF, a survival factor for photoreceptors. Thus, inhibition of PEDF degradation would be beneficial for the treatment of different forms of vascular and neuronal ocular diseases, and direct administration of PEDF could be more effective if accompanied by MMP inhibitors.