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A. Das, G. Menicucci, S. Giebel, E. Colombo, P. McGuire; Plasminogen Activator Inhibitor–1(PAI–1) in Early Diabetic Retinopathy and Retinal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2367.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The serine proteinase urokinase (uPA), its receptor uPAR and the inhibitor PAI–1 together play important roles in the regulation of cell migration, matrix remodeling and fibrinolysis. Previous studies in our laboratory have demonstrated an upregulation of uPA and uPAR in the retina from animals with early diabetic retinopathy and retinal neovascularization. Elevated levels of PAI–1 have been reported in the serum of diabetic patients. The purpose of these studies was to examine the expression of the serine proteinase inhibitor PAI–1 in an animal model of early diabetic retinopathy and retinal neovascularization. Methods:Retinal NV was induced in mice by exposure to 75% oxygen on postnatal days 7–12 followed by exposure to room air on days 12–17. The expression of PAI–1 in the retina of experimental animals at days 12, 15 and 17 was analyzed by real–time RT–PCR and compared to room air controls. Diabetes was induced in eight–week old Sprague Dawley rats by streptozotocin injection (60mg/kg). After 12 weeks of diabetes the retinas of both the diabetic and non–diabetic rats were analyzed for PAI–1 levels by real–time RT–PCR. Results:The expression of PAI–1 is significantly increased in mice with developing retinal neovascularization. PAI–I mRNA is increased nearly 12 fold in the retina of experimental mice at day 12, the beginning of neovascularization. On days 15 and 17, the period of active angiogenesis, the PAI–1 level is 5 fold higher compared to controls of the same age. At the end of the angiogenic period, prior to the beginning of vascular regression in this model, the PAI–1 mRNA level decreases significantly (1.6 fold higher than controls). A similar increase in PAI–1 mRNA (5.74 fold higher than the non–diabetic) was seen in the retina of diabetic rats exhibiting increased vascular permeability. Conclusions:All of the components of the uPA, uPAR, PAI–1 system are upregulated in both early diabetes and active retinal neovascularization. Increased cell motility is a feature of the angiogenic process. High levels of PAI–1 are associated with increased cell motility through the regulation of cell/matrix interactions. High levels of PAI–1 in the diabetic retina may play a role in creating an environment conducive to the development of new vessels occuring in the later stages of diabetes. PAI–1 may thus be an important target molecule for pharmacological intervention in diabetic retinopathy.
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