Plasminogen activator inhibitor (PAI)-1 overexpression in retinal microvessels of PAT-1 transgenic mice

PURPOSE. Previous studies have suggested that disturbances in plasminogen a ctivator inhibitor (PAI)-1 may be relevant to the development of diabetic m icrovascular complications. To determine whether overexpression of PAI-1 in cells of retinal microvasculature would result in a disease similar to tha t observed in diabetes, ocular tissue from transgenic mice that overexpress human PAI-1 were examined. METHODS. Transgenic mice were administered ZnSO4 (25 mM) in their water for up to 49 weeks to activate the metallothionein promoter and stimulate huma n PAI-1. Colloidal gold immunocytochemistry was used to quantify the human PAI-1 antigen at 7, 20, 34, and 49 weeks of ZnSO4 administration. Cross sec tions of retinal microvessels were examined by electron microscopy for chan ges in basement membrane (BM) thickness. Retinal digest preparations were e xamined by light microscopy for possible microangiopathy, including changes in endothelial cell-to-pericyte ratios. RESULTS. Human PAI-1 immunoreactivity was detected throughout the retinal c apillaries of transgenic mice receiving zinc and increased significantly (P < 0.001) after 20 to 49 weeks of ZnSO4 administration compared with age-ma tched transgenic control mice. At 20 and 49 weeks, retinal capillaries of t ransgenic mice that received zinc showed significantly thickened BMs compar ed with control animals (P < 0.001). Moreover, wholemounts of the retinal v asculature from PAI-1 transgenic mice demonstrated an increased endothelial cell-to-pericyte ratio. CONCLUSIONS. PAI-1 overexpression in retinal microvasculature leads to reti nal disease similar to that observed in diabetic retinopathy.