Plasminogen Activator Inhibitor-1 (PAI-1) Facilitates Retinal Angiogenesis in a Model of Oxygen-Induced Retinopathy

PURPOSE. Angiogenesis, or the formation of new retinal blood vessels, is a key feature of many proliferative retinal diseases including diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. The aim of the present study was to investigate the role of the serine proteinase inhibitor plasminogen activator inhibitor-1 (PAI-1) in facilitating retinal angiogenesis. METHODS. The temporal expression of PAI-1 was examined by real-time PCR, Western blot analysis, and immunohistochemistry in retinal tissues from mice with oxygen-induced retinopathy. The requirement for PAI-1 in facilitating the retinal angiogenic response in this model was examined by quantitating the angiogenic response with wild-type and PAI-1 null mice. The mechanism by which PAI-1 mediates angiogenesis was further investigated with isolated human retinal vascular endothelial cells. RESULTS. PAI-1 expression was upregulated in the retinas of mice with oxygen-induced retinopathy, which coincided with a significant increase in the expression of vitronectin in the retina of the experimental mice. There was significant reduction in the angiogenic response of PAI-1(-/-) mice compared with wild-type mice. PAI-1 promotes endothelial cell migration in vitro and facilitates the migration of cells on a vitronectin substrate by regulating alpha v integrin cell surface expression. CONCLUSIONS. These observations suggest a role for PAI-1 during retinal angiogenesis and point to a potential new therapeutic target in the prevention or treatment of retinal neovascularization seen in many ocular diseases. (Invest Ophthalmol Vis Sci. 2009; 50: 4974-4981) DOI: 10.1167/iovs.09-3619