Inflammation that follows tissue injury is believed to be important in the initiation and progression of various diseases including retinopathy, cancer and atherosclerosis. Phospholipase A2s (PLA2s), a group of enzymes that break down phospholipids generating arachidonic acid and lysophospholipids have been implicated in inflammation. 1 of the major events underlying the progression of proliferative retinopathy is angiogenesis. Endothelial cell (EC) migration and proliferation are critical events in angiogenesis. Emerging evidence suggests that PLA2, arachidonic acid and its eicosanoid metabolites play a role in the regulation of cell migration, proliferation, and apoptosis. In addition, recent investigations using nonsteroidal anti- inflammatory drugs reveal a potential role for eicosanoids in angiogenesis. Based on this knowledge, we hypothesize that eicosanoids, particularly the lipoxygenase/monooxygenase metabolites of arachidonic acid, play an important role in angiogenesis and thereby in the pathogenesis of retinopathy. To test the role of eicosanoids in angiogenesis we will address the following 4 specific aims: 1) To identify eicosanoids produced in retinal endothelial cells and determine their effects on angiogenesis using in vitro and in vivo models. 2) To determine the effects of angiogenic eicosanoids on EC migration and proliferation. 3) To test the role of the Jak/STAT and PI3K/Akt pathways in angiogenic eicosanoid-induced EC migration and proliferation. 4) To identify the effector molecules of eicosanoid-induced angiogenesis and study the mechanisms underlying their regulation of expression in EC and retinal pigmentary epithelial cells. The results of this proposal will provide novel information on the identification of specific angiogenic eicosanoids and on elucidation of the underlying mechanisms by which these lipid molecules stimulate angiogenesis. Such knowledge, in turn, could be useful in developing therapeutics in the prevention of progression of diseases such as proliferative retinopathy. ? ?
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