title: Vascular dysfunction in retinopathy-an emerging role for arginase.
abstract: Retinal neovascularization is a leading cause of visual disability. Retinal diseases involving neovascularization all follow the same progression, beginning with vascular inflammatory reactions and injury of the vascular endothelium and ending with neovascularization, fibrosis and retinal detachment. Understanding the mechanisms underlying this process is critical for its prevention and treatment. Research using retinopathy models has revealed that the NOX2 NADPH oxidase has a key role in inducing production of reactive oxygen species and angiogenic cytokines and causing vascular inflammatory reactions and neovascularization. This prospective review addresses the potential role of the urea/ornithine pathway enzyme arginase in this process. Studies of peripheral vessels isolated from diabetic animals have shown that increased arginase activity causes vascular endothelial cell dysfunction by decreasing availability of l-arginine to endothelial cell nitric oxide synthase which decreases nitric oxide bioavailability and increases oxidative stress. Increasing arginase activity also increases formation of polyamines and proline, which can induce cell growth and fibrosis. Studies in models of retinopathy show that increases in oxidative stress and signs of vascular inflammation are correlated with increases in arginase activity and arginase 1 expression and that decreasing arginase expression or inhibiting its activity blocks these effects. Furthermore, the induction of arginase during retinopathy is blocked by knocking out NOX2 or inhibiting NADPH oxidase activity. These observations suggest that NADPH oxidase-induced activation of the arginase pathway has a key role in causing retinal vascular dysfunction during retinopathy. Limiting the actions of arginase could provide a new strategy for treating this potentially blinding condition.
authors.affiliation: Vascular Biology Center, Department of Cellular Biology and Anatomy, VA Medical Center, Augusta, GA 30912, USA. rcaldwel@mail.mcg.edu
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.forename: Maritza J
authors.initials: MJ
authors.lastname: Romero
authors.forename: R William
authors.initials: RW
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015861:Retinal Neovascularization / Q000473:pathology* / Q000503:physiopathology; D012171:Retinal Vessels / Q000201:enzymology*
chemical_list: D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase; D001119:Arginase