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 to 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. Vascular inflammatory reactions and ischemic retinopathyCellular inflammation at the blood-microvascular endothelial cell interface is a common feature of retinal diseases characterized by hyperpermeablity and neovascularization. Recent studies in models of ischemic retinopathy suggest that inflammatory reactions play a key role in initiating vascular injury and dysfunction. [2,28,53,98] Various chemokines and cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, vascular endothelial cell growth factor (VEGF) and monocyte chemotactic protein (MCP)-1 are upregulated in ischemic retinopathy and have been reported to cause pathologic inflammatory reactions [47,49,50,54, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Confl...

Diabetes-induced vascular dysfunction involves arginase I

“…This fibrotic process appears to be caused by an elevation of arginase activity, which increases the production of ornithine and the subsequent production of pyrroline-5-carboxylate and proline, a precursor of collagen. Preventing the elevation of arginase activity or expression prevents the vascular fibrotic response and preserves vascular compliance (1,7).…”

Nitric oxide synthase derangements and hypertension in kidney disease

“…For example superoxide reacts with and inactivates NO and also oxidises tetrahydrobiopterin which is essential for NOS activity and converts the NOS to superoxide generators [36], thus creating a vicious cycle. Also, oxidative stress leads to inflammation which leads to arginase induction which may also reduce arginine, and thence NO, availability [36,38,39]. …”

Anti-Inflammatory Therapy for Diabetic Retinopathy

“…Studies indicate that NO has a biphasic role in vascular and inflammatory diseases depending on the specific source and the amount produced [105]. The constitutively expressed NOSs, endothelial NOS (eNOS) and neuronal NOS (nNOS), are Ca2+-dependent and regulated to produce low levels of NO.…”