Inducible nitric oxide synthase and vascular endothelial growth factor are colocalized in the retinas of human subjects with diabetes

El-Asrar, A M Abu; Meersschaert, A; Dralands, L; Missotten, Luc; Geboes, Karel

doi:10.1038/sj.eye.6700642

Cited by 47 publications

(32 citation statements)

References 36 publications

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“…In some studies, iNOS has been detected in retinal capillary endothelial cells in hyperglycaemia [6,40], whereas others have not detected it [4,5,43]. iNOS-mediated degeneration of retinal capillaries in diabetes is probably not initiated in capillary pericytes, since high glucose has been reported to decrease iNOS expression in retinal pericytes [44].…”

Section: Discussionmentioning

confidence: 99%

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

et al. 2007

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Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the early stages of diabetic retinopathy using iNOS-deficient mice (iNos −/− ). Materials and methods iNos −/− mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities. Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide synthase, prostaglandin E 2 , superoxide and leucostasis were significantly (p<0.05) increased in retinas of WT mice diabetic for 2 months compared with nondiabetic WT mice. All of these abnormalities except PARmodified proteins in retinas were inhibited (p<0.05) in diabetic iNos −/− mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic for 9 months compared with nondiabetic WT controls, these increases being significantly inhibited in diabetic iNos −/− mice (p<0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas diabetic iNos −/− mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos −/− mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram.Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic of the early stages of diabetic retinopathy in mice.

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Section: Discussionmentioning

confidence: 99%

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

et al. 2007

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“…10) (El-Remessy, 2003a;Graier et al, 1999;Graier et al, 1997;Graier et al, 1996) resulting in peroxynitrite formation. Research demonstrating increased levels of the peroxynitrite biomarker nitrotyrosine in retinas of diabetic patients and experimental animal models supports this concept and implies a role for peroxynitrite in the development of diabetic complications (Abu El-Asrar et al, 2004;Du et al, 2002;ElRemessy, 2003b;Kowluru and Odenbach, 2004;Obrosova et al, 2005). Studies in animal and tissue culture models have demonstrated that increased peroxynitrite formation is directly correlated with diabetes, high glucose-induced VEGF expression, and increased retinal vascular permeability (El-Remessy, 2003a;El-Remessy, 2003b;El-Remessy et al, 2006;El-Remessy et al, 2005).…”

Section: Oxidative Stress and Diabetic Retinopathymentioning

confidence: 94%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…Retinal glial cells up-regulate VEGF and down-regulate PEDF under hypoxic and diabetic conditions [8,9,10]. However, the role of glial cells in promoting retinal neovascularization is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Thrombospondin-1 Is Produced by Retinal Glial Cells and Inhibits the Growth of Vascular Endothelial Cells

Yafai¹,

Eichler²,

Iandiev³

et al. 2014

Ophthalmic Res

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Background/Aims: By the release of antiangiogenic factors, Müller glial cells provide an angiostatic environment in the normal and ischemic retina. We determined whether Müller cells produce thrombospondin-1 (TSP-1), a known inhibitor of angiogenesis. Methods: Secretion of TSP-1 by cultured Müller cells was determined with ELISA. Slices of rat retinas and surgically excised retinal membranes of human subjects were immunostained against TSP-1 and the glial marker vimentin. The effects of TSP-1 on the growth of bovine retinal endothelial cells (BRECs) and activation of ERK1/2 were determined with DNA synthesis and migration assays, and Western blotting, respectively. Results: Cultured Müller cells secrete TSP-1 under normoxic and hypoxic (0.2% O₂) conditions. Secretion of TSP-1 was increased in hypoxia compared to normoxia. In rat retinal slices, glial, retinal ganglion, and possibly horizontal cells were stained for TSP-1. Retinal glial cells in preretinal membranes from human subjects with nonhypoxic epiretinal gliosis (macular pucker) and proliferative diabetic retinopathy, respectively, were immunopositive for TSP-1. Exogenous TSP-1 reduced the VEGF-induced proliferation and migration of BRECs and decreased the phosphorylation level of ERK1/2 in BRECs. Conclusion: The data suggest that Müller cells are one major source of TSP-1 in the normal and ischemic retina. Glia-derived TSP1 may inhibit angiogenic responses in the ischemic retina.

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Inducible nitric oxide synthase and vascular endothelial growth factor are colocalized in the retinas of human subjects with diabetes

Cited by 47 publications

References 36 publications

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

Vascular endothelial growth factor in eye disease

Thrombospondin-1 Is Produced by Retinal Glial Cells and Inhibits the Growth of Vascular Endothelial Cells

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