Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy

Boehm, Bernhard O.; Volpert, Olga V.; Jehle, Peter; Kurkhaus, A.; Rosinger, Silke; Lang, Gerhard K.; Bouck, Noël

doi:10.1007/s00125-003-1040-9

Cited by 132 publications

(86 citation statements)

References 34 publications

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“…Parallel actions of high glucose and oxidative stress might inhibit the production of proteins that normally inhibit VEGF expression, enhancing this autocrine process. This hypothesis is supported by studies showing that decreased levels of endostatin and PEDF are correlated with increased VEGF levels in patients with diabetic retinopathy (Boehm et al, 2003;Funatsu et al, 2003) and that treatment with endostatin or PEDF can reduce VEGF-or AGE-induced retinal vascular permeability in vivo Yamagishi et al, 2006).…”

Section: Vegf Alternative Splicing-it Has Been Suggested That the Difmentioning

confidence: 77%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

615

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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Section: Vegf Alternative Splicing-it Has Been Suggested That the Difmentioning

confidence: 77%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

615

527

View full text Add to dashboard Cite

show abstract

“…We reported recently that PEDF is a potent endogenous anti-inflammatory factor (Zhang et al 2006). Decreased intraocular PEDF levels have been observed in patients with diabetic retinopathy and in animal models of type 1 diabetes and spontaneous uveitis (Boehm et al 2003, Zhang et al 2006, Hauck et al 2007. Administration of PEDF into the vitreous significantly inhibits leukostasis and reduces vascular permeability in the retina in STZ-induced diabetic rats, suggesting a potential role of PEDF on leukocyte/ monocyte activation and infiltration in diabetic retinopathy (Yamagishi et al 2006, Zhang et al 2006.…”

Section: Discussionmentioning

confidence: 98%

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Zhang¹,

Wang²,

Dashti³

et al. 2008

Journal of Molecular Endocrinology

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Oxidized and/or glycated low-density lipoprotein (LDL) may mediate capillary injury in diabetic retinopathy. The mechanisms may involve pro-inflammatory and pro-oxidant effects on retinal capillary pericytes. In this study, these effects, and the protective effects of pigment epithelium-derived factor (PEDF), were defined in a primary human pericyte model. Human retinal pericytes were exposed to 100 mg/ml native LDL (N-LDL) or heavily oxidized glycated LDL (HOG-LDL) with or without PEDF at 10-160 nM for 24 h. To assess pro-inflammatory effects, monocyte chemoattractant protein-1 (MCP-1) secretion was measured by ELISA, and nuclear factor-kB (NF-kB) activation was detected by immunocytochemistry. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS), peroxynitrite (ONOO K ) formation, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) production. The results showed that MCP-1 was significantly increased by HOG-LDL, and the effect was attenuated by PEDF in a dose-dependent manner. PEDF also attenuated the HOG-LDL-induced NF-kB activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-kB activation. Further studies demonstrated that HOG-LDL, but not N-LDL, significantly increased ONOO K formation, NO production, and iNOS expression. These changes were also alleviated by PEDF. Moreover, PEDF significantly ameliorated HOG-LDL-induced ROS generation through up-regulation of superoxide dismutase 1 expression. Taken together, these results demonstrate proinflammatory and pro-oxidant effects of HOG-LDL on retinal pericytes, which were effectively ameliorated by PEDF. Suppressing MCP-1 production and thus inhibiting macrophage recruitment may represent a new mechanism for the salutary effect of PEDF in diabetic retinopathy and warrants more studies in future.

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“…39 Among diabetic patients with no or mild retinopathy, those with decreased levels of PEDF in aqueous humor collected at cataract surgery developed progressive retinopathy at increased rates by the time of follow-up compared to nonprogressors and control patients. 40 Overall, genetic influences on the expression of angiogenic inhibitors may have more pronounced effects on angiogenic heterogeneity than variations in expression levels of proangiogenic growth factors.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Chan

Pham

Zhou

et al. 2005

Laboratory Investigation

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Clinical observations suggest that genetic factors may influence heterogeneity of angiogenic responses in cardiovascular disease, proliferative diabetic retinopathy, and neoplasia. Experiments among mouse strains using a corneal micropocket assay indicate that extent of angiogenesis may be genetically determined. Here, we established the strain-dependence of hypoxia-induced retinal angiogenesis in multiple mouse strains which paralleled the rank order found for bFGF-induced corneal angiogenesis. Using quantitative real-time RT-PCR, strain-related gene expression differences in retina/choroid between C57BL/6J and 129S3/SvIM, inbred strains with relatively low and high levels of angiogenesis, respectively, after 0, 6, 12, 24, 48, and 96 h hypoxia were determined for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), angiogenic ligands potently induced by hypoxia, and for pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1), endogenous broad-spectrum antiangiogenic factors. Indirect ELISA was used to correlate VEGF and PEDF protein levels with mRNA expression. At the onset of hypoxia, both PEDF and TSP-1 levels were increased over 15-fold and VEGF was increased over 10-fold compared to Ang-2 in both strains. At the onset of neovascularization (48 h), both VEGF and Ang-2 mRNA levels were increased in the more angiogenic 129S3/ SvIM strain (Po0.02), which was not observed among developmental control animals. PEDF expression was higher in the less angiogenic C57BL/6J strain at 6, 12, 24, and 96 h hypoxia (Po0.03), while TSP-1 expression was higher in C57BL/6J throughout the entire time course of hypoxia (4 days) compared to 129S3/SvIM (Po0.02). Among developmental control animals, PEDF and TSP-1 expression was also increased at P14 and P16 in C57BL/6J strain compared to 129S3/SvIM (Po0.02). Strain-dependent expression of both pro-and antiangiogenic growth factors may determine heterogeneity in the angiogenic response and potentially, susceptibility to angiogenesis-dependent diseases.

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Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy

Cited by 132 publications

References 34 publications

Vascular endothelial growth factor in eye disease

Vascular endothelial growth factor in eye disease

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

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