Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy

Werdich, Xiang Q.; McCollum, Gary W.; Rajaratnam, Veera; Penn, John S.

doi:10.1016/j.exer.2004.07.006

Cited by 62 publications

(50 citation statements)

References 30 publications

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“…Although a number of studies have shown that oxygen concentration regulates the retinal levels of VEGF and PEDF, interactions between these two counterbalancing angiogenic factors are largely unclear (Gao et al 2002a, Eichler et al 2004, Werdich et al 2004). The present study demonstrated for the first time that there is a reciprocal regulation between VEGF and PEDF in the retina.…”

Section: Discussionmentioning

confidence: 99%

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

231

152

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It has been shown that the balance between vascular endothelial growth factor (VEGF), a major angiogenic stimulator, and pigment epithelium-derived factor (PEDF), a potent angiogenic inhibitor, is critical for the regulation of vascular permeability and angiogenesis. However, the regulation of the balance is largely unclear. The present study demonstrated that there is a reciprocal interaction between VEGF and PEDF in the retina. PEDF significantly decreased VEGF expression in both retinal capillary endothelial cells (RCEC) and Mü ller cells. This PEDF effect was confirmed in the retina of rats with oxygen-induced retinopathy. Silencing of the PEDF gene by siRNA in Mü ller cells resulted in a significant upregulation of VEGF expression at both the RNA and protein levels, suggesting that PEDF is an endogenous negative regulator of VEGF. The further study of the mechanism showed that PEDF inhibited hypoxia-induced increases in VEGF promoter activity, HIF-1 nuclear translocation and mitogen activated protein kinase phosphorylation. These results suggest that PEDF inhibits VEGF expression at the transcriptional level. In addition, PEDF effectively inhibited VEGF binding to RCEC. Moreover, in vitro receptor-binding assay demonstrated that PEDF competed with VEGF for binding to VEGF receptor 2, which may represent a new mechanism for PEDF activity. On the other hand, VEGF significantly downregulated PEDF expression in RCEC, but not in retinal Mü ller cells, suggesting a VEGF receptormediated process. These results suggest that the reciprocal regulation between VEGF and PEDF may play a role in angiogenic control. The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes.

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Section: Discussionmentioning

confidence: 99%

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

231

152

View full text Add to dashboard Cite

show abstract

“…This occurred despite the existence of large areas of retinal avascularity in constant hyperoxia-exposed rats. It is possible that variable oxygen results in greater mitogenic activity or production of VEGF, or causes sequestration of VEGF during hyperoxic episodes, leading to an accumulation over time in the variable environment (Werdich et al, 2004;McColm et al, 2004). These experiments argue for tighter control of oxygen saturation fluctuations in premature infants.…”

Section: Implications For Prevention and Treatment Of Ropmentioning

confidence: 99%

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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“…In the DP group, the cycles were evenly spaced every 2 h throughout the day. In the CL group, three episodes of hypoxia were grouped, each 10 min apart, followed by hyperoxia to complete 6 h. These OIR models were modified from a previously validated model (5)(6)(7)(8)(9). Hypoxia of 12% O 2 was used due to the extended time period needed to reach 10% and the desire to keep the hypoxic episodes brief.…”

Section: Methodsmentioning

confidence: 99%

Effects of Brief, Clustered Versus Dispersed Hypoxic Episodes on Systemic and Ocular Growth Factors in a Rat Model of Oxygen-Induced Retinopathy

et al. 2008

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Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy

Cited by 62 publications

References 30 publications

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Vascular endothelial growth factor in eye disease

Effects of Brief, Clustered Versus Dispersed Hypoxic Episodes on Systemic and Ocular Growth Factors in a Rat Model of Oxygen-Induced Retinopathy

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