Vascular Endothelial Growth Factor and Diabetic Retinopathy: Role of Oxidative Stress

Caldwell, Ruth B.; Bartoli, Manuela; Behzadian, M. Ali; El-Remessy, Azza B.; Al‐Shabrawey, Mohamed; Platt, Daniel H.; Liou, Gregory I.; Caldwell, Robert W.

doi:10.2174/1389450054021981

Cited by 199 publications

(144 citation statements)

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“…Previous in vitro studies have provided evidence that cytokines, such as HGF or VEGF may mediate this response (Caldwell et al 2005;Jin et al 2002;Pe'er et al 1995). Moreover, recent clinical studies showed that anti-VEGF medications can reduce macular fluid accumulation (Gragoudas et al 2004;Heier et al 2006;Spaide et al 2006).…”

Section: Discussionmentioning

confidence: 99%

VEGF modulation of retinal pigment epithelium resistance

Ablonczy

Crosson

2007

Experimental Eye Research

127

110

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Fluid accumulation into the subretinal space and the development of macular edema is a common condition in age-related macular degeneration, diabetic retinopathy, and following ocular surgery, or injury. Vascular endothelial growth factor (VEGF) and other cytokines have been implicated in the disruption of retinal pigment epithelium (RPE) barrier function and a reduction in the regulated removal of subretinal fluid; however, the cellular and molecular events linking these agents to the disruption of barrier function have not been established. In the current study, cultures of ARPE-19 and primary porcine retinal pigment epithelium (RPE) cells were utilized to investigate the effects of the VEGF-induced modifications to the barrier properties of the RPE. The barrier function was determined by transepithelial resistance (TER) measurements and morphology of the RPE monolayers. In both ARPE-19 and primary porcine RPE cells the administration of VEGF produced a significant drop in TER, and this response was only observed following apical administration. Maximum reduction in TER was reached 5 hours post VEGF administration. These responses were concentration-dependent with an EC 50 of 502 pg/mL in ARPE-19 cells and 251 pg/mL in primary porcine cells. In both ARPE-19 and primary RPE cells, the response to VEGF was blocked by pretreatment with the relatively selective VEGF-R2 antagonists, SU5416 or ZM323881, or the protein tyrosine kinase inhibitor, genistein. Administration of the relatively selective VEGF-R2 agonist, VEGF-E, also reduced TER in a concentration-dependent manner (EC 50 of 474 pg/mL), while VEGF-R1 agonist, placental growth factor (PlGF), did not significantly alter the TER. Immunolocalization studies demonstrated that confluent monolayers exhibited continuous cell-tocell ZO-1 protein contacts and apical localization of the VEGF-R2 receptors. These data provide evidence that the VEGF-induced breakdown of RPE barrier function is mediated by the activation of apically-oriented VEGF-R2 receptors. Thus, VEGF-mediated increases in RPE permeability are initiated by a rise in intraocular levels of VEGF.

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Section: Discussionmentioning

confidence: 99%

VEGF modulation of retinal pigment epithelium resistance

Ablonczy

Crosson

2007

Experimental Eye Research

127

110

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“…Both of these processes involve increases in the expression levels of VEGF (Caldwell et al, 2005;Duh and Aiello, 1999). Although experimental diabetes in rodent models does not progress to proliferative diabetic retinopathy, many of the early vascular changes seen in patients are evident, such as increased permeability, microaneurysm formation, and leukostasis.…”

Section: Vascular Inflammation and Diabetic Retinopathymentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

614

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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“…10,11 Additionally, increased flux via the hexosamine pathway results in modulation of transcription factors leading to pathological changes in gene expression. Hyperglycaemia-induced overproduction of superoxide by the mitochondria has been proposed as the key unifying mechanism that activates all four pathways.…”

Section: Pathogenesis Of Diabetic Eye Diseasementioning

confidence: 99%

Management of diabetic retinopathy: could lipid-lowering be a worthwhile treatment modality?

Dodson

2009

Eye

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Diabetic eye disease confers substantial burden on the patient quality of life. Current therapeutic strategies indicate an unmet clinical need for preventive therapy. Tight control of blood pressure and glycaemia are mandatory components of primary prevention strategies, but are insufficient to eliminate risk in all patients. A body of evidence supports a role for lipid-modifying therapy in reducing the diabetic retinopathy endpoints. Although inconclusive for statin therapy, results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study show beneficial effects of fenofibrate in reducing the requirement for laser therapy, and particularly in preventing disease progression in patients with pre-existing diabetic retinopathy. However, there is a need for confirmation of these findings in large prospective studies with progression of retinopathy as the primary endpoint, such as the ACCORD-EYE (Action to Control Cardiovascular Risk in Diabetes-EYE) study, and in a clinical trial specifically conducted for diabetic maculopathy. In addition, elucidation of the mechanism(s) of effect of fenofibrate is indicated.

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Vascular Endothelial Growth Factor and Diabetic Retinopathy: Role of Oxidative Stress

Cited by 199 publications

References 0 publications

VEGF modulation of retinal pigment epithelium resistance

VEGF modulation of retinal pigment epithelium resistance

Vascular endothelial growth factor in eye disease

Management of diabetic retinopathy: could lipid-lowering be a worthwhile treatment modality?

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