Vascular Endothelial Growth Factor-A Is a Survival Factor for Retinal Neurons and a Critical Neuroprotectant during the Adaptive Response to Ischemic Injury

Nishijima, Kazuaki; Ng, Y. Jack; Zhong, Lihua; Bradley, Jeremy T.; Schubert, William; Jo, Nobuo; Akita, Jo; Samuelsson, Steven J.; Robinson, G. A.; Adamis, Anthony P.; Shima, David T.

doi:10.2353/ajpath.2007.061237

Cited by 641 publications

(500 citation statements)

References 45 publications

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“…An intriguing possibility for the observed protective role of crystallins in retinal degeneration is the potential differential regulation of hypoxia-inducible genes with neuroprotective function (eg Pigment epithelial derived factor, VEGF) or those that affect vascular permeability (eg. VEGF) in crystallin knockouts and controls (Nishijima et al, 2007;Takita et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Yaung

Kannan

Wawrousek

et al. 2008

Experimental Eye Research

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This study evaluated the role of crystallins in retinal degeneration induced by chemical hypoxia. Wild type, αA-crystallin (−/−), and αB-crystallin (−/−) mice received intravitreal injection of 12 nmol (low dose), 33 nmol (intermediate dose) or 60 nmol (high dose) cobalt chloride (CoCl 2 ). Hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) stains were performed after 24 hours, 96 hours, and 1 week post-injection, while immunofluorescent stains for αA-and αB-crystallin were performed 1 week post-injection. The in vitro effects of CoCl 2 on αB-crystallin expression in ARPE-19 cells were determined by real time RT-PCR, Western blot, and confocal microscopy and studies evaluating subcellular distribution of αB-crystallin in the mitochondria and cytosol were also performed. Histologic studies revealed progressive retinal degeneration with CoCl 2 injection in wild type mice. Retinas of CoCl 2 injected mice showed transient increased expression of HIF-1α which was maximal 24 hours after injection. Intermediate dose CoCl 2 injection was associated with increased retinal immunofluorescence for both αA-and αB-crystallin; however, after high dose injection, increased retinal degeneration was associated with decreased levels of crystallin expression. Injection of CoCl 2 at either intermediate or high dose in αA-crystallin (−/−) and αB-crystallin (−/−) mice resulted in much more severe retinal degeneration compared to wild type eyes. A decrease in ARPE-19 total and cytosolic αB-crystallin expression with increasing CoCl2 treatment and an increase in mitochondrial αB-crystallin were found. We conclude that lack of α-crystallins accentuates retinal degeneration in chemically-induced hypoxia in vivo.

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Section: Discussionmentioning

confidence: 99%

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Yaung

Kannan

Wawrousek

et al. 2008

Experimental Eye Research

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“…Again, VEGF receptors have been identified in retinal neurons, glia, microglia and RPE (Forstreuter et al, 2002;Hollborn et al, 2006;Robinson et al, 2001), and VEGF has been shown to play a key role in retinal development and survival of retinal neurons following ischemia/reperfusion injury (Nishijima et al, 2007;Yang and Cepko, 1996). As has been explained above, diabetes/high glucose stimulates increases in VEGF expression, and agents that block VEGF activity can prevent diabetes-induced retinal damage.…”

Section: Vegf and Diabetic Retinopathymentioning

confidence: 95%

“…IRES-dependent production of alternatively spliced VEGF isoforms may also contribute to the pathological effects of VEGF in the diabetic retina. 165 is a potent inducer of retinal vascular inflammation as well as a mediator of neuronal survival, whereas VEGF 121 promotes neuronal survival, but does not induce vascular inflammation (Ishida et al, 2003;Nishijima et al, 2007). Decreased levels of the dominant negative splice variant VEGF 165b were found in vitreous samples from patients with diabetic retinopathy, suggesting that a molecular switch between the VEGF 165 and VEGF 165b could be involved the development of diabetic retinopathy (Perrin et al, 2005).…”

Section: Post-transcriptional Regulation Of Vegf Expression-mentioning

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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“…102 Although the use of VEGF-blocking agents has shown efficacy in patients with sightthreatening proliferative retinopathy, the use of such agents is controversial as they do not address the underlying vascular insufficiency and there are appropriate concerns that such therapy could compromise retinal neuroglial and functional microvascular survival. [103][104][105] There is a pressing need for phase III clinical trials of anti-VEGF strategies in the context of diabetic retinopathy.…”

Section: Preretinal Neovascularizationmentioning

confidence: 99%

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Curtis

Gardiner

Stitt

2009

Eye

318

231

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Retinopathy is a major complication of diabetes mellitus and this condition remains a leading cause of blindness in the working population of developed countries. As diabetic retinopathy progresses a range of neuroglial and microvascular abnormalities develop although it remains unclear how these pathologies relate to each other and their net contribution to retinal damage. From a haemodynamic perspective, evidence suggests that there is an early reduction in retinal perfusion before the onset of diabetic retinopathy followed by a gradual increase in blood flow as the complication progresses. The functional reduction in retinal blood flow observed during early diabetic retinopathy may be additive or synergistic to proinflammatory changes, leucostasis and vasoocclusion and thus be intimately linked to the progressive ischaemic hypoxia and increased blood flow associated with later stages of the disease. In the current review a unifying framework is presented that explains how arteriolar dysfunction and haemodynamic changes may contribute to late stage microvascular pathology and vision loss in human diabetic retinopathy.

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Vascular Endothelial Growth Factor-A Is a Survival Factor for Retinal Neurons and a Critical Neuroprotectant during the Adaptive Response to Ischemic Injury

Cited by 641 publications

References 45 publications

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Vascular endothelial growth factor in eye disease

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

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