Effects of Ischemic Preconditioning and Bevacizumab on Apoptosis and Vascular Permeability Following Retinal Ischemia–Reperfusion Injury

Abcouwer, Steve F.; Lin, Ching-Fang; Wolpert, Ellen B.; Shanmugam, Sumathi; Schaefer, Eric; Freeman, Willard M.; Barber, Alistair J.; Antonetti, David A.

doi:10.1167/iovs.10-5264

Cited by 78 publications

(94 citation statements)

References 72 publications

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“…The R28 cell-line is derived from postnatal day 6 Sprague-Dawley rat retinal tissue immortalized with the 12S E1A gene of adenovirus and shown to express neurotransmitter receptors to dopamine, serotonin, glycine, acetylcholine, and glutamate (43). Cells were grown in DMEM containing 5 mM glucose supplemented with 10% FBS (Flow Laboratories) and differentiated to neurons on laminin-coated plates with addition of cell-permeable cAMP (MilliporeSigma) as described previously (44).…”

Section: Methodsmentioning

confidence: 99%

A specific phosphorylation regulates the protective role of αA-crystallin in diabetes

Ruebsam¹,

Dulle²,

Myers³

et al. 2018

JCI Insight

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Section: Methodsmentioning

confidence: 99%

A specific phosphorylation regulates the protective role of αA-crystallin in diabetes

Ruebsam¹,

Dulle²,

Myers³

et al. 2018

JCI Insight

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“…3 The Evans Blue content in blood plasma after 2 hours of circulation was used for normalization, and values expressed as microliters of plasma per gram of retina (dry weight) per hour of circulation.…”

Section: Evans Blue Assaymentioning

confidence: 99%

“…3 To determine whether the early vascular IR injury causes BRB breakdown A Muthusamy et al permeability response to IR injury is VEGF mediated, eyes were pretreated with bevacizumab 48 hours before IR. Bevacizumab pretreatment prevented the IR induced early vascular permeability measured by Evans Blue dye injection beginning after only 15 minutes of reperfusion ( Figure 7A).…”

Section: Blockade Of Vascular Endothelial Growth Factor Receptor-2 Acmentioning

confidence: 99%

Ischemia–Reperfusion Injury Induces Occludin Phosphorylation/Ubiquitination and Retinal Vascular Permeability in a VEGFR-2-Dependent Manner

Muthusamy

Lin

Shanmugam

et al. 2014

J Cereb Blood Flow Metab

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Retinal ischemia-reperfusion (IR) induces neurodegenaration as well as blood-retinal barrier (BRB) breakdown causing vascular permeability. Whereas the neuronal death has been extensively studied, the molecular mechanisms related to BRB breakdown in IR injury remain poorly understood. In this study, we investigated the early changes in tight junctional (TJ) proteins in response to IR injury. Ischemia-reperfusion injury was induced in male rat retinas by increasing the intraocular pressure for 45 minutes followed by natural reperfusion. The results demonstrate that IR injury induced occludin Ser490 phosphorylation and ubiquitination within 15 minutes of reperfusion with subsequent vascular permeability. Immunohistochemical analysis revealed a rapid increase in occludin Ser490 phosphorylation and loss of Zonula occludens-1 (ZO-1) protein, particularly in arterioles. Ischemia-reperfusion injury also rapidly induced the activation and phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) at tyrosine 1175. Blocking vascular endothelial growth factor (VEGF) function by intravitreal injection of bevacizumab prevented VEGFR-2 activation, occludin phosphorylation, and vascular permeability. These studies suggest a novel mechanism of occludin Ser490 phosphorylation and ubiquitination downstream of VEGFR2 activation associated with early IR-induced vascular permeability. Flow & Metabolism (2014) 34, 522-531; doi:10.1038/jcbfm.2013; published online 8 January 2014 Journal of Cerebral BloodKeywords: blood-retinal barrier; ischemia-reperfusion injury; occludin phosphorylation; tight junction; vascular endothelial growth factor; vascular permeability INTRODUCTIONRetinal ischemia-reperfusion models several components of various eye disease pathologies such as retinal vein occlusion, diabetic retinopathy, and glaucoma. [1][2][3][4][5][6] The IR model has been widely used for studying retinal neuronal cell damage after ischemic insult 6 and consists of transient ischemia followed by natural reperfusion leading to an inflammatory and neurodegenerative response in the intact retina. 7 Histologic analysis demonstrated that the IR injury causes selective neuronal loss indicated by reduced thickness of retinal layers including the ganglion cell layer, inner nuclear layer, and inner plexiform layer. 8,9 A recent study demonstrated that IR also induced vascular abnormalities such as capillary dropout after 8 to 14 days of reperfusion and concluded these vascular changes occurred after neuronal loss. 6 Recently IR was shown to increase retinal vascular permeability in a vascular endothelial growth factor (VEGF)-dependent manner, suggesting that this model could be used to investigate the mechanisms and drugs targeting VEGFinduced permeability. 3 Vascular endothelia growth factor, a hypoxia-responsive angiogenic and vasopermeability factor, contributes to vascular leakage in multiple retinal pathologies. 10 Although many studies have demonstrated perturbations of retina glial and neuronal elements in IR injury, no stu...

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“…Some studies have used microarrays to investigate animal models of glaucoma,15–26 while others have investigated the altered expressions of a few selected genes in response to ischemia 27–29. However, there is very little information in the literature related to differences that may exist between the gene responses evident in initial, intermediate, and prolonged reperfusion times following an acute ischemic insult.…”

Section: Introductionmentioning

confidence: 99%

Time-Dependent Gene Profiling Indicates the Presence of Different Phases for Ischemia/Reperfusion Injury in Retina

et al. 2014

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Ischemia/reperfusion (IR) injury has been associated with several retinal pathologies, and a few genes/gene products have been linked to IR injury. However, the big picture of temporal changes, regarding the affected gene networks, pathways, and processes remains to be determined. The purpose of the present study was to investigate initial, intermediate, and later stages to characterize the etiology of IR injury in terms of the pathways affected over time. Analyses indicated that at the initial stage, 0-hour reperfusion following the ischemic period, the ischemia-associated genes were related to changes in metabolism. In contrast, at the 24-hour time point, the signature events in reperfusion injury include enhanced inflammatory and immune responses as well as cell death indicating that this would be a critical period for the development of any interventional therapeutic strategies. Genes in the signal transduction pathways, particularly transmitter receptors, are downregulated at this time. Activation of the complement system pathway clearly plays an important role in the later stages of reperfusion injury. Together, these results demonstrate that the etiology of injury related to IR is characterized by the appearance of specific patterns of gene expression at any given time point during retinal IR injury. These results indicate that evaluation of treatment strategies with respect to time is very critical.

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Effects of Ischemic Preconditioning and Bevacizumab on Apoptosis and Vascular Permeability Following Retinal Ischemia–Reperfusion Injury

Cited by 78 publications

References 72 publications

A specific phosphorylation regulates the protective role of αA-crystallin in diabetes

A specific phosphorylation regulates the protective role of αA-crystallin in diabetes

Ischemia–Reperfusion Injury Induces Occludin Phosphorylation/Ubiquitination and Retinal Vascular Permeability in a VEGFR-2-Dependent Manner

Time-Dependent Gene Profiling Indicates the Presence of Different Phases for Ischemia/Reperfusion Injury in Retina

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