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      Investigation of Retinal Morphology Alterations Using Spectral Domain Optical Coherence Tomography in a Mouse Model of Retinal Branch and Central Retinal Vein Occlusion

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          Retinal vein occlusion is a leading cause of visual impairment. Experimental models of this condition based on laser photocoagulation of retinal veins have been described and extensively exploited in mammals and larger rodents such as the rat. However, few reports exist on the use of this paradigm in the mouse. The objective of this study was to investigate a model of branch and central retinal vein occlusion in the mouse and characterize in vivo longitudinal retinal morphology alterations using spectral domain optical coherence tomography. Retinal veins were experimentally occluded using laser photocoagulation after intravenous application of Rose Bengal, a photo-activator dye enhancing thrombus formation. Depending on the number of veins occluded, variable amounts of capillary dropout were seen on fluorescein angiography. Vascular endothelial growth factor levels were markedly elevated early and peaked at day one. Retinal thickness measurements with spectral domain optical coherence tomography showed significant swelling (p<0.001) compared to baseline, followed by gradual thinning plateauing two weeks after the experimental intervention (p<0.001). Histological findings at day seven correlated with spectral domain optical coherence tomography imaging. The inner layers were predominantly affected by degeneration with the outer nuclear layer and the photoreceptor outer segments largely preserved. The application of this retinal vein occlusion model in the mouse carries several advantages over its use in other larger species, such as access to a vast range of genetically modified animals. Retinal changes after experimental retinal vein occlusion in this mouse model can be non-invasively quantified by spectral domain optical coherence tomography, and may be used to monitor effects of potential therapeutic interventions.

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          Most cited references 37

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          Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization.

          Adults maintain a reservoir of hematopoietic stem cells that can enter the circulation to reach organs in need of regeneration. We developed a novel model of retinal neovascularization in adult mice to examine the role of hematopoietic stem cells in revascularizing ischemic retinas. Adult mice were durably engrafted with hematopoietic stem cells isolated from transgenic mice expressing green fluorescent protein. We performed serial long-term transplants, to ensure activity arose from self-renewing stem cells, and single hematopoietic stem-cell transplants to show clonality. After durable hematopoietic engraftment was established, retinal ischemia was induced to promote neovascularization. Our results indicate that self-renewing adult hematopoietic stem cells have functional hemangioblast activity, that is, they can clonally differentiate into all hematopoietic cell lineages as well as endothelial cells that revascularize adult retina. We also show that recruitment of endothelial precursors to sites of ischemic injury has a significant role in neovascularization.
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            Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6.

            To determine whether correlations between vascular endothelial growth factor (VEGF) or interleukin-6 (IL-6) contribute to the pathogenesis of macular edema in eyes of patients with branch retinal vein occlusion (BRVO). Retrospective case-control study. Nineteen patients with macular edema with BRVO and seven patients with non-ischemic ocular disease (control group) were studied. The degree of retinal ischemia was evaluated in terms of the area of capillary non-perfusion, and the severity of macular edema was examined by optical coherence tomography. Aqueous humor samples were obtained at the time of combined vitrectomy and cataract surgery, and VEGF and IL-6 levels in aqueous humor and plasma were determined by enzyme-linked immunosorbent assay. Aqueous levels of VEGF (351 +/- 273 pg/ml) and IL-6 (7.10 +/- 6.51 pg/ml) were significantly elevated in patients with BRVO compared with the control patients (119 +/- 38.7 pg/ml and 2.27 +/- 1.11 pg/ml, respectively) (P = .0017 and P = .0052, respectively). Aqueous level of VEGF was significantly correlated with that of IL-6 (P = .0396), and aqueous levels of VEGF and IL-6 were correlated with the size of the BRVO non-perfused area (P < .0001 and P = .0331, respectively). Aqueous level of VEGF was correlated with the severity of macular edema (P = .0306). VEGF and IL-6 may be involved in the pathogenesis of macular edema with BRVO. The increase in these cytokines might be used as a unique index of BRVO, through which we can determine the severity of the ischemic condition as being in a quiescent state or an exacerbation of macular edema.
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              Branch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature.

              Retinal vein occlusion is the second most common retinal vascular disorder after diabetic retinopathy and is considered to be an important cause of visual loss. In this review, the purpose is to make an update of the literature about the classification, epidemiology, pathogenesis, risk factors, clinical features, and complications of branch retinal vein occlusion (BRVO). Eligible articles were identified using a comprehensive literature search of MEDLINE, using the terms "branch retinal vein occlusion," "pathogenesis," "epidemiology," "risk factors," "clinical features," "diagnosis," and "complications." Additional articles were also selected from reference lists of articles identified by the electronic database search. Classification, epidemiology, pathogenesis, risk factors, clinical features, and complications are analyzed. Branch retinal vein occlusion has an incidence of 0.5% to 1.2%. Several risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, thrombophilia and hypercoagulation, systemic and inflammatory diseases, medications, and ocular conditions, have found to be associated with BRVO. The symptoms depended on the site and severity of the occlusion. The average reduction in visual acuity for ischemic BRVO is 20/50 and for nonischemic BRVO is 20/60. Acute BRVO can be detected by fundoscopy, where flame hemorrhages, dot and blot hemorrhages, cotton wool spots, hard exudates, retinal edema, and dilated tortuous veins can be observed. Chronic BRVO would be more subtle and characterized by the appearance of venous collateral formation and vascular sheathing, in addition to complications previously mentioned. Areas of ischemia can be evaluated using fluorescein angiography. The extent of macular edema and the presence of retinal detachment can be detected by fundoscopic examination or fluorescein angiography, although optical coherence tomography is considered to be the best method. As far as complications, the most common is macular edema, followed by retinal neovascularization, vitreous hemorrhage, or retinal detachment.

                Author and article information

                Role: Academic Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                16 March 2015
                : 10
                : 3
                Department of Ophthalmology, Bern University Hospital, Inselspital, and University of Bern, Bern, Switzerland
                Justus-Liebig-University Giessen, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AE CD CA MZ. Performed the experiments: AE CD CA MZ. Analyzed the data: AE CD CA MZ. Contributed reagents/materials/analysis tools: AE MZ. Wrote the paper: AE MZ CA.


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 6, Tables: 0, Pages: 15
                These studies were supported by grants from the Inselspital Bern and the OPOS foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
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