Renno RZ, Youssri AI, Michaud N, et al. Expression of pigment epithelium-derived factor in experimental choroidal neovascularization

Angiogenesis Laboratory, Retina Research Institute, Massachusetts Eye and Ear Infirmary, 245 Charles Street, Boston, MA 02114, USA.
Investigative Ophthalmology &amp Visual Science (Impact Factor: 3.66). 06/2002; 43(5):1574-80.
Source: PubMed

ABSTRACT To investigate the expression of pigment epithelium-derived factor (PEDF) in the rat laser-injury model of choroidal neovascularization (CNV).
Retinas were immunostained for PEDF at different times (1, 2, and 3 weeks) after laser injury. Levels of PEDF protein in the vitreous at 1, 3, 7, 14, and 28 days after laser injury were also assayed by Western blot.
Protein levels of PEDF in the vitreous were increased during the first 7 days after CNV induction. Immunostaining for PEDF was observed throughout normal nonlasered control retinas, sham-lasered retinas, and areas remote to laser lesions, which were generally more intense in the outer nuclear layer (ONL) and less intense in the internal nuclear layer (INL). Decreased expression of PEDF was observed in flanking areas adjacent to the injury site and was confined mainly to the ONL. In the injury sites, immunostaining within the ONL was either absent or decreased for up to 3 weeks after laser injury (the duration of the study). Preadsorption of the anti-PEDF antibody with the immunizing peptide blocked specific labeling in the retina.
These results demonstrate an inverse correlation of expression of PEDF and formation of CNV in the experimental model and suggest that decreased expression of PEDF plays a permissive role in the formation of CNV. PEDF analogues may be a reasonable treatment strategy for CNV.

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    • "Resting RPE cells in addition to proangiogenic factors also secrete potent inhibitors of angiogenesis, such as the pigment epithel derived factor (PEDF) (Ohno-Matsui et al. 2001) and throm- bospondin-1(Miyajima-Uchida et al. 2000). The secretion of PEDF has been shown to be downregulated in human and experimental conditions with ocular neovascularization such as exudative AMD (Renno et al. 2002; Holekamp et al. 2002). Leading to the suggestion that CNV is caused by an equilibrium shift between pro-and anti-angiogenic factors, rather than merely by an increase in the production of VEGF (Ohno-Matsui et al. 2001). "
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    ABSTRACT: The purpose of the present thesis was to develop an animal model of CNV in order to study the early formation of CNV and to test the effects of an anti-angiogenic treatment. Porcine eyes were chosen as a substrate for CNV induction, since they are similar to human eyes in terms of both macroscopic and microscopic morphology. However, a major difference is that pigs lack a fovea; instead they have a visual streak, with a relatively stable and high concentration of cones. By surgical perforation of Bruch's membrane we were able to induce formation of CNV membranes. The morphology and cellular composition of these membranes varied with the surgical technique employed. When RPE cells were locally removed at the time of perforation, the resulting CNV was thinner, contained fewer blood vessels and was less prone to leak on fluorescein angiography than when RPE cells were left intact at induction. The neuroretina overlying the perforation site was not damaged by any of the surgical techniques, thus allowing the subsequent retinal damage to be ascribed to the actual process of CNV formation. Using this animal model allowed us to directly map histological findings onto fluorescein angiograms and thereby perform meaningful correlations between histopathologic and photographic features. Such correlations have been hampered in human subjects, since human eyes are not enucleated as a consequence of CNV and are therefore only available for post-mortem studies. In such studies there often is a considerable time-gap between the death of the patient and the latest available fluorescein angiogram, thereby allowing macular pathology to evolve in the interim. Histological examination of the porcine membranes demonstrated that they were composed of RPE cells, glial cells, macrophages, endothelial cells, collagen and smooth muscle fibres, which are the same cellular and fibrillar elements that dominate human CNV membranes. The porcine model was applied to test the effects, in a randomized and masked fashion, of intravitreally injected bevacizumab. Bevacizumab, a pan VEGF A antibody, was found to reduce both the proliferation of endothelial cells in CNV membranes and the propensity to leak in fluorescein angiograms. Immunohistochemically, bevacizumab was detected in the inner limiting membrane, in retinal blood vessels and binding uniformly to the entire CNV membrane without any cellular predisposition. Based on the above findings we believe that the porcine CNV model shows a bearing to human disease and therefore might be used as a tool to obtain improved treatments for this debilitating condition.
    Acta ophthalmologica 10/2008; 86 Thesis 2:1-24. DOI:10.1111/j.1755-3768.2008.01412.x · 2.51 Impact Factor
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    ABSTRACT: Based on the results of the ARED study, a prophylactic treatment with a combination of vitamin C, vitamin E, β-carotene, and zinc is recommended for patients meeting the fundoscopic criteria described as categories 3 and 4 in the study. For all other nutritional supplementation including lutein or zeaxanthin,which increase macular pigment density, there is as yet no proven efficacy with regard to the prevention of AMD. However, many new antiangiogenic therapies are currently under investigation in large multicentre trials and hold exciting potential for patients with neovascular AMD. Further insight into the angiogenic process and its inhibition may lead to more targets that may be transferred for use in patients with neovascular AMD.
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