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: 3.4). 06/2002; 43(5):1574-80.
Source: PubMed


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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    • "Although degeneration times vary in different experimental conditions, I/R-induced injury and retinal degeneration is initially observed primarily in inner retinal layers [e.g. the inner plexiform layer (IPL) and inner nuclear layer (INL)] that are supplied by the central retinal artery, in contrast to the outer nuclear layer (ONL) that is generally less affected [18-21]. Differently from inner retinal layers, the choroid supplies blood and nutrients to the photoreceptors and ONL [22,23]. This structural difference may influence the initiation stage of I/R injury. "
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    ABSTRACT: Retinal ischemia/reperfusion (I/R) injury is an important cause of visual impairment. However, questions remain on the overall I/R mechanisms responsible for progressive damage to the retina. In this study, we used a mouse model of I/R and characterized the pathogenesis by analyzing temporal changes of retinal morphology and function associated with changes in retinal gene expression. Transient ischemia was induced in one eye of C57BL/6 mice by raising intraocular pressure to 120 mmHg for 60 min followed by retinal reperfusion by restoring normal pressure. At various time points post I/R, retinal changes were monitored by histological assessment with H&E staining and by SD-OCT scanning. Retinal function was also measured by scotopic ERG. Temporal changes in retinal gene expression were analyzed using cDNA microarrays and real-time RT-PCR. In addition, retinal ganglion cells and gliosis were observed by immunohistochemistry. H&E staining and SD-OCT scanning showed an initial increase followed by a significant reduction of retinal thickness in I/R eyes accompanied with cell loss compared to contralateral control eyes. The greatest reduction in thickness was in the inner plexiform layer (IPL) and inner nuclear layer (INL). Retinal detachment was observed at days 3 and 7 post- I/R injury. Scotopic ERG a- and b-wave amplitudes and implicit times were significantly impaired in I/R eyes compared to contralateral control eyes. Microarray data showed temporal changes in gene expression involving various gene clusters such as molecular chaperones and inflammation. Furthermore, immunohistochemical staining confirmed Muller cell gliosis in the damaged retinas. The time-dependent changes in retinal morphology were significantly associated with functional impairment and altered retinal gene expression. We demonstrated that I/R-mediated morphological changes the retina closely associated with functional impairment as well as temporal changes in retinal gene expression. Our findings will provide further understanding of molecular pathogenesis associated with ischemic injury to the retina.
    Molecular Neurodegeneration 06/2013; 8(1):21. DOI:10.1186/1750-1326-8-21 · 6.56 Impact Factor
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    • "PEDF synthesis is upregulated under hyperemic conditions and downregulated in hypoxia.67 PEDF levels have been found to be low within choroidal neovascular tissues,68,69 and expression of PEDF is inversely correlated with the formation of CNVM in animal models.70 "
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    ABSTRACT: Age-related macular degeneration (AMD) has become a major public health problem and a leading cause of blindness in industrialized nations. AMD results from the ageing eye's inability to metabolize and dispose completely of photoreceptor outer segments and other waste products. As a result, lipids, particularly apolipoproteins, accumulate within Bruch's membrane, leading to chronic ischemia and inflammation. The subsequent upregulation of inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF), induces the growth of neovascular membranes from the choriocapillaris into the subretinal or subretinal pigment epithelium spaces. To counter this, intravitreally administered drugs (pegaptanib, bevacizumab, ranibizumab) that specifically target VEGF have become the standard treatment for exudative AMD. Aflibercept, a recently approved fusion protein, binds to all isoforms of both VEGF-A and placental growth factor with high affinity. Phase III trials showed that monthly or every other month injections of aflibercept prevent vision loss (fewer than 15 letters) in 95% of patients. Additionally, aflibercept injections every 4 or 8 weeks produce average vision gains of 6.9 letters to 10.9 letters, comparable with those achieved with monthly ranibizumab. After one year of regularly administered aflibercept injections, patients required an average of only 4.2 injections during the second year. Aflibercept promises to decrease the injection frequency required for many patients and appears to serve as an effective "salvage" therapy for patients who respond poorly to other anti-VEGF drugs.
    Clinical Ophthalmology 07/2012; 6(1):1175-86. DOI:10.2147/OPTH.S33372 · 0.76 Impact Factor
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    • "Second, vitreous PEDF concentrations were found to be significantly decreased in eyes with exudative AMD [16]. Additional evidence comes from an animal laser injury model showing an inverse correlation between PEDF expression and formation of choroidal neovascularizations [17,18]. Finally, the administration of recombinant natural PEDF or adenoviral vector-delivered PEDF has been found either to inhibit the development of choroidal neovascularizations or to reduce its extent [19–21]. "
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    ABSTRACT: Exudative age-related macular degeneration (exudative AMD) is a common vision-threatening disease, with both environmental and genetic factors contributing to its development. Recently, homozygosity for the 72Met variant of the pigment epithelium-derived factor (PEDF) Met72Thr gene polymorphism (rs1136287) was identified as a novel risk factor for exudative AMD in Chinese patients from Taiwan. The role of this polymorphism, however, has not yet been determined in a white European population. In addition, two other PEDF gene polymorphisms, -5736T>C (rs12150053) and -5304C>T (rs12948385), have been associated with increased risk of diabetic retinopathy, but have not yet been studied among patients with exudative AMD. The purpose of the present study was thus to investigate a hypothesized association between these PEDF polymorphisms and the presence of exudative AMD in a white European population. The present case-control study comprised 269 patients with exudative AMD and 155 control subjects. Genotypes of the PEDF polymorphisms were determined by 5'-exonuclease assays (TaqMan). PEDF genotype and allele frequencies were not significantly different between AMD patients and control subjects. The two promoter polymorphisms, -5736T>C (rs12150053) and -5304C>T (rs12948385), were in complete association. Presence of the homozygous PEDF 72 Met/Met genotype was associated with a nonsignificant odds ratio of 1.00 (95% confidence interval: 0.67-1.49, p=0.99). Similarly, presence of the homozygous PEDF -5736 TT genotype or -5304 CC genotype was associated with a nonsignificant odds ratio of 0.99 (95% confidence interval: 0.56 - 1.75, p=0.97). Both promoter polymorphisms were in linkage disequilibrium with the Met72Thr (rs1136287) polymorphism (D'=0.83) and formed three common and one rare haplotype. Haplotype frequencies were similar between AMD patients and control subjects (p>0.05). Our data suggest that none of the investigated PEDF polymorphisms is likely a major risk factor for exudative AMD in a white European population.
    Molecular vision 02/2009; 15:343-8. · 1.99 Impact Factor
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