Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy

Ehlken, Christoph; Martin, Gottfried; Lange, Clemens; Gogaki, Eleni; Fiedler, Ulrike; Schaffner, Florence; Hansen, Lutz L.; Augustin, Hellmut G.; Agostini, Hansjürgen

doi:10.1111/j.1755-3768.2009.01609.x

Cited by 30 publications

(28 citation statements)

References 41 publications

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“…These results indicated that ephrin-A4 is another potential target against retinal NV, and further studies should be conducted to determine the value of its clinical application. Ephrin-B2, EphB4, and EphA2 have previously been shown to be involved in retinal neovasculogenesis [7][8][9][10][11] ; ephrin-A4 is a new member of the Eph/ephrin molecule family involved in the process of retinal NV. Further studies on the Eph/ephrin signaling system may identify other genes that control the retinal angiogenesis process.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6] Ephrin-B2, EphB4, and EphA2 have been shown to be involved in retinal neovasculogenesis. [7][8][9][10][11] A comparative retinal gene expression analysis in two rodent models of oxygen-induced retinopathy (OIR) identified increased expression levels of members of the VEGF and ephrin receptor signaling pathways in both models. 12 These previous studies underscore the role of the Eph/ephrin signaling pathway in retinal NV and suggest that further studies on the Eph/ephrin signaling pathway in the ROP would help to further understand the mechanism of retinal NV and to find new treatment opportunities.…”

Section: R Etinal Neovascularization (Nv) Is Characteristic Of Retinomentioning

confidence: 99%

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Ephrin-A4 Is Involved in Retinal Neovascularization by Regulating the VEGF Signaling Pathway

Du¹,

Yu²,

Huang³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Retinal neovascularization (NV) is a major cause of blindness. Recent research suggests that factors other than VEGF participate in this process. This study aimed to determine the role of ephrin-A4 in retinal NV. METHODS.The expression and effect of ephrin-A4 was investigated in a mouse model of oxygen-induced retinopathy (OIR) and the RF/6A retina endothelial cell line. Ephrin-A4 expression and VEGF signaling pathway phosphorylation were determined by PCR, immunohistochemistry, and western blot analyses. ShRNA was used to silence ephrin-A4 in vitro and in vivo. Retinal flat mounts and tube formation assays were performed to evaluate ephrin-A4 function in the NV process in vivo and in vitro.RESULTS. Ephrin-A4 was overexpressed in the retina of OIR mice and in RF/6A and RPE cells after CoCl 2 stimulation. In vitro, Ephrin-A4/Fc treatment significantly increased the tube number of RF/6A cells on a membrane preparation and the phosphorylation levels of VEGR2, Akt1, and ERK1/2 in RF/6A cells. Moreover, ephrin-A4 knockout markedly suppressed pathologic neovascularization in vivo and inhibited the proliferation and tube formation capacity of RF/6A cells in vitro. Furthermore, in the absence of ephrin-A4, the phosphorylation of VEGFR2, Akt1, and ERK1/2 was defective under VEGF 165 stimulation, and the proangiogenic function of VEGF 165 was also compromised.CONCLUSIONS. This study suggests that ephrin-A4 plays an important role in retinal NV and is a potential target against retinal NV. The proangiogenic function of ephrin-A4 may be linked to its crucial role in the VEGF signaling pathway. (Invest Ophthalmol Vis Sci. 2012;53:1990-1998) DOI:10.1167/ iovs.11-8788 R etinal neovascularization (NV) is characteristic of retinopathy of prematurity (ROP). In phase I of ROP, relative hyperoxia leads to the suppression of oxygen-regulated growth factors, such as vascular endothelial growth factor (VEGF), which causes a loss of preestablished vessels and cessation of normal retina vessel development. In phase II, a group of overexpressed growth factors from ischemic retina induces pathologic retinal NV. Research and clinical trials have confirmed that VEGF is the principal mediator of retinal NV. However, laboratory and clinical observations suggest that factors other than VEGF are also involved in both normal retinal vasculogenesis and retinal NV. 1,2 It is possible that further investigations of other factors and pathways may yield new therapeutic options.Significant progress has been made in recent years to identify factors promoting pathologic retinal NV, such as the Eph/ephrin signaling pathway. Eph receptors include EphA and EphB, and ephrin ligands include ephrin-A and transmembranous ephrin-B. Eph/ephrin molecules are critical regulators of cell contact-dependent signaling and patterning. Eph receptors and their ephrin ligands form an important cell communication system with widespread roles in normal physiology and disease pathogenesis, controlling cell migration and cytoskeletal organization.3-6 Ephrin-B2, EphB4...

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Section: Discussionmentioning

confidence: 99%

Section: R Etinal Neovascularization (Nv) Is Characteristic Of Retinomentioning

confidence: 99%

Ephrin-A4 Is Involved in Retinal Neovascularization by Regulating the VEGF Signaling Pathway

Du¹,

Yu²,

Huang³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…10,11 In addition, EphB4 has been shown to be overexpressed in a wide range of tumor cells and tissues, including cancers found in the ovary, 12 bladder, 13 prostate, 14,15 breast, 16 and colon. 17,18 These findings have qualified EphB4 as an interesting angiogenic target for antitumor and antiretinopathic therapies, and different approaches have been taken to target EphB4, including small molecules, [19][20][21][22][23][24][25] peptides, 26 soluble extracellular domains, 11,[27][28][29][30][31] or functional blocking antibodies. [32][33][34] On the molecular level, ligand-receptor interactions in the Eph family are characterized by clustering of the proteins at the membrane followed by bidirectional intracellular signaling events into both the Eph receptor expressing cell and the ephrin expressing cell.…”

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confidence: 97%

EphB4 Cellular Kinase Activity Assayed Using an Enzymatic Protein Interaction System

Wehrman

Nguyen

Feng

et al. 2013

ASSAY and Drug Development Technologies

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Receptor tyrosine kinases (RTKs) are important players in various cellular processes, including proliferation, migration, metabolism, and neuronal development. EphB4 RTK is essential for the development of a functional arterial-venous network in embryonic and adult neoangiogenesis. To develop novel inhibitors of EphB4 that might have applications in severe diseases like cancer and retinopathies, assays need to be in place that resemble, in a most physiological fashion, the activation and downstream function of the kinase. In addition, such assays need to be amenable to high-throughput screening to serve efficiently the modern drug discovery processes in the pharmaceutical industry. The authors have developed an enzyme fragment complementation assay that measures the interaction of a downstream docking protein to the activated and phosphorylated full-length EphB4 kinase in cells. The assay is specific, robust, and amenable to miniaturization and high-throughput screening. It covers most steps in the activation process of EphB4, including ligand binding, autophosphorylation, and docking of a downstream interactor. This assay format can be transferred to other RTKs and adds an important cell-based kinase assay option to researchers in the field.

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“…qPCR was performed using standard methods [17,19]. RT-PCR was performed with CNV-RPE-69 but was not possible for CNV-RPE-88 as the amount of material was limited.…”

Section: Microarray Analysismentioning

confidence: 99%

Expression of Angiogenic and Inflammatory Factors in Choroidal Neovascularisation-Derived Retinal Pigment Epithelium

Ehlken

Guichard²,

Schlunck³

et al. 2017

Ophthalmic Res

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Purpose: Anti-angiogenic treatment is well established in the management of exudative age-related macular degeneration (AMD), but not sufficient in all patients. The characterisation of factors driving this chronic disease could serve to identify additional treatment options. The purpose of this study was to assess gene expression patterns and distinct changes in cells derived from surgically extracted choroidal neovascularisation (CNV) membranes. Materials and Methods: The expression of >11,000 genes was analysed by means of a microarray in cells cultured from 2 late-stage CNV membranes compared to primary human retinal pigment epithelium (RPE) and ARPE-19 cells. A pathway analysis was performed to identify gene expression patterns associated with exudative AMD. Results: The analysis revealed significant alterations in gene sets associated with inflammatory processes in CNV-derived cells, involving the upregulation of pro-inflammatory factors IL6, C3, and C5, and downregulation of anti-inflammatory complement factor B and complement factor I. Factors associated with angiogenesis, such as VEGFA or ANGPT2, were not significantly regulated in the 2 RPE-derived cell lines. Conclusion: In late-stage CNV membrane-derived RPE, gene expression was shifted towards a pro-inflammatory state. Angiogenesis-associated factors were regulated differently in the 2 CNV-derived RPE membranes. While inflammation seems to be continuously stimulated by RPE associated with late exudative AMD, this appears not to be the case with regard to angioregulatory mechanisms.

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Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy

Cited by 30 publications

References 41 publications

Ephrin-A4 Is Involved in Retinal Neovascularization by Regulating the VEGF Signaling Pathway

Ephrin-A4 Is Involved in Retinal Neovascularization by Regulating the VEGF Signaling Pathway

EphB4 Cellular Kinase Activity Assayed Using an Enzymatic Protein Interaction System

Expression of Angiogenic and Inflammatory Factors in Choroidal Neovascularisation-Derived Retinal Pigment Epithelium

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