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      Vascular Endothelial Growth Factor Receptor-2 in Macular Oedema with Retinal Vein Occlusion

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          Abstract

          Background: To evaluate the relationships among vitreous fluid levels of soluble vascular endothelial growth factor receptor-2 (sVEGFR-2), vascular endothelial growth factor (VEGF), and the severity of macular oedema secondary to branch retinal vein occlusion (BRVO). Methods: Twenty-five BRVO patients with macular oedema were enrolled. Vitreous fluid samples were obtained during vitreoretinal surgery to measure the levels of sVEGFR-2 and VEGF. Macular oedema was examined by optical coherence tomography. Results: The vitreous fluid levels of VEGF and sVEGFR-2 were significantly correlated with the severity of macular oedema (ρ = 0.54, p = 0.008 and ρ = 0.40, p = 0.047, respectively). The sVEGFR-2 × VEGF product was also significantly correlated with the severity of macular oedema (ρ = 0.62, p = 0.003). Conclusions: The severity of macular oedema was more closely associated with sVEGFR-2 × VEGF than sVEGFR-2 or VEGF alone, suggesting that macular oedema in BRVO patients may be influenced by both VEGF and sVEGFR-2.

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          Most cited references 7

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          VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling.

          Vascular endothelial growth factor (VEGF)-A and the VEGF receptors are critical for regulating angiogenesis during development and homeostasis and in pathological conditions, such as cancer and proliferative retinopathies. Most effects of VEGF-A are mediated by the VEGFR2 and its coreceptor, neuropilin (NRP)-1. Here, we show that VEGFR2 is shed from cells by the metalloprotease disintegrin ADAM17, whereas NRP-1 is released by ADAM10. VEGF-A enhances VEGFR2 shedding by ADAM17 but not shedding of NRP-1 by ADAM10. VEGF-A activates ADAM17 via the extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase pathways, thereby also triggering shedding of other ADAM17 substrates, including tumor necrosis factor alpha, transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, and Tie-2. Interestingly, an ADAM17-selective inhibitor shortens the duration of VEGF-A-stimulated ERK phosphorylation in human umbilical vein endothelial cells, providing evidence for an ADAM17-dependent crosstalk between the VEGFR2 and ERK signaling. Targeting the sheddases of VEGFR2 or NRP-1 might offer new opportunities to modulate VEGF-A signaling, an already-established target for treatment of pathological neovascularization.
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            Multivariate analyses of inflammatory cytokines in eyes with branch retinal vein occlusion: relationships to bevacizumab treatment.

            To characterize the differential expression of intraocular inflammatory cytokines in eyes with branch retinal vein occlusion (BRVO) and to assess their roles as prognostic determinants of BRVO. A prospective cohort study of 38 eyes with BRVO. Aqueous humor samples were collected just before the intravitreal injection of bevacizumab and were assessed for 18 cytokines, chemokines, and growth factors. For control, aqueous humor was collected from 28 eyes before cataract surgery. In the aqueous of eyes with BRVO, the IL-23, IL-8, IL-6, IL-15, IL-12, and IL-17 levels were significantly higher than that in control eyes. Pretreatment visual acuity was significantly correlated with the concentrations of IL-8, IL-10, IL-2, IL-1β, IL-5, IL-6, IL-23, IL-4, MCP-1, IL-1α, IL-12, IL-13, IFN-γ, and IL-15. The pretreatment nonperfused area (NPA) was significantly correlated with the concentrations of IL-8, IL-2, MCP-1, and IL-6. Logistic regression analyses revealed significant associations between the BRVO and the concentrations of IL-8, IL-23, IL-12, IL-15, IL-10, IL-1β, and IL-13. IL-8 had the highest odds ratio (OR) and was significantly associated with NPA, central retinal thickness (CRT), and visual acuity. Bevacizumab treatment significantly improved visual acuity and CRT after 1 month. Refractoriness to bevacizumab (defined as CRT recovery 1 month after treatment by <90%) was significantly associated with the IL-12 level. Of the induced cytokines in eyes with BRVO, IL-8 was the most significantly associated with the disease parameters of BRVO. IL-12 is most likely a factor that blocks the effect of bevacizumab treatment. (www.umin.ac.jp/ctr number, UMIN000003854.).
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              Role of soluble vascular endothelial growth factor receptor-2 in macular oedema with central retinal vein occlusion.

              To measure soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) in the vitreous fluid of patients with central retinal vein occlusion (CRVO) and macular oedema or patients with idiopathic macular hole, and to investigate the relation between sVEGFR-2 and vascular endothelial growth factor (VEGF). Vitreous fluid samples were obtained from 44 patients during vitreoretinal surgery (29 patients with CRVO and 15 with macular hole). Then the sVEGFR-2 and VEGF levels were measured by ELISA. Retinal ischaemia was evaluated by measuring the area of capillary nonperfusion on fluorescein angiograms with the public domain Scion Image program. Macular oedema was examined by optical coherence tomography. CRVO patients had significantly higher vitreous levels of sVEGFR-2 (median (IQR): 1200 pg/ml (835-1740)) than macular hole patients (945 pg/ml (691-1292), p=0.042)). They also had significantly higher vitreous VEGF levels (324 pg/ml (114-1218) vs 15.6 pg/ml (15.6-15.6), p<0.001). In CRVO patients, the vitreous level of VEGF was significantly correlated with the severity of macular oedema (ρ=0.50, p=0.008), but the sVEGFR-2 level was not. The product (sVEGFR-2×VEGF) was also significantly correlated with the severity of macular oedema (ρ=0.49, p=0.008). The strength of the association with macular oedema was similar for the product (sVEGFR-2×VEGF) and for VEGF alone. These findings suggest that macular oedema in CRVO patients is more closely related to VEGF than sVEGFR-2.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2012
                June 2012
                09 March 2012
                : 48
                : 1
                : 56-58
                Affiliations
                aDepartment of Ophthalmology, Yachiyo Medical Center, Tokyo Women’s Medical University, Chiba, bDepartment of Ophthalmology, University of Tokyo Graduate School of Medicine, Tokyo, and cDepartment of Ophthalmology, Eguchi Eye Hospital, Hakodate, Japan
                Author notes
                *Hidetaka Noma, MD, Department of Ophthalmology, Yachiyo Medical Center, Tokyo Women’s Medical University, 477-96, Owada-shinden, Yachiyo, Chiba 276-8524 (Japan), Tel. +81 47 450 6000, E-Mail nomahide@tymc.twmu.ac.jp
                Article
                336020 Ophthalmic Res 2012;48:56–58
                10.1159/000336020
                22415022
                © 2012 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Pages: 3
                Categories
                Short Communication

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