Ophthalmic Research
Original Paper
Expression of Angiogenic and Inflammatory Factors in Choroidal Neovascularisation-Derived Retinal Pigment EpitheliumEhlken C.a, b · Guichard M.-M.a, d · Schlunck G.d · Bühler A.D.c, d · Martin G.d · Agostini H.T.daDepartment of Ophthalmology, University Hospital Schleswig-Holstein, Campus Kiel, Faculty of Medicine, Christian-Albrechts-University, Kiel, bEye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, and cUniversity Eye Hospital, Hannover Medical School, Hannover, Germany; dDepartment of Ophthalmology, University Hospital of Basel, Basel, Switzerland
|
|
Log in to MyKarger to check if you already have access to this content.
KAB
Buy a Karger Article Bundle (KAB) and profit from a discount!
If you would like to redeem your KAB credit, please log in.
Save over 20% compared to the individual article price.
Article / Publication Details
Received: February 13, 2017
Accepted: August 31, 2017
Published online: October 20, 2017
Issue release date: April 2019
Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 4
ISSN: 0030-3747 (Print)
eISSN: 1423-0259 (Online)
For additional information: https://www.karger.com/ORE
Abstract
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.
© 2017 S. Karger AG, Basel
Related Articles:
References
-
Klein R, Klein BEK: The prevalence of age-related eye diseases and visual impairment in aging: current estimates. Invest Opthalmol Vis Sci 2013;54:ORSF5.
-
Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, Zlateva G, et al: Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 2010;10:31.
-
Velez-Montoya R, Oliver SCN, Olson JL, Fine SL, Quiroz-Mercado H, Mandava N: Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention. Retina (Philadelphia) 2014;34:423-441.
-
Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS: Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014;8:CD005139.
-
Ozaki E, Campbell M, Kiang A-S, Humphries M, Doyle SL, Humphries P: Inflammation in age-related macular degeneration. Adv Exp Med Biol 2014;801:229-235.
-
Stanton CM, Wright AF: Inflammatory biomarkers for AMD. Adv Exp Med Biol 2014;801:251-257.
-
Horie-Inoue K, Inoue S: Genomic aspects of age-related macular degeneration. Biochem Biophys Res Commun 2014;452:263-275.
-
Finger RP, Wickremasinghe SS, Baird PN, Guymer RH: Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration. Surv Ophthalmol 2014;59:1-18.
-
Kinnunen K, Petrovski G, Moe MC, Berta A, Kaarniranta K: Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration. Acta Ophthalmol 2012;90:299-309.
-
Sparrow JR, Ueda K, Zhou J: Complement dysregulation in AMD: RPE-Bruch's membrane-choroid. Mol Aspects Med 2012;33:436-445.
-
Mettu PS, Wielgus AR, Ong SS, Cousins SW: Retinal pigment epithelium response to oxidant injury in the pathogenesis of early age-related macular degeneration. Mol Aspects Med 2012;33:376-398.
-
Hangai M, Murata T, Miyawaki N, Spee C, Lim JI, He S, et al: Angiopoietin-1 upregulation by vascular endothelial growth factor in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 2001;42:1617-1625.
-
Nagineni CN, Samuel W, Nagineni S, Pardhasaradhi K, Wiggert B, Detrick B, et al: Transforming growth factor-β induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J Cell Physiol 2003;197:453-462.
-
Zhao B, Ma A, Cai J, Boulton M: VEGF-A regulates the expression of VEGF-C in human retinal pigment epithelial cells. Br J Ophthalmol 2006;90:1052-1059.
-
Fletcher EL, Jobling AI, Greferath U, Mills SA, Waugh M, Ho T, et al: Studying age-related macular degeneration using animal models. Optom Vis Sci 2014;91:878-886.
-
Schlunck G, Martin G, Agostini HT, Camatta G, Hansen LL: Cultivation of retinal pigment epithelial cells from human choroidal neovascular membranes in age related macular degeneration. Exp Eye Res 2002;74:571-576.
-
Martin G, Schlunck G, Hansen LL, Agostini HT: Differential expression of angioregulatory factors in normal and CNV-derived human retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol 2004;242:321-326.
-
Yaari G, Bolen CR, Thakar J, Kleinstein SH: Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations. Nucleic Acids Res 2013;41:e170-e170.
-
Ehlken C, Martin G, Lange C, Gogaki EG, Fiedler U, Schaffner F, et al: Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy. Acta Ophthalmol 2011;89:82-90.
-
Ritz C, Spiess AN: qpcR: an R package for sigmoidal model selection in quantitative real-time polymerase chain reaction analysis. Bioinformatics 2008;24:1549-1551.
-
Schiaffino MV: Signaling pathways in melanosome biogenesis and pathology. Int J Biochem Cell Biol 2010;42:1094-1104.
-
van Lookeren Campagne M, LeCouter J, Yaspan BL, Ye W: Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol 2014;232:151-164.
-
Schnabolk G, Coughlin B, Joseph K, Kunchithapautham K, Bandyopadhyay M, O'Quinn EC, et al: Local production of the alternative pathway component factor B is sufficient to promote laser-induced choroidal neovascularization. Invest Ophthalmol Vis Sci 2015;56:1850-1863.
-
Rohrer B, Long Q, Coughlin B, Wilson RB, Huang Y, Qiao F, et al: A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:3056-3064.
-
Haas P, Kubista KE, Krugluger W, Huber J, Binder S: Impact of visceral fat and pro-inflammatory factors on the pathogenesis of age-related macular degeneration. Acta Ophthalmol 2015;93:533-538.
-
Hagihara K, Nishikawa T, Isobe T, Song J, Sugamata Y, Yoshizaki K: IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system. Biochem Biophys Res Commun 2004;314:363-369.
-
de Oliveira Dias JR, Rodrigues EB, Maia M, Magalhães O, Penha FM, Farah ME: Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy. Br J Ophthalmol 2011;95:1631-1637.
-
Stahl A, Paschek L, Martin G, Feltgen N, Hansen LL, Agostini HT: Combinatory inhibition of VEGF and FGF2 is superior to solitary VEGF inhibition in an in vitro model of RPE-induced angiogenesis. Graefes Arch Clin Exp Ophthalmol 2009;247:767-773.
-
Lim JI, Spee C, Hangai M, Rocha J, Ying HS, Ryan SJ, et al: Neuropilin-1 expression by endothelial cells and retinal pigment epithelial cells in choroidal neovascular membranes. Am J Ophthalmol 2005;140:1044-1050.
-
Hera R, Keramidas M, Peoc'h M, Mouillon M, Romanet J-P, Feige J-J: Expression of VEGF and angiopoietins in subfoveal membranes from patients with age-related macular degeneration. Am J Ophthalmol 2005;139:589-596.
-
Cui JZ, Hinz BJ, Greve MDJ, Potter MJ, Hornan D, Samad A, et al: Expression of neuropilin-1 in choroidal neovascular membranes. Can J Ophthalmol 2003;38:41-45.
-
Nagineni CN, Kommineni VK, William A, Detrick B, Hooks JJ: Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration. J Cell Physiol 2012;227:116-126.
-
Takagi H, Koyama S, Seike H, Oh H, Otani A, Matsumura M, et al: Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization. Invest Ophthalmol Vis Sci 2003;44:393-402.
-
Jaksik R, Iwanaszko M, Rzeszowska-Wolny J, Kimmel M: Microarray experiments and factors which affect their reliability. Biol Direct 2015;10:46.
-
Morooka S, Hoshina M, Kii I, Okabe T, Kojima H, Inoue N, et al: Identification of a dual inhibitor of SRPK1 and CK2 that attenuates pathological angiogenesis of macular degeneration in mice. Mol Pharmacol 2015;88:316-325.
-
Bhutto I, Lutty G: Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. Mol Aspects Med 2012;33:295-317.
-
Cai J, Yin G, Lin B, Wang X, Liu X, Chen X, et al: Roles of NFκB-miR-29s-MMP-2 circuitry in experimental choroidal neovascularization. J Neuroinflammation 2014;11:88.
-
Askou AL: Development of gene therapy for treatment of age-related macular degeneration. Acta Ophthalmol 2014;92(thesis 3):1-38.
-
Cashman SM, Bowman L, Christofferson J, Kumar-Singh R: Inhibition of choroidal neovascularization by adenovirus-mediated delivery of short hairpin RNAs targeting VEGF as a potential therapy for AMD. Invest Ophthalmol Vis Sci 2006;47:3496-3504.
Article / Publication Details
Received: February 13, 2017
Accepted: August 31, 2017
Published online: October 20, 2017
Issue release date: April 2019
Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 4
ISSN: 0030-3747 (Print)
eISSN: 1423-0259 (Online)
For additional information: https://www.karger.com/ORE
Copyright / Drug Dosage / Disclaimer
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.

Get Permission