Wet age-related macular degeneration (AMD) attacks the integrity of the retinal pigment epithelium (RPE) barrier system. The pathogenic process was hypothesized to be mediated by vascular endothelial growth factor (VEGF) and antagonized by pigment epithelium-derived factor (PEDF). To dissect these functional interactions, monolayer cultures of RPE cells were established, and changes in transepithelial resistance were evaluated after administration of PEDF, placenta growth factor (VEGF-R1 agonist), and VEGF-E (VEGF-R2 agonist). A recently described mechanism of VEGF inhibition in endothelia required the release of VEGF-R1 intracellular domain by γ-secretase. To evaluate this pathway in the RPE, cells were pretreated with inhibitors DAPT or LY411575. Processing of VEGF receptors was assessed by Western blot analysis. Administration of VEGF-E rapidly increased RPE permeability, and PEDF inhibited the VEGF-E response dose-dependently. Both γ-secretase antagonists prevented the inhibitory effects of PEDF. The co-administration of PEDF and VEGF-E depleted the amount of VEGF-R2 in the membrane and increased the amount of VEGF-R2 ectodomain in the media. Therefore, the inhibitory effect of PEDF appears to be mediated via the processing of VEGF-R2 by γ-secretase. γ-Secretase generates the amyloid-β (Aβ) peptide of Alzheimer disease from its precursor (amyloid precursor protein). This peptide is also a component of drusen in dry AMD. The results support the hypothesis that misregulation of γ-secretase may not only lead to Aβ deposits in dry AMD but can also be damaging to RPE function by blocking the protective effects of PEDF to prevent VEGF from driving the dry to wet AMD transition. Wet age-related macular degeneration (AMD) attacks the integrity of the retinal pigment epithelium (RPE) barrier system. The pathogenic process was hypothesized to be mediated by vascular endothelial growth factor (VEGF) and antagonized by pigment epithelium-derived factor (PEDF). To dissect these functional interactions, monolayer cultures of RPE cells were established, and changes in transepithelial resistance were evaluated after administration of PEDF, placenta growth factor (VEGF-R1 agonist), and VEGF-E (VEGF-R2 agonist). A recently described mechanism of VEGF inhibition in endothelia required the release of VEGF-R1 intracellular domain by γ-secretase. To evaluate this pathway in the RPE, cells were pretreated with inhibitors DAPT or LY411575. Processing of VEGF receptors was assessed by Western blot analysis. Administration of VEGF-E rapidly increased RPE permeability, and PEDF inhibited the VEGF-E response dose-dependently. Both γ-secretase antagonists prevented the inhibitory effects of PEDF. The co-administration of PEDF and VEGF-E depleted the amount of VEGF-R2 in the membrane and increased the amount of VEGF-R2 ectodomain in the media. Therefore, the inhibitory effect of PEDF appears to be mediated via the processing of VEGF-R2 by γ-secretase. γ-Secretase generates the amyloid-β (Aβ) peptide of Alzheimer disease from its precursor (amyloid precursor protein). This peptide is also a component of drusen in dry AMD. The results support the hypothesis that misregulation of γ-secretase may not only lead to Aβ deposits in dry AMD but can also be damaging to RPE function by blocking the protective effects of PEDF to prevent VEGF from driving the dry to wet AMD transition. Age-related macular degeneration (AMD) 2The abbreviations used are: AMDage-related macular degenerationVEGFvascular endothelial growth factorPEDFpigment epithelium-derived factorTERtransepithelial resistanceDAPT(3,5-difluorophenylacetyl)-l-alanyl-l-2-phenylglycine t-butylesterAPPamyloid precursor proteinAβamyloid-βCTFαC-terminal fragment after α-secretase cleavage of APPBELbromoenol lactoneRPEretinal pigment epitheliumADAMa disintegrin and metalloproteinasePBSphosphate-buffered salineBELbromoenol lactoneDMSOdimethyl sulfoxide. is often diagnosed by the appearance of subretinal fluid. This fluid causes a local detachment of the retina in the macular area resulting in decreased visual acuity in the center of the visual field (1Tranos P.G. Wickremasinghe S.S. Stangos N.T. Topouzis F. Tsinopoulos I. Pavesio C.E. Surv. Ophthalmol. 2004; 49: 470-490Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). The resulting macular edema can lead to complete vision loss (2Augustin A.J. Puls S. Offermann I. Retina. 2007; 27: 133-140Crossref PubMed Scopus (182) Google Scholar). Although the excessive fluid mainly comes from capillaries in the inner retina, the removal of subretinal fluid is dependent on the RPE. The maintenance of RPE barrier function is essential for the efficient removal of the fluid (3Marmor M.F. Documenta Ophthalmologica. 1999; 97: 239-249Crossref PubMed Google Scholar), and the disruption of the RPE barrier can eventually lead to choroidal neovascularization. age-related macular degeneration vascular endothelial growth factor pigment epithelium-derived factor transepithelial resistance (3,5-difluorophenylacetyl)-l-alanyl-l-2-phenylglycine t-butylester amyloid precursor protein amyloid-β C-terminal fragment after α-secretase cleavage of APP bromoenol lactone retinal pigment epithelium a disintegrin and metalloproteinase phosphate-buffered saline bromoenol lactone dimethyl sulfoxide. Recent clinical studies have shown that intravitreally administered anti-VEGF compounds are effective therapies for choroidal neovascularization (4Gragoudas E.S. Adamis A.P. Cunningham Jr., E.T. Feinsod M. Guyer D.R. N. Engl. J. Med. 2004; 351: 2805-2816Crossref PubMed Scopus (2130) Google Scholar, 5Heier J.S. Antoszyk A.N. Pavan P.R. Leff S.R. Rosenfeld P.J. Ciulla T.A. Dreyer R.F. Gentile R.C. Sy J.P. Hantsbarger G. Shams N. Ophthalmology. 2006; 113 (e641–644): 642Abstract Full Text Full Text PDF Scopus (359) Google Scholar, 6Spaide R.F. Laud K. Fine H.F. Klancnik Jr., J.M. Meyerle C.B. Yannuzzi L.A. Sorenson J. Slakter J. Fisher Y.L. Cooney M.J. Retina. 2006; 26: 383-390Crossref PubMed Scopus (603) Google Scholar). Originally, VEGF was described as an endothelial angiogenic and vasopermeability factor. The leakage through the vessels of the inner retina increases in response to VEGF (7Antcliff R.J. Marshall J. Semin. Ophthalmol. 1999; 14: 223-232Crossref PubMed Scopus (270) Google Scholar, 8Gillies M.C. Documenta Ophthalmologica. 1999; 97: 251-260Crossref PubMed Google Scholar). However, the release of VEGF also affects RPE function (9Ghassemifar R. Lai C.M. Rakoczy P.E. Cell Tissue Res. 2006; 323: 117-125Crossref PubMed Scopus (50) Google Scholar, 10Hartnett M.E. Lappas A. Darland D. McColm J.R. Lovejoy S. D'Amore P.A. Exp. Eye Res. 2003; 77: 593-599Crossref PubMed Scopus (84) Google Scholar, 11Miyamoto N. de Kozak Y. Jeanny J.C. Glotin A. Mascarelli F. Massin P. BenEzra D. Behar-Cohen F. Diabetologia. 2007; 50: 461-470Crossref PubMed Scopus (120) Google Scholar). We have recently shown that RPE barrier integrity is modulated by VEGF through apically oriented VEGF-R2 receptors (12Ablonczy Z. Crosson C.E. Exp. Eye Res. 2007; 85: 762-771Crossref PubMed Scopus (113) Google Scholar). Thus, there is a growing body of evidence that intraocular VEGF can increase the permeability of both the inner and outer blood-retina barriers, contributing to the accumulation of subretinal fluid and macular edema. Pigment epithelium-derived factor was initially identified as a neurotrophic agent secreted by fetal human RPE cells (13Tombran-Tink J. Chader G.G. Johnson L.V. Exp. Eye Res. 1991; 53: 411-414Crossref PubMed Scopus (563) Google Scholar). Subsequent experiments have recognized that PEDF is an endogenous antagonist of VEGF (14Tombran-Tink J. Front. Biosci. 2005; 10: 2131-2149Crossref PubMed Scopus (73) Google Scholar). In the eye, studies have provided evidence that endothelial quiescence and barrier function is achieved through a balance of VEGF and PEDF (15Ohno-Matsui K. Morita I. Tombran-Tink J. Mrazek D. Onodera M. Uetama T. Hayano M. Murota S.I. Mochizuki M. J. Cell. Physiol. 2001; 189: 323-333Crossref PubMed Scopus (237) Google Scholar). The PEDF secretion pattern from the RPE cells is predominantly apical, and the interphotoreceptor matrix around the RPE microvilli is a major reservoir of PEDF (16Maminishkis A. Chen S. Jalickee S. Banzon T. Shi G. Wang F.E. Ehalt T. Hammer J.A. Miller S.S. Invest. Ophthalmol. Vis. Sci. 2006; 47: 3612-3624Crossref PubMed Scopus (324) Google Scholar, 17Tombran-Tink J. Shivaram S.M. Chader G.J. Johnson L.V. Bok D. J. Neurosci. 1995; 15: 4992-5003Crossref PubMed Google Scholar). Therefore, we hypothesize that PEDF can antagonize the breakdown of RPE function induced by the apical actions of VEGF. Several schemes have been proposed for the anti-VEGF activity of PEDF. A PEDF receptor has been identified, which has phospholipase A2 activity (18Notari L. Baladron V. Aroca-Aguilar J.D. Balko N. Heredia R. Meyer C. Notario P.M. Saravanamuthu S. Nueda M.L. Sanchez-Sanchez F. Escribano J. Laborda J. Becerra S.P. J. Biol. Chem. 2006; 281: 38022-38037Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar). PEDF binding proteins without clear receptor activity have also been found (19Alberdi E. Aymerich M.S. Becerra S.P. J. Biol. Chem. 1999; 274: 31605-31612Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). In endothelial cells, PEDF has also been shown to compete with VEGF for binding at the VEGF-R2 receptor (20Zhang S.X. Wang J.J. Gao G. Parke K. Ma J.X. J. Mol. Endocrinol. 2006; 37: 1-12Crossref PubMed Scopus (205) Google Scholar). PEDF was found to regulate VEGF expression (20Zhang S.X. Wang J.J. Gao G. Parke K. Ma J.X. J. Mol. Endocrinol. 2006; 37: 1-12Crossref PubMed Scopus (205) Google Scholar, 21Yamagishi S. Matsui T. Nakamura K. Yoshida T. Shimizu K. Takegami Y. Shimizu T. Inoue H. Imaizumi T. Microvasc. Res. 2006; 71: 222-226Crossref PubMed Scopus (27) Google Scholar) and decrease VEGF receptor phosphorylation (14Tombran-Tink J. Front. Biosci. 2005; 10: 2131-2149Crossref PubMed Scopus (73) Google Scholar). A recent study in endothelia has elucidated a novel inhibitory mechanism of VEGF signaling via the PEDF-induced intramembrane proteolysis of VEGF-R1 by γ-secretase (22Cai J. Jiang W.G. Grant M.B. Boulton M. J. Biol. Chem. 2006; 281: 3604-3613Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). The goal of study is to PEDF as an agent in the RPE and to to the mechanism in this were to (12Ablonczy Z. Crosson C.E. Exp. Eye Res. 2007; 85: 762-771Crossref PubMed Scopus (113) Google Scholar). The cells were to the RPE cultures were from from a local The cells were not Both and RPE cells were on Fisher or with fetal and in a at in The was resistance and permeability assessed barrier was with an with an for were from and for the resistance of the membrane at experiments were are as the and by A of was monolayer cultures with for cells and for RPE cells (12Ablonczy Z. Crosson C.E. Exp. Eye Res. 2007; 85: 762-771Crossref PubMed Scopus (113) Google were VEGF placenta growth factor or VEGF-E was administered to the apical or of membrane with to in the or of PEDF transepithelial resistance was at and to administration this resistance was at To evaluate the actions of the γ-secretase cultures were pretreated to the with DAPT to to or dimethyl To evaluate the phospholipase A2 of the PEDF cells were pretreated to the with or saline were with The permeability was from the apical to of of were with as and to the apical of membrane with after with apical VEGF apical VEGF and apical PEDF or The the VEGF and that was in was found to and after VEGF administration (12Ablonczy Z. Crosson C.E. Exp. Eye Res. 2007; 85: 762-771Crossref PubMed Scopus (113) Google Scholar). of were from the at the of and to and by of without The were with of fluid and in a are as the of and by the was from of the amount of in the were and was the were in in at The were in at and with at The the were in at in and and were in an The were on in at and by to in for at the were in at and with for at were with The were in and with for at The were with and a and were to on membrane The apical and was with and the cells were to to described VEGF-E PEDF PEDF and VEGF-E DAPT and PEDF and VEGF-E the of the the apical and was To the was for at the was and to a of with at through a of was on and by Western an the ectodomain of the VEGF-R2 receptor or VEGF-R1 receptor to and of the VEGF receptors through the human VEGF-R2 and VEGF-R1 was used as The were with a after with and with the at experiments were are as the and by A of was these were to on The cells were with and the were with and the cells were to to described VEGF-E DAPT and PEDF and VEGF-E PEDF and VEGF-E the of the the cultures were with and with the of of complete the were from and the was from The cells were with a and for at and the was of the by protein were on and by the of VEGF-R2 and VEGF-R1 from or the amyloid precursor protein at experiments were are as the and by A of was VEGF has been shown to RPE barrier through apical VEGF-R2 receptors (12Ablonczy Z. Crosson C.E. Exp. Eye Res. 2007; 85: 762-771Crossref PubMed Scopus (113) Google Scholar). Thus, and RPE cells were on membrane and with apical VEGF-E and apical or PEDF on and RPE In both apically administered VEGF-E the This was by the apical administration of PEDF. administration of PEDF not the in in in resistance was after apical with placenta growth factor by apical or administration of PEDF not The of in is a of barrier function In was Administration of apical VEGF a increase in to the of the with both apical VEGF and apical PEDF in a of which was to the in the The results that only apical with PEDF antagonize the apical RPE response and that PEDF compete with VEGF for binding at the VEGF-R2 receptor (20Zhang S.X. Wang J.J. Gao G. Parke K. Ma J.X. J. Mol. Endocrinol. 2006; 37: 1-12Crossref PubMed Scopus (205) Google Scholar), a mechanism in which the of the VEGF and PEDF response is by VEGF-R2 of were used to the of VEGF-R2 in The of the the inner and outer and the In the RPE, only the apical was the of VEGF-R2 in to the In without the VEGF-R2 was in the RPE, the were at the In a PEDF at and with VEGF for binding at VEGF-R2 (20Zhang S.X. Wang J.J. Gao G. Parke K. Ma J.X. J. Mol. Endocrinol. 2006; 37: 1-12Crossref PubMed Scopus (205) Google Scholar). and RPE were with VEGF-E and of PEDF To functional the in at to In both the decrease induced by VEGF-E was inhibited by PEDF. was for cells and for RPE The of the were not from This was by the VEGF-E in cells and in the of of PEDF and the in in at in the and of PEDF. of these a of the of an antagonist required to a of the of and a of for PEDF. Thus, the to PEDF are with a and the binding was The that PEDF induced a inhibition of the Therefore, in we used of PEDF. The that the actions of PEDF are with a VEGF-R2 However, the VEGF response was by PEDF at required to VEGF binding to Recent studies in endothelial cells have provided evidence that PEDF of VEGF-R1 via the of γ-secretase (22Cai J. Jiang W.G. Grant M.B. Boulton M. J. Biol. Chem. 2006; 281: 3604-3613Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). receptors may as we evaluated γ-secretase was for PEDF to VEGF actions in RPE of and RPE cells were pretreated with the γ-secretase DAPT or to with PEDF VEGF-E with DAPT prevented PEDF from blocking the in PEDF DAPT the resistance To these monolayer cultures of cells were pretreated with of DAPT or to with PEDF and VEGF-E is a γ-secretase DAPT A. E. H. A. P. G. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). shown in both antagonists the inhibitory of PEDF on the barrier breakdown in a However, the response for was with DAPT The activity of γ-secretase was by APP processing Y. A. C. A. S. Y. S.M. K. J. PubMed Scopus Google Scholar). APP is by α-secretase to the and the C-terminal fragment which is by γ-secretase. Thus, the activity of γ-secretase is to the amount of were pretreated with DAPT or to with VEGF-E PEDF and that the of VEGF-E a but not increase in γ-secretase of PEDF and VEGF-E for increased γ-secretase activity by in with the results of (22Cai J. Jiang W.G. Grant M.B. Boulton M. J. Biol. Chem. 2006; 281: 3604-3613Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar) for this with DAPT γ-secretase activity and an accumulation of as to (22Cai J. Jiang W.G. Grant M.B. Boulton M. J. Biol. Chem. 2006; 281: 3604-3613Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar), PEDF not γ-secretase activity in not that the expression of the of not the To the of a recently PEDF receptor (18Notari L. Baladron V. Aroca-Aguilar J.D. Balko N. Heredia R. Meyer C. Notario P.M. Saravanamuthu S. Nueda M.L. Sanchez-Sanchez F. Escribano J. Laborda J. Becerra S.P. J. Biol. Chem. 2006; 281: 38022-38037Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar) is required to antagonize RPE barrier monolayer cultures of cells were pretreated with a phospholipase A2 A2 activity has been a of receptor (18Notari L. Baladron V. Aroca-Aguilar J.D. Balko N. Heredia R. Meyer C. Notario P.M. Saravanamuthu S. Nueda M.L. Sanchez-Sanchez F. Escribano J. Laborda J. Becerra S.P. J. Biol. Chem. 2006; 281: 38022-38037Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar). that with to with PEDF VEGF-E not the of PEDF to the decrease induced by γ-secretase are to the to the C-terminal fragment is by γ-secretase to release the intracellular domain I. H. A. T. C. C. L. K. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). provided evidence in RPE cells, VEGF-R2 can be a of γ-secretase. To to this we the release of VEGF-R2 ectodomain the of the membrane in response to with PEDF and VEGF-E and with DAPT or Western blot with an the ectodomain of VEGF-R2 in the apical media. A at is shown with a for VEGF-R2 J.M. G. S. P.E. D. Mol. Res. 2004; Google Scholar). the of in experiments to the found in the The amount of VEGF-R2 ectodomain was not after not with PEDF and VEGF-E to an increase in the of VEGF-R2 This increase was by with The not VEGF-R2 ectodomain not To that VEGF-R2 is from RPE we the of VEGF-R2 in membrane a C-terminal VEGF-R2 cells were with PEDF and VEGF-E to the experiments Western blot and the VEGF-R2 at was in VEGF or PEDF not the expression of VEGF-R2 in the However, in with PEDF and the was with DAPT prevented the decrease in Although changes in were not with the VEGF-R1 placenta growth VEGF receptors can VEGF-R1 and VEGF-R2 M. J. D. A. L. D. J. S. M. F. S. G. K. D. M. S. D. P. C. G. J.M. D. M. D. P. Med. 2003; PubMed Scopus Google Scholar). Therefore, the that VEGF-R1 receptor is after VEGF-E binding to To VEGF-R1 ectodomain were in the apical with PEDF, and DAPT as A to the ectodomain of VEGF-R1 was in the However, the of the not in response to with PEDF and VEGF-E or pretreated with DAPT release of VEGF-R1 from the was with the VEGF-R1 The VEGF-R1 was not by the Therefore, appears that VEGF-R2 and not VEGF-R1 is the of processing in the RPE. in and in experiments have shown that in VEGF secretion from RPE cells predominantly at the (16Maminishkis A. Chen S. Jalickee S. Banzon T. Shi G. Wang F.E. Ehalt T. Hammer J.A. Miller S.S. Invest. Ophthalmol. Vis. Sci. 2006; 47: 3612-3624Crossref PubMed Scopus (324) Google Scholar, H. A.N. P. T.A. K. M.E. A. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and is required for H. A.N. P. T.A. K. M.E. A. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Y. N. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). 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In the RPE cells, the proteolysis of VEGF-R1 was not required and Although results support the that an of VEGF-R2 is the of γ-secretase in the RPE, be at this that γ-secretase is mediated by the cleavage of a protein or the activity of which is by PEDF. experiments provided evidence that both VEGF-E and PEDF are required to on VEGF-R2 have a activity can the of the proposed mechanism of γ-secretase is with the of VEGF-R2 signaling are shown in In of the of is that the PEDF as a of the this can be γ-secretase cleavage the of an as have been identified in A. J.A. M.E. H.F. PubMed Scopus Google Scholar), and matrix are to as are to be by RPE cells A. L. Marshall J. Invest. Ophthalmol. Vis. Sci. Google Scholar). the expression of and the of in the RPE have not been In a recent has been shown to be the for the of VEGF-R2 ectodomain in cells S. K. G. K. P. A. S. Res. PubMed Scopus Google Scholar). of increased VEGF-R2 ectodomain in the apical both VEGF-E and PEDF were can be to a the ectodomain of VEGF-R2 can VEGF-R2 as an effective In the VEGF-R2 ectodomain has been used with to in Y. L. G. Wang Y. J. Shi Y. Exp. Mol. 2004; PubMed Scopus Google Scholar). VEGF-R2 has been identified in of endothelial cells as as from the J.M. G. S. P.E. D. Mol. Res. 2004; Google Scholar). that the hypothesized to be a can be a of PEDF-induced proteolysis of The of γ-secretase in the maintenance of RPE barrier function is an Aβ of is a component of drusen in dry AMD A.J. E. Johnson L.V. Exp. Eye Res. 2004; PubMed Scopus Google Scholar, T. Mol. Vis. 2003; Google Scholar, L.V. A.J. M.J. Sci. PubMed Scopus Google Scholar). results that PEDF and VEGF are both the processing of APP is the that and γ-secretase may to the of drusen a This that may be for in Alzheimer disease and drusen in dry AMD. results are with the hypothesis that Aβ is with the of AMD T. K. S. T. N. T. Mochizuki M. Morita I. J. Invest. 2005; PubMed Scopus Google Scholar). In and have provided evidence that PEDF can RPE barrier function in the of VEGF-R2 The functional response of RPE cells to PEDF is to the apical the VEGF-R2 receptors are and is mediated by γ-secretase. Thus, in apical VEGF is PEDF RPE barrier function through the proteolysis of VEGF-R2 and membrane proteins as contributing to the of dry AMD. that the from dry to wet AMD the proteolysis of VEGF-R2 by γ-secretase is VEGF signaling in the RPE. is in to the of the mechanism of VEGF-R2 processing by the system. We to and for
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