Epithelial-mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

被引:24
作者
Ohlmann, Andreas [1 ]
Scholz, Michael [2 ]
Koch, Marcus [1 ]
Tamm, Ernst R. [1 ]
机构
[1] Univ Regensburg, Inst Human Anat & Embryol, Univ Str 31, D-93053 Regensburg, Germany
[2] Univ Erlangen Nurnberg, Inst Anat 2, Erlangen, Germany
关键词
Age-related macula degeneration; Transforming growth factor-beta; Transgenic mice; Photoreceptor apoptosis; Angiogenesis; ENDOTHELIAL GROWTH-FACTOR; SMOOTH MUSCLE ACTIN; MACULAR DEGENERATION; VISUAL IMPAIRMENT; CELLS; EXPRESSION; VEGF; RPE; TGF-BETA-1; TRANSDIFFERENTIATION;
D O I
10.1007/s00418-016-1461-4
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Epithelial-to-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is commonly observed at sites of choroidal neovascularization in patients suffering from age-related macular degeneration. To learn in an experimental model how RPE EMT affects the biology of the choroidal vasculature, we studied transgenic mice (beta B1-TGF-beta 1) with ocular overexpression of transforming growth factor-beta 1 (TGF-beta 1). RPE EMT was detectable at postnatal day (P)1 and included marked structural and functional alterations such as loss of the outer blood-retina barrier and reduced mRNA expression of the RPE-characteristic molecules Rlbp1, Rpe65, Rbp1 and Vegfa. Moreover, vascular endothelial growth factor (VEGF) was not detectable by immunohistochemistry at the RPE/choroid interface, while RPE cells stained intensely for alpha-smooth muscle actin. The choriocapillaris, the characteristic choroidal capillary network adjacent to the RPE, developed normally and was not obviously changed in embryonic transgenic eyes but was absent at P1 indicating its atrophy. At around the same time, photoreceptors stopped to differentiate and photoreceptor apoptosis was abundant in the second week of life. Structural changes were also seen in the retinal vasculature of transgenic animals, which did not form intraretinal vessels, and the hyaloid vasculature, which did not regress. In addition, the amounts of retinal HIF-1 alpha and its mRNA were markedly reduced. We conclude that high amounts of active TGF-beta 1 in the mouse eye cause transdifferentiation of the RPE to a mesenchymal phenotype. The loss of epithelial differentiation leads to the diminished synthesis of RPE-characteristic molecules including that of VEGF. Lack of RPE-derived VEGF causes atrophy of the choriocapillaris, a scenario that disrupts photoreceptor differentiation and finally results in photoreceptor apoptosis. Lack of retinal vessel formation and of hyaloid vessel regression might be caused by the decrease in the metabolic requirements of the neuroretina leading to low amounts of retinal HIF-1 alpha. In summary, our data indicate that failure of RPE differentiation may well precede and cause atrophy of the choriocapillaris. In contrast, RPE EMT is not sufficient to cause choroidal neovascularization.
引用
收藏
页码:769 / 780
页数:12
相关论文
共 70 条
[1]   Mechanisms of Age-Related Macular Degeneration [J].
Ambati, Jayakrishna ;
Fowler, Benjamin J. .
NEURON, 2012, 75 (01) :26-39
[2]   Choriocapillaris breakdown precedes retinal degeneration in age-related macular degeneration [J].
Biesemeier, Antje ;
Taubitz, Tatjana ;
Julien, Sylvie ;
Yoeruek, Efdal ;
Schraermeyer, Ulrich .
NEUROBIOLOGY OF AGING, 2014, 35 (11) :2562-2573
[3]  
Bochaton-Piallat ML, 2000, INVEST OPHTH VIS SCI, V41, P2336
[4]   Deletion of Ocular Transforming Growth Factor β Signaling Mimics Essential Characteristics of Diabetic Retinopathy [J].
Braunger, Barbara M. ;
Leimbeck, Sarah V. ;
Schlecht, Anja ;
Volz, Cornelia ;
Jaegle, Herbert ;
Tamm, Ernst R. .
AMERICAN JOURNAL OF PATHOLOGY, 2015, 185 (06) :1749-1768
[5]   TGF-β Signaling Protects Retinal Neurons from Programmed Cell Death during the Development of the Mammalian Eye [J].
Braunger, Barbara M. ;
Pielmeier, Stefan ;
Demmer, Cora ;
Landstorfer, Victoria ;
Kawall, Daniela ;
Abramov, Natalie ;
Leibinger, Marco ;
Kleiter, Ingo ;
Fischer, Dietmar ;
Jaegle, Herbert ;
Tamm, Ernst R. .
JOURNAL OF NEUROSCIENCE, 2013, 33 (35) :14246-14258
[6]   Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage [J].
Braunger, Barbara M. ;
Ohlmann, Andreas ;
Koch, Marcus ;
Tanimoto, Naoyuki ;
Volz, Cornelia ;
Yang, Ying ;
Boesl, Michael R. ;
Cvekl, Ales ;
Jaegle, Herbert ;
Seeliger, Mathias W. ;
Tamm, Ernst R. .
NEUROBIOLOGY OF DISEASE, 2013, 50 :1-12
[7]  
Chen X, 2014, ABSTR APPL ANAL, V2014, P1, DOI DOI 10.1371/J0URNAL.P0NE.0096365
[8]   CORRELATION OF FIBROSIS AND TRANSFORMING GROWTH FACTOR-BETA TYPE-2 LEVELS IN THE EYE [J].
CONNOR, TB ;
ROBERTS, AB ;
SPORN, MB ;
DANIELPOUR, D ;
DART, LL ;
MICHELS, RG ;
DEBUSTROS, S ;
ENGER, C ;
KATO, H ;
LANSING, M ;
HAYASHI, H ;
GLASER, BM .
JOURNAL OF CLINICAL INVESTIGATION, 1989, 83 (05) :1661-1666
[9]   Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1 [J].
Cvetanovic, Marija ;
Patel, Jay M. ;
Marti, Hugo H. ;
Kini, Ameet R. ;
Opal, Puneet .
NATURE MEDICINE, 2011, 17 (11) :1445-1447
[10]   GROWTH-FACTOR EFFECTS ON CELLS OF THE VASCULAR WALL - A SURVEY [J].
DAMORE, PA ;
SMITH, SR .
GROWTH FACTORS, 1993, 8 (01) :61-75