Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells

Molecular Vision

Volumn 19, Issue , 2013, Pages 2274-2297

  Whitmore, S Scott ^a,b   Braun, Terry A ^a,b   Skeie, Jessica M ^a,b   Haas, Christine M ^a,b   Sohn, Elliott H ^a,b   Stone, Edwin M ^a,b   Scheetz, Todd E ^a,b   Mullins, Robert F ^a,b  

^a UNIVERSITY OF IOWA   (United States)

^b UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COMPLEMENT FACTOR H;

ADAMTS9 GENE; AGED; ARTICLE; CHOROID; CHOROID CAPILLARY LAYER; CHOROIDAL ENDOTHELIAL CELL; CLINICAL ARTICLE; COMPLEMENT FACTOR H GENE; CONTROLLED STUDY; DRY EYE; ENDOTHELIUM CELL; EXON; FEMALE; GENE; GENE EXPRESSION; GENETIC RISK; GENOTYPE; HUMAN; HUMAN TISSUE; MALE; MICROARRAY ANALYSIS; PIGMENT EPITHELIUM; PRIORITY JOURNAL; RETINA MACULA AGE RELATED DEGENERATION; VASCULAR ENDOTHELIUM;

AGED, 80 AND OVER; CASE-CONTROL STUDIES; CHOROID; COMPLEMENT FACTOR H; COMPUTATIONAL BIOLOGY; ENDOTHELIAL CELLS; ENDOTHELIUM, VASCULAR; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MACULAR DEGENERATION; MALE; QUALITY CONTROL; RETINAL PIGMENT EPITHELIUM; RISK FACTORS;

EID: 84887838450     PISSN: None     EISSN: 10900535     Source Type: Journal    
DOI: None     Document Type: Article

References (67)

1. Coleman HR, Chan CC, Ferris FL, Chew EY. Age-related macular degeneration. Lancet 2008; 372:1835-1845. PMID: 19027484.
2. Strauss O. The retinal pigment epithelium in visual function. Physiol Rev 2005; 85:845-881. PMID: 15987797.
3. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D'Amore PA. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci USA 2009; 106:18751-18756. PMID: 19841260.
4. Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M. Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest 2012; 122:4213-4217. PMID: 23093773.
5. Curcio CA, Millican CL. Basal linear deposit and large drusen are specific for early age-related maculopathy. Arch Ophthalmol 1999; 117:329-339. PMID: 10088810.
6. Curcio CA, Millican CL. Age-Related Eye Disease Study Research Group. A random-ized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001; 119:1417-1436. PMID: 11594942.
7. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004; 122:598-614. PMID: 15078679.
8. Ambati J, Fowler BJ. Mechanisms of age-related macular degeneration. Neuron 2012; 75:26-39. PMID: 22794258.
9. Mullins RF, Johnson MN, Faidley EA, Skeie JM, Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 2011; 52:1606-1612. PMID: 21398287.
10. McLeod DS, Grebe R, Bhutto I, Merges C, Baba T, Lutty GA. Relationship between RPE and choriocapillaris in age-related macular degeneration. Invest Ophthalmol Vis Sci 2009; 50:4982-4991. PMID: 19357355.
11. Grunwald JE, Metelitsina TI, Dupont JC, Ying G-S, Maguire MG. Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci 2005; 46:1033-1038. PMID: 15728562.
12. Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 1996; 37:1929-1934. PMID: 8759365.
13. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, the MARINA Study Group. Ranibi-zumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1419-1431. PMID: 170 21318.
14. Newman AM, Gallo NB, Hancox LS, Miller NJ, Radeke CM, Maloney MA, Cooper JB, Hageman GS, Anderson DH, Johnson LV, Radeke MJ. Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks. Genome Medicine 2012; 4:16PMID: 22364233.
15. Hunter A, Spechler PA, Cwanger A, Song Y, Zhang Z, Ying GS, Hunter AK, Dezoeten E, Dunaief JL. DNA methylation is associated with altered gene expression in AMD. Invest Ophthalmol Vis Sci 2012; 53:2089-2105. PMID: 22410570.
16. Swiderski RE, Nishimura DY, Mullins RF, Olvera MA, Ross JL, Huang J, Stone EM, Sheffield VC. Gene expression analysis of photoreceptor cell loss in bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage. Invest Ophthalmol Vis Sci 2007; 48:3329-3340. PMID: 17591906.
17. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4:249-264. PMID: 12925520.
18. Emig D, Salomonis N, Baumbach J, Lengauer T, Conklin BR, Albrecht M. AltAnalyze and DomainGraph: analyzing and visualizing exon expression data. Nucleic Acids Res 2010; 38:W755-W762. PMID: 20513647.
19. Leek JT, Scharpf RB, Bravo HC, Simcha D, Langmead B, Johnson WE, Geman D, Baggerly K, Irizarry RA. Tackling the widespread and critical impact of batch effects in high-throughput data. Nat Rev Genet 2010; 11:733-739. PMID: 20838408.
20. Walker WL, Liao IH, Gilbert DL, Wong B, Pollard KS, McCulloch CE, Lit L, Sharp FR. Empirical Bayes accomo-dation of batch-effects in microarray data using identical replicate reference samples: application to RNA expression profiling of blood from Duchenne muscular dystrophy patients. BMC Genomics 2008; 9:494PMID: 18937867.
21. Chen C, Grennan K, Badner J, Zhang D, Gershon E, Jin L, Liu C. Removing batch effects in analysis of expression micro-array data: an evaluation of six batch adjustment methods. PLoS ONE 2011; 6:e17238PMID: 21386892.
22. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc, B 1995; 57:289-300.
23. R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. 2011.
24. Gentleman R, Ding B, Dudoit S, Ibrahim J. Distance Measures in DNA Microarray Data Analysis. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. New York, NY: Springer Science+Business Media; 2005. p. 189-208.
25. Affymetrix. Alternative transcript analysis methods for exon arrays. Affymetrix whitepapers. 2005
26. Smoot ME, Ono K, Ruscheinski J, Wang P-L, Ideker T. Cyto-scape 2.8: new features for data integration and network visualization. Bioinformatics 2011; 27:431-432. PMID:21149340.
27. Kauffmann A, Gentleman R, Huber W. arrayqualitymetrics-a bioconductor package for quality assessment of microarray data. Bioinformatics 2009; 25:415-416. PMID: 1910 6121.
28. Kinsella RJ, Kähäri A, Haider S, Zamora J, Proctor G, Spudich G, Almeida-King J, Staines D, Derwent P, Kerhornou A, Kersey P, Flicek P. Ensembl BioMarts: a hub for data retrieval across taxonomic space. Database (Oxford) 2011; 2011:bar030-PMID: 2178 514 2.
29. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102:15545-15550. PMID: 1619 9517.
30. Reich M, Liefeld T, Gould J, Lerner J, Tamayo P, Mesirov JP. GenePattern 2.0. Nat Genet 2006; 38:500-501. PMID: 166 420 0 9.
31. Huang W, Sherman BT, Lempicki RA. Systematic and integra-tive analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4:44-57. PMID: 19131956.
32. Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, de Jong PT, Klaver CC, Klein BE, Klein R. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 1995; 39:367-374. PMID: 7604360.
33. Booij JC, Ten Brink JB, Swagemakers SMA, Verkerk AJMH, Essing AHW, van der Spek PJ, Bergen AAB. A new strategy to identify and annotate human RPE-specific gene expression. PLoS ONE 2010; 5:e9341PMID: 20479888.
34. Steele FR, Chader GJ, Johnson LV, Tombran-Tink J. Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc Natl Acad Sci USA 1993; 90:1526-1530. PMID: 8 434014.
35. Bernat JA, Crawford GE, Ogurtsov AY, Collins FS, Ginsburg D, Kondrashov AS. Distant conserved sequences flanking endothelial-specific promoters contain tissue-specific DNase-hypersensitive sites and over-represented motifs. Hum Mol Genet 2006; 15:2098-2105. PMID: 16723375.
36. Bowes Rickman C, Ebright JN, Zavodni ZJ, Yu L, Wang T, Daiger SP, Wistow G, Boon K, Hauser MA. Defining the human macula transcriptome and candidate retinal disease genes using EyeSAGE. Invest Ophthalmol Vis Sci 2006; 47:2305-2316. PMID: 16723438.
37. van Soest SS, de Wit GMJ, Essing AHW, Ten Brink JB, Kamphuis W, de Jong PTVM, Bergen AAB. Comparison of human retinal pigment epithelium gene expression in macula and periphery highlights potential topographic differences in Bruch's membrane. Mol Vis 2007; 13:1608-1617. PMID: 17893662.
38. Bonilha VL, Rayborn ME, Bhattacharya SK, Gu X, Crabb JS, Crabb JW, Hollyfield JG. The retinal pigment epithelium apical microvilli and retinal function. Adv Exp Med Biol 2006; 572:519-524. PMID: 17249618.
39. Hageman GS, Marmor MF, Yao XY, Johnson LV. The inter-photoreceptor matrix mediates primate retinal adhesion. Arch Ophthalmol 1995; 113:655-660. PMID: 7748138.
40. Yuan X, Gu X, Crabb JS, Yue X, Shadrach K, Hollyfield JG, Crabb JW. Quantitative proteomics: comparison of the macular Bruch membrane/choroid complex from age-related macular degeneration and normal eyes. Mol Cell Proteomics 2010; 9:1031-1046. PMID: 2 0177130.
41. Mullins RF, Dewald AD, Streb LM, Wang K, Kuehn MH, Stone EM. Elevated membrane attack complex in human choroid with high risk complement factor H genotypes. Exp Eye Res 2011; 93:565-567. PMID: 21729696.
42. Koo B-H, Coe DM, Dixon LJ, Somerville RPT, Nelson CM, Wang LW, Young ME, Lindner DJ, Apte SS. ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells. Am J Pathol 2010; 176:1494-1504. PMID: 20093484.
43. The AMD Gene Consortium, Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, Zack DJ, Arakawa S, Cipriani V, Ripke S, Igo RP, Buitendijk GHS, Sim X, Weeks DE, Guymer RH, Merriam JE, Francis PJ, Hannum G, Agarwal A, Armbrecht A-M, Audo I, Aung T, Barile GR, Benchaboune M, Bird AC, Bishop PN, Branham KE, Brooks M, Brucker AJ, Cade WH, Cain MS, Campochiaro PA, Chan CC, Cheng CY, Chew EY, Chin KA, Chowers I, Clayton DG, Cojocaru R, Conley YP, Cornes BK, Daly MJ, Dhillon B, Edwards AO, Evangelou E, Fagerness J, Ferreyra HA, Friedman JS, Geirsdóttir A, George RJ, Gieger C, Gupta N, Hagstrom SA, Harding SP, Haritoglou C, Heckenlively JR, Holz FG, Hughes G, Ioannidis JPA, Ishibashi T, Joseph P, Jun G, Kamatani Y, Katsanis NN, Keilhauer C, Khan JC, Kim IK, Kiyohara Y, Klein BEK, Klein R, Kovach JL, Kozak I, Lee CJ, Lee KE, Lichtner P, Lotery AJ, Meitinger T, Mitchell P, Mohand-Saïd S, Moore AT, Morgan DJ, Morrison MA, Myers CE, Naj AC, Nakamura Y, Okada Y, Orlin A, Ortube MC, Othman MI, Pappas C, Park KH, Pauer GJT, Peachey NS, Poch O, Priya RR, Reynolds R, Richardson AJ, Ripp R, Rudolph G, Ryu E, Sahel JA, Schaumberg DA, Scholl HPN, Schwartz SG, Scott WK, Shahid H, Sigurdsson H, Silvestri G, Sivakumaran TA, Smith RT, Sobrin L, Souied EH, Stambolian DE, Stefansson H, Sturgill-Short GM, Takahashi A, Tosakulwong N, Truitt BJ, Tsironi EE, Uitter-linden AG, van Duijn CM, Vijaya L, Vingerling JR, Vithana EN, Webster AR, Wichmann H-E, Winkler TW, Wong TY, Wright AF, Zelenika D, Zhang M, Zhao L, Zhang K, Klein ML, Hageman GS, Lathrop GM, Stefansson K, Allikmets R, Baird PN, Gorin MB, Wang JJ, Klaver CCW, Seddon JM, Pericak-Vance MA, Iyengar SK, Yates JRW, Swaroop A, Weber BHF, Kubo M, DeAngelis MM, Léveillard T, Thor-steinsdottir U, Haines JL, Farrer LA, Heid IM, Abecasis GR. Seven new loci associated with age-related macular degeneration. Nat Genet 2013; 45:433-439. PMID: 23455636.
44. Bevitt DJ, Mohamed J, Catterall JB, Li Z, Arris CE, Hiscott P, Sheridan C, Langton KP, Barker MD, Clarke MP, McKie N. Expression of ADAMTS metalloproteinases in the retinal pigment epithelium derived cell line ARPE-19: transcrip-tional regulation by TNFalpha. Biochim Biophys Acta 2003; 1626:83-91. PMID: 12697333.
45. Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, Seddon JM. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 2006; 38:1055-1059. PMID: 16936732.
46. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, Group AGCS, Hageman GS, Dean M, Allikmets R. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006; 38:458-462. PMID: 16518 4 03.
47. Yates JRW, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht A-M, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT, The Genetic Factors in AMD Study Group. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007; 357:553-561. PMID: 17634448.
48. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007; 39:1200-1201. PMID: 1776715 6.
49. Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, Kamei M, Hasan A, Yan L, Rayborn ME, Salomon RG, Hollyfield JG. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 2002; 99:14682-14687. PMID: 12391305.
50. Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308:421-424. PMID: 15761121.
51. Klein RJ, Zeiss C, Chew EY, Tsai J-Y, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308:385-389. PMID: 1576112 2.
52. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308:419-421. PMID: 15761120.
53. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, Tosakulwong N, Pericak-Vance MA, Campochiaro PA, Klein ML, Tan PL, Conley YP, Kanda A, Kopplin L, Li Y, Augustaitis KJ, Karoukis AJ, Scott WK, Agarwal A, Kovach JL, Schwartz SG, Postel EA, Brooks M, Baratz KH, Brown WL, Brucker AJ, Orlin A, Brown G, Ho A, Regillo C, Donoso L, Tian L, Kaderli B, Hadley D, Hagstrom SA, Peachey NS, Klein R, Klein BEK, Gotoh N, Yamashiro K, Ferris Iii F, Fagerness JA, Reynolds R, Farrer LA, Kim IK, Miller JW, Cortón M, Carracedo A, Sanchez-Salorio M, Pugh EW, Doheny KF, Brion M, DeAngelis MM, Weeks DE, Zack DJ, Chew EY, Heckenlively JR, Yoshimura N, Iyengar SK, Francis PJ, Katsanis N, Seddon JM, Haines JL, Gorin MB, Abecasis GR, Swaroop A. Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Group. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci USA 2010; 107:7401-7406. PMID: 20385819.
54. Wang L, Clark ME, Crossman DK, Kojima K, Messinger JD, Mobley JA, Curcio CA. Abundant lipid and protein components of drusen. PLoS ONE 2010; 5:e10329. PMID: 20428236.
55. Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 2009; 17: 100-104. PMID: 186 85559.
56. Tuo J, Ning B, Bojanowski CM, Lin Z-N, Ross RJ, Reed GF, Shen D, Jiao X, Zhou M, Chew EY, Kadlubar FF, Chan CC. Synergic effect of polymorphisms in ERCC6 5′ flanking region and complement factor H on age-related macular degeneration predisposition. Proc Natl Acad Sci USA 2006; 103:9256-9261. PMID: 16754848.
57. Yu Y, Bhangale TR, Fagerness J, Ripke S, Thorleifsson G, Tan PL, Souied EH, Richardson AJ, Merriam JE, Buitendijk GHS, Reynolds R, Raychaudhuri S, Chin KA, Sobrin L, Evangelou E, Lee PH, Lee AY, Leveziel N, Zack DJ, Campochiaro B, Campochiaro P, Smith RT, Barile GR, Guymer RH, Hogg R, Chakravarthy U, Robman LD, Gustafsson O, Sigurdsson H, Ortmann W, Behrens TW, Stefansson K, Uitterlinden AG, van Duijn CM, Vingerling JR, Klaver CCW, Allikmets R, Brantley MA, Baird PN, Katsanis N, Thorsteinsdottir U, Ioannidis JPA, Daly MJ, Graham RR, Seddon JM. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet 2011; 20:3699-3709. PMID: 21665990.
58. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005; 77:389-407. PMID: 16 0 8 0115.
59. Dewan A, Liu M, Hartman S, Zhang SSM, Liu DTL, Zhao C, Tam POS, Chan WM, Lam DSC, Snyder M, Barnstable C, Pang CP, Hoh J. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006; 314:989-992. PMID: 170 5310 8.
60. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006; 314:992-993. PMID: 170 5310 9.
61. Arakawa S, Takahashi A, Ashikawa K, Hosono N, Aoi T, Yasuda M, Oshima Y, Yoshida S, Enaida H, Tsuchihashi T, Mori K, Honda S, Negi A, Arakawa A, Kadonosono K, Kiyohara Y, Kamatani N, Nakamura Y, Ishibashi T, Kubo M. Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nat Genet 2011; 43:1001-1004. PMID: 21909106.
62. Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agarwal A, Postel EA, Olson L, Kenealy SJ, Hauser M, Gilbert JR, Pericak-Vance MA. Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci 2006; 47:329-335. PMID: 16384981.
63. McLeod DS, Lefer DJ, Merges C, Lutty GA. Enhanced expres-sion of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol 1995; 147:642-653. PMID: 7545873.
64. Mullins RF, Skeie JM, Folk JC, Solivan-Timpe FM, Oetting TA, Huang J, Wang K, Stone EM, Fingert JH. Evaluation of variants in the selectin genes in age-related macular degeneration. BMC Med Genet 2011; 12:58. PMID: 21521525.
65. Almulki L, Noda K, Nakao S, Hisatomi T, Thomas KL, Hafezi-Moghadam A. Localization of vascular adhesion protein-1 (VAP-1) in the human eye. Exp Eye Res 2010; 90:26-32. PMID: 19761765.
66. Hageman GS, Zhu XL, Waheed A, Sly WS. Localization of carbonic anhydrase IV in a specific capillary bed of the human eye. Proc Natl Acad Sci USA 1991; 88:2716-2720. PMID: 19 01414.
67. Otani A, Takagi H, Oh H, Koyama S, Matsumura M, Honda Y. Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci 1999; 4 0:1912-1920. PMID: 10440243.