RNA-Seq analysis of gene expression profiling in human retinal vascular endothelial cells after anti-vascular endothecial growth factor treatment_Chinese Journal of Ocular Fundus Diseases

Authors：

Niu Rui , Dong Lijie , Ma Teng , Du Xueli , He Yanhua , Cui Weina ,  Hu Bojie

Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute, Tianjin Medical University School of Optometry and Ophthalmology, Tianjin 300384, China;

Corresponding author：

Hu Bojie, Email: bhu07@tmu.edu.cn

Keywords：

Retinal Vessels/cytology; Endothelial cells; Gene expression profiling; Angiogenesis Inhibitors/therapeutic use

DOI：

10.3760/cma.j.issn.1005-1015.2018.03.016

Video：

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ObjectiveTo observe RNA-Seq analysis of gene expression profiling in human retinal vascular endothelial cells after anti-vascular endothecial growth factor (VEGF) treatment.MethodsCultured the retinal vascular endothelial cells in vitro and logarithmic growth phase cells were used for experiments. The cells were divided into VEGF group and VEGF combined with anti-VEGF drugs group. The VEGF group cells were treated with 50 ng/ml VEGF for 72 h to simulate the high VEGF survival conditions of vascular endothelial cells in diabetic retinopathy. VEGF combined with anti-VEGF drug group cells was treated with 50 ng/ml VEGF and 2.5 μg/ml anti-VEGF drugs for 72 h to imitate the microenvironment of cells following the anti-VEGF drugs treatment, and whole transcriptome sequencing approach was applied to the above two groups of cells through RNA-Seq. Now with biological big data obtained as a basis, to analyze the differentially expressed genes (DEGs). And through enrichment analysis to explain the differential functions of DEGs and their signal pathways.ResultsThe gene expression profiles of the two groups of cells were obtained. Through analysis, 328 DEGs were found, including 194 upregulated and 133 downregulated ones. The functions of DEGs were influenced by regulations over molecular biological process, cellular energy metabolism and protein synthesis, etc. Among these genes, SI,PRX and HPGD were related to protein synthesis, BIRCT to cellular apoptosis, and ABLIM1 and CRB2 to retinal development, and ABCG1, ABCA9 and ABCA12 were associated with the cholesterol of macrophage and the transfer of phospholipid. GO enrichment analysis showed that DEGs mainly act in three ways: regulating biological behavior, organizing cellular component and performing molecular function. Pathway enrichment analysis showed that gene expressions of the two cell groups were differentiated in ECM receptor pathway, and Notch, mitogen-activated protein kinase, transforming growth factor (TGF)-β and Wnt signal pathways. Among them, the gene expression in TGF-β signal pathway attracts most attention, where the DEGs, such as CAMK2B, COL3A1, CYGB, PTGER2 and HS6ST2, among others, were closely related to fibrosis process.ConclusionThe anti-VEGF drugs may enhance the expression of CAMK2B, COL3A1, CYGB, PTGER2 and others genes related to TGF-β signal pathway and aggravate retinal fibrosis disease.

Citation： Niu Rui, Dong Lijie, Ma Teng, Du Xueli, He Yanhua, Cui Weina, Hu Bojie. RNA-Seq analysis of gene expression profiling in human retinal vascular endothelial cells after anti-vascular endothecial growth factor treatment. Chinese Journal of Ocular Fundus Diseases, 2018, 34(3): 275-280. doi: 10.3760/cma.j.issn.1005-1015.2018.03.016 Copy

1.	Wei Q, Zhang T, Jiang R, et al. Vitreous fibronectin and fibrinogen expression increased in eyes with proliferative diabetic retinopathy after intravitreal anti-VEGF therapy[J]. Invest Ophthalmol Vis Sci, 2017, 58(13): 5783-5791. DOI: 10.1167/iovs.17-22345.
2.	Geest RJV, Lesnikoberstein SY, Tan HS, et al. A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy[J]. Br J Ophthalmol, 2012, 96(4): 587-590. DOI: 10.1136/bjophthalmol-2011-301005.
3.	胡博杰, 曾勍, 刘新玲, 等. Avastin玻璃体腔注射后糖尿病视网膜病变增生膜中细胞因子的变化[J]. 中华实验眼科杂志, 2013, 31(1): 55-59. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.013.Hu BJ, Zeng Q, Liu XL, et al. Influence of intravitreal avastin on the expression of cell factors in retinal proliferative membrane in proliferative diabetic retinopathy eye[J]. Chin J Exp Ophthalmol, 2013, 31(1): 55-59. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.013.
4.	Mi VDR, La Heij EC, De JY, et al. A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections[J]. Retina, 2011, 31(8): 1449-1469. DOI: 10.1097/IAE.0b013e3182278ab4.
5.	Zhang M, Chu S, Zeng F, et al. Bevacizumab modulates the process of fibrosis in vitro.[J]. Clin Exp Ophthalmol, 2015, 43(2): 173-179. DOI: 10.1111/ceo.12374.
6.	Arevalo J, Maia MHJ, Saravia M, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy[J]. Br J Ophthalmol, 2008, 92(2): 213-216. DOI: 10.1136/bjo.2007.127142.
7.	Jonas JB, Schmidbauer M, Rensch F. Progression of tractional retinal detachment following intravitreal bevacizumab[J]. Acta Ophthalmol, 2009, 87(5): 571-572. DOI: 10.1111/j.1755-3768.2008.01225.x.
8.	Batman C, Ozdamar Y. The relation between bevacizumab injection and the formation of subretinal fibrosis in diabetic patients with panretinal photocoagulation[J]. Ophthalmic Surg Lasers Imaging, 2010, 41(2): 190-195. DOI: 10.3928/15428877-20100303-06.
9.	Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics[J]. Nat Rev Genet, 2009, 10(1): 57-63. DOI: 10.1038/nrg2484.
10.	Xiang L, Chen GH, Wei YZ, et al. Genome-wide transcriptional analysis of maize endosperm in response to ae wx double mutations[J]. J Genet Genomics, 2010, 37(11): 749-762. DOI: 10.1016/S1673-8527(09)60092-8.
11.	Massagué J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders[J]. Cell, 2000, 103(2): 295-309.
12.	Liu JC, Wang F, Xie ML, et al. Osthole inhibits the expressions of collagen I and III through Smad signaling pathway after treatment with TGF-β1 in mouse cardiac fibroblasts[J]. Int J Cardiol, 2017, 228: 388-393. DOI: 10.1016/j.ijcard.2016.11.202.
13.	Cui L, Wang Y, Yu R, et al. Jia-Shen decoction-medicated serum inhibits angiotensin-Ⅱ induced cardiac fibroblast proliferation via the TGF-β1/Smad signaling pathway[J]. Mol Med Rep, 2016, 14(2): 1610-1616. DOI: 10.3892/mmr.2016.5405.
14.	Ihn H. Pathogenesis of fibrosis: role of TGF-beta and CTGF[J]. Curr Opin Rheumatol, 2002, 14(6): 681-685.
15.	Hung CM, Kuo DH, Chou CH, et al. Osthole suppresses hepatocyte growth factor (HGF)-induced epithelial-mesenchymal transition via repression of the c-Met/Akt/mTOR pathway in human breast cancer cells[J]. J Agric Food Chem, 2011, 59(17): 9683-9690. DOI: 10.1021/jf2021489.
16.	Xu P, Liu J, Derynck R. Post-translational regulation of TGF-β receptor and Smad signaling[J]. FEBS Lett, 2012, 586(14): 1871-1884. DOI: 10.1016/j.febslet.2012.05.010.
17.	Massagué J, Xi Q. TGF-β control of stem cell differentiation genes[J]. FEBS Lett, 2012, 586(14): 1953-1958. DOI: 10.1016/j.febslet.2012.03.023.
18.	Santalla M, Valverde CA, Harnichar E, et al. Aging and CaMKⅡ alter intracellular Ca²⁺ transients and heart rhythm in Drosophila melanogaster[J/OL]. PLoS One, 2014, 9(7): 101871[2014-07-08]. http://dx.plos.org/10.1371/journal.pone.0101871. DOI: 10.1371/journal.pone.0101871.
19.	Mukherjee S, Sheng W, Sun R, et al. Ca²⁺/calmodulin-dependent protein kinase Ⅱβ and Ⅱδ mediate TGFβ-induced transduction of fibronectin and collagen in human pulmonary fibroblasts[J]. Am J Physiol Lung Cell Mol Physiol, 2017, 312(4): 510-519. DOI: 10.1152/ajplung.00084.2016.
20.	Li X, Wu Z, Ni J, et al. Cathepsin B regulates collagen expression by fibroblasts via prolonging TLR2/NF-κB activation[J/OL]. Oxid Med Cell Longev, 2016, 2016(7): 7894247[2016-08-28]. https://dx.doi.org/10.1155/2016/7894247. DOI: 10.1155/2016/7894247.
21.	Man KNM, Philipsen S, Tan-Un KC. Localization and expression pattern of cytoglobin in carbon tetrachloride-induced liver fibrosis[J]. Toxicol Lett, 2008, 183(1-3): 36-44. DOI: 10.1016/j.toxlet.2008.09.015.
22.	Li YJ, Wang XQ, Sato T, et al. Prostaglandin E₂ inhibits human lung fibroblast chemotaxis through disparate actions on different E-prostanoid receptors[J]. Am J Respir Cell Mol Biol, 2011, 44(1): 99-107. DOI: 10.1165/rcmb.2009-0163OC.
23.	Nakanishi M, Sato T, Li Y, et al. Prostaglandin E2 stimulates the production of vascular endothelial growth factor through the E-prostanoid–2 receptor in cultured human lung fibroblasts[J]. Am J Respir Cell Mol Biol, 2012, 46(2): 217-223. DOI: 10.1165/rcmb.2010-0115OC.
24.	Bonanno A, Albano GD, Siena L, et al. Prostaglandin E₂ possesses different potencies in inducing vascular endothelial growth factor and interleukin-8 production in COPD human lung fibroblasts[J]. Prostaglandins Leukot Essent Fatty Acids, 2016, 106: 11-18. DOI: 10.1016/j.plefa.2016.01.005.
25.	Gao L, Liu B, Mao W, et al. PTGER2 activation induces PTGS-2 and growth factor gene expression in endometrial epithelial cells of cattle[J]. Anim Reprod Sci, 2017, 187: 54-63. DOI: 10.1016/j.anireprosci.2017.10.005.
26.	Maybin JA, Barcroft J, Thiruchelvam U, et al. The presence and regulation of connective tissue growth factor in the human endometrium[J]. Hum Reprod, 2012, 27(4): 1112-1121. DOI: 10.1093/humrep/der476.
27.	Maybin JA, Nikhil H, Jabbour HN, et al. Novel roles for hypoxia and prostaglandin E2 in the regulation of IL-8 during endometrial repair[J]. Am J Pathol, 2011, 178(3): 1245-1256. DOI: 10.1016/j.ajpath.2010.11.070.
28.	Jabbour HN, Boddy SC. Prostaglandin E2 induces proliferation of glandular epithelial cells of the human endometrium via extracellular regulated kinase 1/2-mediated pathway[J]. J Clin Endocrinol Metab, 2003, 88(9): 4481-4487. DOI: 10.1210/jc.2003-030297.
29.	Kato K, Zemskova MA, Hanss AD, et al. Muc1 deficiency exacerbates pulmonary fibrosis in a mouse model of silicosis[J]. Biochem Biophys Res Commun, 2017, 493(3): 1230-1235. DOI: 10.1016/j.bbrc.2017.09.047.
30.	Zhang L, Gallup M, Zlock L, et al. Pivotal role of MUC1 glycosylation by cigarette smoke in modulating disruption of airway adherens junctions in vitro[J]. J Pathol, 2015, 234(1): 60-73. DOI: 10.1002/path.4375.
31.	Albertsmeyer AC, Kakkassery V, Spurrmichaud S, et al. Effect of pro-inflammatory mediators on membrane-associated mucins expressed by human ocular surface epithelial cells[J]. Exp Eye Res, 2010, 90(3): 444-451. DOI: 10.1016/j.exer.2009.12.009.
32.	Beatty PL, Plevy SE, Sepulveda AR, et al. Cutting edge: transgenic expression of human MUC1 in IL-10^-/- mice accelerates inflammatory bowel disease and progression to colon cancer[J]. J Immunol, 2007, 179(2): 735-739.
33.	Cascio S, Finn OJ. Intra- and extra-cellular events related to altered glycosylation of MUC1 promote chronic inflammation, tumor progression, invasion, and metastasis[J/OL]. Biomolecules, 2016, 6(4): 39[2016-10-13]. http://www.mdpi.com/resolver?pii=biom6040039. DOI: 10.3390/biom6040039.
34.	Sedita J, Izvolsky K, Cardoso WV. Differential expression of heparan sulfate 6-O-sulfotransferase isoforms in the mouse embryo suggests distinctive roles during organogenesis[J]. Dev Dyn, 2004, 231(4): 782-794. DOI: 10.1002/dvdy.20173.
35.	Song K, Li Q, Peng YB, et al. Silencing of hHS6ST2 inhibits progression of pancreatic cancer through inhibition of Notch signalling[J]. Biochem J, 2011, 436(2): 271-282. DOI: 10.1042/BJ20110297.
36.	Wang W, Ju X, Sun Z, et al. Overexpression of heparan sulfate 6-O-sulfotransferase-2 enhances fibroblast growth factor-mediated chondrocyte growth and differentiation[J]. Int J Mol Med, 2015, 36(3): 825-832. DOI: 10.3892/ijmm.2015.2272.

1. Wei Q, Zhang T, Jiang R, et al. Vitreous fibronectin and fibrinogen expression increased in eyes with proliferative diabetic retinopathy after intravitreal anti-VEGF therapy[J]. Invest Ophthalmol Vis Sci, 2017, 58(13): 5783-5791. DOI: 10.1167/iovs.17-22345.
2. Geest RJV, Lesnikoberstein SY, Tan HS, et al. A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy[J]. Br J Ophthalmol, 2012, 96(4): 587-590. DOI: 10.1136/bjophthalmol-2011-301005.
3. 胡博杰, 曾勍, 刘新玲, 等. Avastin玻璃体腔注射后糖尿病视网膜病变增生膜中细胞因子的变化[J]. 中华实验眼科杂志, 2013, 31(1): 55-59. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.013.Hu BJ, Zeng Q, Liu XL, et al. Influence of intravitreal avastin on the expression of cell factors in retinal proliferative membrane in proliferative diabetic retinopathy eye[J]. Chin J Exp Ophthalmol, 2013, 31(1): 55-59. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.013.
4. Mi VDR, La Heij EC, De JY, et al. A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections[J]. Retina, 2011, 31(8): 1449-1469. DOI: 10.1097/IAE.0b013e3182278ab4.
5. Zhang M, Chu S, Zeng F, et al. Bevacizumab modulates the process of fibrosis in vitro.[J]. Clin Exp Ophthalmol, 2015, 43(2): 173-179. DOI: 10.1111/ceo.12374.
6. Arevalo J, Maia MHJ, Saravia M, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy[J]. Br J Ophthalmol, 2008, 92(2): 213-216. DOI: 10.1136/bjo.2007.127142.
7. Jonas JB, Schmidbauer M, Rensch F. Progression of tractional retinal detachment following intravitreal bevacizumab[J]. Acta Ophthalmol, 2009, 87(5): 571-572. DOI: 10.1111/j.1755-3768.2008.01225.x.
8. Batman C, Ozdamar Y. The relation between bevacizumab injection and the formation of subretinal fibrosis in diabetic patients with panretinal photocoagulation[J]. Ophthalmic Surg Lasers Imaging, 2010, 41(2): 190-195. DOI: 10.3928/15428877-20100303-06.
9. Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics[J]. Nat Rev Genet, 2009, 10(1): 57-63. DOI: 10.1038/nrg2484.
10. Xiang L, Chen GH, Wei YZ, et al. Genome-wide transcriptional analysis of maize endosperm in response to ae wx double mutations[J]. J Genet Genomics, 2010, 37(11): 749-762. DOI: 10.1016/S1673-8527(09)60092-8.
11. Massagué J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders[J]. Cell, 2000, 103(2): 295-309.
12. Liu JC, Wang F, Xie ML, et al. Osthole inhibits the expressions of collagen I and III through Smad signaling pathway after treatment with TGF-β1 in mouse cardiac fibroblasts[J]. Int J Cardiol, 2017, 228: 388-393. DOI: 10.1016/j.ijcard.2016.11.202.
13. Cui L, Wang Y, Yu R, et al. Jia-Shen decoction-medicated serum inhibits angiotensin-Ⅱ induced cardiac fibroblast proliferation via the TGF-β1/Smad signaling pathway[J]. Mol Med Rep, 2016, 14(2): 1610-1616. DOI: 10.3892/mmr.2016.5405.
14. Ihn H. Pathogenesis of fibrosis: role of TGF-beta and CTGF[J]. Curr Opin Rheumatol, 2002, 14(6): 681-685.
15. Hung CM, Kuo DH, Chou CH, et al. Osthole suppresses hepatocyte growth factor (HGF)-induced epithelial-mesenchymal transition via repression of the c-Met/Akt/mTOR pathway in human breast cancer cells[J]. J Agric Food Chem, 2011, 59(17): 9683-9690. DOI: 10.1021/jf2021489.
16. Xu P, Liu J, Derynck R. Post-translational regulation of TGF-β receptor and Smad signaling[J]. FEBS Lett, 2012, 586(14): 1871-1884. DOI: 10.1016/j.febslet.2012.05.010.
17. Massagué J, Xi Q. TGF-β control of stem cell differentiation genes[J]. FEBS Lett, 2012, 586(14): 1953-1958. DOI: 10.1016/j.febslet.2012.03.023.
18. Santalla M, Valverde CA, Harnichar E, et al. Aging and CaMKⅡ alter intracellular Ca²⁺ transients and heart rhythm in Drosophila melanogaster[J/OL]. PLoS One, 2014, 9(7): 101871[2014-07-08]. http://dx.plos.org/10.1371/journal.pone.0101871. DOI: 10.1371/journal.pone.0101871.
19. Mukherjee S, Sheng W, Sun R, et al. Ca²⁺/calmodulin-dependent protein kinase Ⅱβ and Ⅱδ mediate TGFβ-induced transduction of fibronectin and collagen in human pulmonary fibroblasts[J]. Am J Physiol Lung Cell Mol Physiol, 2017, 312(4): 510-519. DOI: 10.1152/ajplung.00084.2016.
20. Li X, Wu Z, Ni J, et al. Cathepsin B regulates collagen expression by fibroblasts via prolonging TLR2/NF-κB activation[J/OL]. Oxid Med Cell Longev, 2016, 2016(7): 7894247[2016-08-28]. https://dx.doi.org/10.1155/2016/7894247. DOI: 10.1155/2016/7894247.
21. Man KNM, Philipsen S, Tan-Un KC. Localization and expression pattern of cytoglobin in carbon tetrachloride-induced liver fibrosis[J]. Toxicol Lett, 2008, 183(1-3): 36-44. DOI: 10.1016/j.toxlet.2008.09.015.
22. Li YJ, Wang XQ, Sato T, et al. Prostaglandin E₂ inhibits human lung fibroblast chemotaxis through disparate actions on different E-prostanoid receptors[J]. Am J Respir Cell Mol Biol, 2011, 44(1): 99-107. DOI: 10.1165/rcmb.2009-0163OC.
23. Nakanishi M, Sato T, Li Y, et al. Prostaglandin E2 stimulates the production of vascular endothelial growth factor through the E-prostanoid–2 receptor in cultured human lung fibroblasts[J]. Am J Respir Cell Mol Biol, 2012, 46(2): 217-223. DOI: 10.1165/rcmb.2010-0115OC.
24. Bonanno A, Albano GD, Siena L, et al. Prostaglandin E₂ possesses different potencies in inducing vascular endothelial growth factor and interleukin-8 production in COPD human lung fibroblasts[J]. Prostaglandins Leukot Essent Fatty Acids, 2016, 106: 11-18. DOI: 10.1016/j.plefa.2016.01.005.
25. Gao L, Liu B, Mao W, et al. PTGER2 activation induces PTGS-2 and growth factor gene expression in endometrial epithelial cells of cattle[J]. Anim Reprod Sci, 2017, 187: 54-63. DOI: 10.1016/j.anireprosci.2017.10.005.
26. Maybin JA, Barcroft J, Thiruchelvam U, et al. The presence and regulation of connective tissue growth factor in the human endometrium[J]. Hum Reprod, 2012, 27(4): 1112-1121. DOI: 10.1093/humrep/der476.
27. Maybin JA, Nikhil H, Jabbour HN, et al. Novel roles for hypoxia and prostaglandin E2 in the regulation of IL-8 during endometrial repair[J]. Am J Pathol, 2011, 178(3): 1245-1256. DOI: 10.1016/j.ajpath.2010.11.070.
28. Jabbour HN, Boddy SC. Prostaglandin E2 induces proliferation of glandular epithelial cells of the human endometrium via extracellular regulated kinase 1/2-mediated pathway[J]. J Clin Endocrinol Metab, 2003, 88(9): 4481-4487. DOI: 10.1210/jc.2003-030297.
29. Kato K, Zemskova MA, Hanss AD, et al. Muc1 deficiency exacerbates pulmonary fibrosis in a mouse model of silicosis[J]. Biochem Biophys Res Commun, 2017, 493(3): 1230-1235. DOI: 10.1016/j.bbrc.2017.09.047.
30. Zhang L, Gallup M, Zlock L, et al. Pivotal role of MUC1 glycosylation by cigarette smoke in modulating disruption of airway adherens junctions in vitro[J]. J Pathol, 2015, 234(1): 60-73. DOI: 10.1002/path.4375.
31. Albertsmeyer AC, Kakkassery V, Spurrmichaud S, et al. Effect of pro-inflammatory mediators on membrane-associated mucins expressed by human ocular surface epithelial cells[J]. Exp Eye Res, 2010, 90(3): 444-451. DOI: 10.1016/j.exer.2009.12.009.
32. Beatty PL, Plevy SE, Sepulveda AR, et al. Cutting edge: transgenic expression of human MUC1 in IL-10^-/- mice accelerates inflammatory bowel disease and progression to colon cancer[J]. J Immunol, 2007, 179(2): 735-739.
33. Cascio S, Finn OJ. Intra- and extra-cellular events related to altered glycosylation of MUC1 promote chronic inflammation, tumor progression, invasion, and metastasis[J/OL]. Biomolecules, 2016, 6(4): 39[2016-10-13]. http://www.mdpi.com/resolver?pii=biom6040039. DOI: 10.3390/biom6040039.
34. Sedita J, Izvolsky K, Cardoso WV. Differential expression of heparan sulfate 6-O-sulfotransferase isoforms in the mouse embryo suggests distinctive roles during organogenesis[J]. Dev Dyn, 2004, 231(4): 782-794. DOI: 10.1002/dvdy.20173.
35. Song K, Li Q, Peng YB, et al. Silencing of hHS6ST2 inhibits progression of pancreatic cancer through inhibition of Notch signalling[J]. Biochem J, 2011, 436(2): 271-282. DOI: 10.1042/BJ20110297.
36. Wang W, Ju X, Sun Z, et al. Overexpression of heparan sulfate 6-O-sulfotransferase-2 enhances fibroblast growth factor-mediated chondrocyte growth and differentiation[J]. Int J Mol Med, 2015, 36(3): 825-832. DOI: 10.3892/ijmm.2015.2272.

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RNA-Seq analysis of gene expression profiling in human retinal vascular endothelial cells after anti-vascular endothecial growth factor treatment

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