Targeting neovascularization in ischemic retinopathy: recent advances

References

• Buch H, Vinding T, Nielsen NV. Prevalence and causes of visual impairment according to World Health Organization and United States criteria in an aged, urban Scandinavian population: the Copenhagen City Eye Study. Ophthalmology 108(12), 2347–2357 (2001).
   PubMed Web of Science ®Google Scholar
• Congdon N, O’Colmain B, Klaver CC et al.; Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch. Ophthalmol. 122(4), 477–485 (2004).
   PubMed Web of Science ®Google Scholar
• Rein DB, Wittenborn JS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J; Vision Health Cost–Effectiveness Study Group. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch. Ophthalmol. 127(4), 533–540 (2009).
   PubMedGoogle Scholar
• Saaddine JB, Honeycutt AA, Narayan KM, Zhang X, Klein R, Boyle JP. Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus: United States, 2005–2050. Arch. Ophthalmol. 126(12), 1740–1747 (2008).
   PubMed Web of Science ®Google Scholar
• Folkman J, Ingber D. Inhibition of angiogenesis. Semin. Cancer Biol. 3(2), 89–96 (1992).
   PubMedGoogle Scholar
• Folkman J, Shing Y. Angiogenesis. J. Biol. Chem. 267(16), 10931–10934 (1992).
   PubMed Web of Science ®Google Scholar
• Cao Y. Endogenous angiogenesis inhibitors and their therapeutic implications. Int. J. Biochem. Cell Biol. 33(4), 357–369 (2001).
   PubMed Web of Science ®Google Scholar
• Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J. Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett. 489(2–3), 270–276 (2001).
   PubMed Web of Science ®Google Scholar
• Gao G, Ma J. Tipping the balance for angiogenic disorders. Drug Discov. Today 7(3), 171–172 (2002).
   PubMed Web of Science ®Google Scholar
• Ma JX, Zhang SX, Wang JJ. Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications. Curr. Diabetes Rev. 1(2), 183–196 (2005).
   PubMedGoogle Scholar
• Battegay EJ. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J. Mol. Med. 73(7), 333–346 (1995).
   PubMed Web of Science ®Google Scholar
• Kim J, Kim CS, Lee YM, Jo K, Shin SD, Kim JS. Methylglyoxal induces hyperpermeability of the blood–retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases. Graefes Arch. Clin. Exp. Ophthalmol. 250(5), 691–697 (2012).
   PubMed Web of Science ®Google Scholar
• Peng S, Gan G, Rao VS, Adelman RA, Rizzolo LJ. Effects of proinflammatory cytokines on the claudin-19 rich tight junctions of human retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 53(8), 5016–5028 (2012).
   PubMed Web of Science ®Google Scholar
• Armulik A, Genové G, Mäe M et al. Pericytes regulate the blood–brain barrier. Nature 468(7323), 557–561 (2010).
   PubMed Web of Science ®Google Scholar
• Hosoya K, Fujita K, Tachikawa M. Involvement of reduced folate carrier 1 in the inner blood–retinal barrier transport of methyltetrahydrofolate. Drug Metab. Pharmacokinet. 23(4), 285–292 (2008).
   PubMed Web of Science ®Google Scholar
• Runkle EA, Antonetti DA. The blood–retinal barrier: structure and functional significance. Methods Mol. Biol. 686, 133–148 (2011).
   PubMedGoogle Scholar
• Ejaz S, Chekarova I, Ejaz A, Sohail A, Lim CW. Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. Diabetes. Obes. Metab. 10(1), 53–63 (2008).
   PubMed Web of Science ®Google Scholar
• Asahara T, Murohara T, Sullivan A et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275(5302), 964–967 (1997).
   PubMed Web of Science ®Google Scholar
• Patan S. Vasculogenesis and angiogenesis. Cancer Treat. Res. 117, 3–32 (2004).
   PubMedGoogle Scholar
• Hughes S, Yang H, Chan-Ling T. Vascularization of the human fetal retina: roles of vasculogenesis and angiogenesis. Invest. Ophthalmol. Vis. Sci. 41(5), 1217–1228 (2000).
   PubMed Web of Science ®Google Scholar
• Chan-Ling T, McLeod DS, Hughes S et al. Astrocyte–endothelial cell relationships during human retinal vascular development. Invest. Ophthalmol. Vis. Sci. 45(6), 2020–2032 (2004).
   PubMed Web of Science ®Google Scholar
• Flower RW, McLeod DS, Lutty GA, Goldberg B, Wajer SD. Postnatal retinal vascular development of the puppy. Invest. Ophthalmol. Vis. Sci. 26(7), 957–968 (1985).
   PubMed Web of Science ®Google Scholar
• Grant MB, May WS, Caballero S et al. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat. Med. 8(6), 607–612 (2002).
   PubMed Web of Science ®Google Scholar
• Abu El-Asrar AM, Nawaz MI, Kangave D, Siddiquei MM, Ola MS, Opdenakker G. Angiogenesis regulatory factors in the vitreous from patients with proliferative diabetic retinopathy. Acta Diabetol. doi:10.1007/s00592-011-0330-9 (2011) (Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Abu El-Asrar AM, Struyf S, Opdenakker G, Van Damme J, Geboes K. Expression of stem cell factor/c-kit signaling pathway components in diabetic fibrovascular epiretinal membranes. Mol. Vis. 16, 1098–1107 (2010).
   PubMed Web of Science ®Google Scholar
• Sengupta N, Caballero S, Mames RN, Timmers AM, Saban D, Grant MB. Preventing stem cell incorporation into choroidal neovascularization by targeting homing and attachment factors. Invest. Ophthalmol. Vis. Sci. 46(1), 343–348 (2005).
   PubMed Web of Science ®Google Scholar
• Ash JD, Overbeek PA. Lens-specific VEGF-A expression induces angioblast migration and proliferation and stimulates angiogenic remodeling. Dev. Biol. 223(2), 383–398 (2000).
   PubMed Web of Science ®Google Scholar
• Sengupta N, Caballero S, Mames RN, Butler JM, Scott EW, Grant MB. The role of adult bone marrow-derived stem cells in choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 44(11), 4908–4913 (2003).
   PubMed Web of Science ®Google Scholar
• Tarr JM, Kaul K, Wolanska K, Kohner EM, Chibber R. Retinopathy in diabetes. Adv. Exp. Med. Biol. 771, 88–106 (2012).
   PubMed Web of Science ®Google Scholar
• Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J. Biol. Chem. 274(33), 23463–23467 (1999).
   PubMed Web of Science ®Google Scholar
• Antonetti DA, Lieth E, Barber AJ, Gardner TW. Molecular mechanisms of vascular permeability in diabetic retinopathy. Semin. Ophthalmol. 14(4), 240–248 (1999).
   PubMedGoogle Scholar
• Leal EC, Manivannan A, Hosoya K et al. Inducible nitric oxide synthase isoform is a key mediator of leukostasis and blood–retinal barrier breakdown in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 48(11), 5257–5265 (2007).
   PubMed Web of Science ®Google Scholar
• Di Fiore JM, Kaffashi F, Loparo K et al. The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants. Pediatr. Res. 72(6), 606–612 (2012).
   PubMed Web of Science ®Google Scholar
• Grimm C, Willmann G. Hypoxia in the eye: a two-sided coin. High Alt. Med. Biol. 13(3), 169–175 (2012).
   PubMed Web of Science ®Google Scholar
• Steinle JJ. Retinal endothelial cell apoptosis. Apoptosis 17(12), 1258–1260 (2012).
   PubMed Web of Science ®Google Scholar
• Li SY, Fu ZJ, Lo AC. Hypoxia-induced oxidative stress in ischemic retinopathy. Oxid. Med. Cell. Longev. 2012, 426769 (2012).
   PubMed Web of Science ®Google Scholar
• Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc. Ophthalmol. 124(1), 15–26 (2012).
   PubMed Web of Science ®Google Scholar
• Reichenbach A, Wurm A, Pannicke T, Iandiev I, Wiedemann P, Bringmann A. Müller cells as players in retinal degeneration and edema. Graefes Arch. Clin. Exp. Ophthalmol. 245(5), 627–636 (2007).
   PubMed Web of Science ®Google Scholar
• Klaassen I, Hughes JM, Vogels IM, Schalkwijk CG, Van Noorden CJ, Schlingemann RO. Altered expression of genes related to blood–retina barrier disruption in streptozotocin-induced diabetes. Exp. Eye Res. 89(1), 4–15 (2009).
   PubMed Web of Science ®Google Scholar
• Kubota Y, Suda T. Feedback mechanism between blood vessels and astrocytes in retinal vascular development. Trends Cardiovasc. Med. 19(2), 38–43 (2009).
   PubMed Web of Science ®Google Scholar
• Tretiach M, Madigan MC, Wen L, Gillies MC. Effect of Müller cell co-culture on in vitro permeability of bovine retinal vascular endothelium in normoxic and hypoxic conditions. Neurosci. Lett. 378(3), 160–165 (2005).
   PubMed Web of Science ®Google Scholar
• Eichler W, Yafai Y, Keller T, Wiedemann P, Reichenbach A. PEDF derived from glial Müller cells: a possible regulator of retinal angiogenesis. Exp. Cell Res. 299(1), 68–78 (2004).
   PubMed Web of Science ®Google Scholar
• Duh EJ, Yang HS, Suzuma I et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest. Ophthalmol. Vis. Sci. 43(3), 821–829 (2002).
   PubMed Web of Science ®Google Scholar
• Coorey NJ, Shen W, Chung SH, Zhu L, Gillies MC. The role of glia in retinal vascular disease. Clin. Exp. Optom. 95(3), 266–281 (2012).
   PubMed Web of Science ®Google Scholar
• Robaszkiewicz J, Chmielewska K, Figurska M, Wierzbowska J, Stankiewicz A. Müller glial cells – the mediators of vascular disorders with vitreomacular interface pathology in diabetic maculopathy. Klin. Oczna. 112(10–12), 328–332 (2010).
   PubMedGoogle Scholar
• Michaelson IC, Herz N, Lewkowitz E, Kertesz D. Effect of increased oxygen on the development of the retinal vessels; an experimental study. Br. J. Ophthalmol. 38(10), 577–587 (1954).
   PubMed Web of Science ®Google Scholar
• Aiello LP, Avery RL, Arrigg PG et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331(22), 1480–1487 (1994).
   PubMed Web of Science ®Google Scholar
• Adamis AP, Miller JW, Bernal MT et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 118(4), 445–450 (1994).
   PubMed Web of Science ®Google Scholar
• Miller JW, Adamis AP, Shima DT et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am. J. Pathol. 145(3), 574–584 (1994).
   PubMed Web of Science ®Google Scholar
• Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch. Ophthalmol. 113(12), 1538–1544 (1995).
   PubMed Web of Science ®Google Scholar
• Aiello LP, Pierce EA, Foley ED et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Natl Acad. Sci. USA 92(23), 10457–10461 (1995).
   PubMed Web of Science ®Google Scholar
• Krzystolik MG, Afshari MA, Adamis AP et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch. Ophthalmol. 120(3), 338–346 (2002).
   PubMed Web of Science ®Google Scholar
• Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch. Ophthalmol. 114(8), 964–970 (1996).
   PubMed Web of Science ®Google Scholar
• Tolentino MJ, Miller JW, Gragoudas ES et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 103(11), 1820–1828 (1996).
   PubMed Web of Science ®Google Scholar
• Lashkari K, Hirose T, Yazdany J, McMeel JW, Kazlauskas A, Rahimi N. Vascular endothelial growth factor and hepatocyte growth factor levels are differentially elevated in patients with advanced retinopathy of prematurity. Am. J. Pathol. 156(4), 1337–1344 (2000).
   PubMed Web of Science ®Google Scholar
• Funatsu H, Yamashita H, Ikeda T, Nakanishi Y, Kitano S, Hori S. Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular edema and other retinal disorders. Am. J. Ophthalmol. 133(4), 537–543 (2002).
   PubMed Web of Science ®Google Scholar
• Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 110(9), 1690–1696 (2003).
   PubMed Web of Science ®Google Scholar
• Funatsu H, Yamashita H, Sakata K et al. Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule 1 are related to diabetic macular edema. Ophthalmology 112(5), 806–816 (2005).
   PubMed Web of Science ®Google Scholar
• Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am. J. Ophthalmol. 133(1), 70–77 (2002).
   PubMed Web of Science ®Google Scholar
• Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT. Increased expression of angiogenic growth factors in age-related maculopathy. Br. J. Ophthalmol. 81(2), 154–162 (1997).
   PubMed Web of Science ®Google Scholar
• Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest. Ophthalmol. Vis. Sci. 37(5), 855–868 (1996).
   PubMed Web of Science ®Google Scholar
• Frank RN, Amin RH, Eliott D, Puklin JE, Abrams GW. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am. J. Ophthalmol. 122(3), 393–403 (1996).
   PubMed Web of Science ®Google Scholar
• Grossniklaus HE, Ling JX, Wallace TM et al. Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol. Vis. 8, 119–126 (2002).
   PubMed Web of Science ®Google Scholar
• Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW. The vascular endothelial growth factor family of polypeptides. J. Cell. Biochem. 47(3), 211–218 (1991).
   PubMed Web of Science ®Google Scholar
• Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc. Natl Acad. Sci. USA 92(3), 905–909 (1995).
   PubMed Web of Science ®Google Scholar
• Dorey CK, Aouididi S, Reynaud X, Dvorak HF, Brown LF. Correlation of vascular permeability factor/vascular endothelial growth factor with extraretinal neovascularization in the rat. Arch. Ophthalmol. 114(10), 1210–1217 (1996).
   PubMed Web of Science ®Google Scholar
• Pe’er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E. Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab. Invest. 72(6), 638–645 (1995).
   PubMed Web of Science ®Google Scholar
• Lu M, Amano S, Miyamoto K et al. Insulin-induced vascular endothelial growth factor expression in retina. Invest. Ophthalmol. Vis. Sci. 40(13), 3281–3286 (1999).
   PubMed Web of Science ®Google Scholar
• Ray D, Mishra M, Ralph S, Read I, Davies R, Brenchley P. Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes 53(3), 861–864 (2004).
   PubMed Web of Science ®Google Scholar
• Braun L, Kardon T, Reisz-Porszasz ZS, Banhegyi G, Mandl J. The regulation of the induction of vascular endothelial growth factor at the onset of diabetes in spontaneously diabetic rats. Life Sci. 69(21), 2533–2542 (2001).
   PubMed Web of Science ®Google Scholar
• Qaum T, Xu Q, Joussen AM et al. VEGF-initiated blood–retinal barrier breakdown in early diabetes. Invest. Ophthalmol. Vis. Sci. 42(10), 2408–2413 (2001).
   PubMed Web of Science ®Google Scholar
• Murata T, Nakagawa K, Khalil A, Ishibashi T, Inomata H, Sueishi K. The relation between expression of vascular endothelial growth factor and breakdown of the blood–retinal barrier in diabetic rat retinas. Lab. Invest. 74(4), 819–825 (1996).
   PubMed Web of Science ®Google Scholar
• Hu J, Song X, He YQ et al. Heparanase and vascular endothelial growth factor expression is increased in hypoxia-induced retinal neovascularization. Invest. Ophthalmol. Vis. Sci. 53(11), 6810–6817 (2012).
   PubMed Web of Science ®Google Scholar
• Ishida S, Usui T, Yamashiro K et al. VEGF164 is proinflammatory in the diabetic retina. Invest. Ophthalmol. Vis. Sci. 44(5), 2155–2162 (2003).
   PubMed Web of Science ®Google Scholar
• Kinose F, Roscilli G, Lamartina S et al. Inhibition of retinal and choroidal neovascularization by a novel KDR kinase inhibitor. Mol. Vis. 11, 366–373 (2005).
   PubMed Web of Science ®Google Scholar
• McLeod DS, Taomoto M, Otsuji T, Green WR, Sunness JS, Lutty GA. Quantifying changes in RPE and choroidal vasculature in eyes with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 43(6), 1986–1993 (2002).
   PubMed Web of Science ®Google Scholar
• Krantz SB. Erythropoietin. Blood 77(3), 419–434 (1991).
   PubMed Web of Science ®Google Scholar
• Erbayraktar S, Yilmaz O, Gökmen N, Brines M. Erythropoietin is a multifunctional tissue-protective cytokine. Curr. Hematol. Rep. 2(6), 465–470 (2003).
   PubMedGoogle Scholar
• Carlini RG, Reyes AA, Rothstein M. Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int. 47(3), 740–745 (1995).
   PubMed Web of Science ®Google Scholar
• Alvarez Arroyo MV, Castilla MA, González Pacheco FR et al. Role of vascular endothelial growth factor on erythropoietin-related endothelial cell proliferation. J. Am. Soc. Nephrol. 9(11), 1998–2004 (1998).
   PubMed Web of Science ®Google Scholar
• Chong ZZ, Kang JQ, Maiese K. Angiogenesis and plasticity: role of erythropoietin in vascular systems. J. Hematother. Stem Cell Res. 11(6), 863–871 (2002).
   PubMedGoogle Scholar
• Grimm C, Wenzel A, Groszer M et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat. Med. 8(7), 718–724 (2002).
   PubMed Web of Science ®Google Scholar
• Morita M, Ohneda O, Yamashita T et al. HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J. 22(5), 1134–1146 (2003).
   PubMed Web of Science ®Google Scholar
• Watanabe D, Suzuma K, Matsui S et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N. Engl. J. Med. 353(8), 782–792 (2005).
   PubMed Web of Science ®Google Scholar
• Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA 293(1), 90–95 (2005).
   PubMed Web of Science ®Google Scholar
• Aiello LP. Angiogenic pathways in diabetic retinopathy. N. Engl. J. Med. 353(8), 839–841 (2005).
   PubMed Web of Science ®Google Scholar
• Mitsuhashi J, Morikawa S, Shimizu K, Ezaki T, Yasuda Y, Hori S. Intravitreal injection of erythropoietin protects against retinal vascular regression at the early stage of diabetic retinopathy in streptozotocin-induced diabetic rats. Exp. Eye Res. 106, 64–73 (2013).
   PubMed Web of Science ®Google Scholar
• Delafontaine P, Song YH, Li Y. Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arterioscler. Thromb. Vasc. Biol. 24(3), 435–444 (2004).
   PubMed Web of Science ®Google Scholar
• Lambooij AC, van Wely KH, Lindenbergh-Kortleve DJ, Kuijpers RW, Kliffen M, Mooy CM. Insulin-like growth factor-I and its receptor in neovascular age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 44(5), 2192–2198 (2003).
   PubMed Web of Science ®Google Scholar
• Hellström A, Carlsson B, Niklasson A et al. IGF-I is critical for normal vascularization of the human retina. J. Clin. Endocrinol. Metab. 87(7), 3413–3416 (2002).
   PubMed Web of Science ®Google Scholar
• Hellstrom A, Perruzzi C, Ju M et al. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc. Natl Acad. Sci. USA 98(10), 5804–5808 (2001).
   PubMed Web of Science ®Google Scholar
• Smith LE. Pathogenesis of retinopathy of prematurity. Growth Horm. IGF Res. 14(Suppl. A), S140–S144 (2004).
   PubMed Web of Science ®Google Scholar
• Ruberte J, Ayuso E, Navarro M et al. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J. Clin. Invest. 113(8), 1149–1157 (2004).
   PubMed Web of Science ®Google Scholar
• Nourhaghighi N, Teichert-Kuliszewska K, Davis J, Stewart DJ, Nag S. Altered expression of angiopoietins during blood–brain barrier breakdown and angiogenesis. Lab. Invest. 83(8), 1211–1222 (2003).
   PubMed Web of Science ®Google Scholar
• Valable S, Montaner J, Bellail A et al. VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: both effects decreased by Ang-1. J. Cereb. Blood Flow Metab. 25(11), 1491–1504 (2005).
   PubMed Web of Science ®Google Scholar
• Nambu H, Nambu R, Oshima Y et al. Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood–retinal barrier. Gene Ther. 11(10), 865–873 (2004).
   PubMed Web of Science ®Google Scholar
• Hackett SF, Wiegand S, Yancopoulos G, Campochiaro PA. Angiopoietin-2 plays an important role in retinal angiogenesis. J. Cell. Physiol. 192(2), 182–187 (2002).
   PubMed Web of Science ®Google Scholar
• Das A, Fanslow W, Cerretti D, Warren E, Talarico N, McGuire P. Angiopoietin/Tek interactions regulate MMP-9 expression and retinal neovascularization. Lab. Invest. 83(11), 1637–1645 (2003).
   PubMed Web of Science ®Google Scholar
• Oshima Y, Deering T, Oshima S et al. Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor. J. Cell. Physiol. 199(3), 412–417 (2004).
   PubMed Web of Science ®Google Scholar
• Umeda N, Ozaki H, Hayashi H, Miyajima-Uchida H, Oshima K. Colocalization of Tie2, angiopoietin 2 and vascular endothelial growth factor in fibrovascular membrane from patients with retinopathy of prematurity. Ophthalmic Res. 35(4), 217–223 (2003).
   PubMed Web of Science ®Google Scholar
• Das A, McGuire PG. Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition. Prog. Retin. Eye Res. 22(6), 721–748 (2003).
   PubMed Web of Science ®Google Scholar
• Mohr S, Xi X, Tang J, Kern TS. Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients. Diabetes 51(4), 1172–1179 (2002).
   PubMed Web of Science ®Google Scholar
• Anderson RE, Rapp LM, Wiegand RD. Lipid peroxidation and retinal degeneration. Curr. Eye Res. 3(1), 223–227 (1984).
   PubMed Web of Science ®Google Scholar
• Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 52(3), 818–823 (2003).
   PubMed Web of Science ®Google Scholar
• Kowluru RA, Atasi L, Ho YS. Role of mitochondrial superoxide dismutase in the development of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 47(4), 1594–1599 (2006).
   PubMed Web of Science ®Google Scholar
• Al-Shabrawey M, Bartoli M, El-Remessy AB et al. Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 49(7), 3231–3238 (2008).
   PubMed Web of Science ®Google Scholar
• Al-Shabrawey M, Bartoli M, El-Remessy AB et al. Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am. J. Pathol. 167(2), 599–607 (2005).
   PubMed Web of Science ®Google Scholar
• Al-Shabrawey M, Rojas M, Sanders T et al. Role of NADPH oxidase in retinal vascular inflammation. Invest. Ophthalmol. Vis. Sci. 49(7), 3239–3244 (2008).
   PubMed Web of Science ®Google Scholar
• Miwa K, Nakamura J, Hamada Y et al. The role of polyol pathway in glucose-induced apoptosis of cultured retinal pericytes. Diabetes Res. Clin. Pract. 60(1), 1–9 (2003).
   PubMed Web of Science ®Google Scholar
• Al-Shabrawey M, El-Remessy A, Gu X et al. Normal vascular development in mice deficient in endothelial NO synthase: possible role of neuronal NO synthase. Mol. Vis. 9, 549–558 (2003).
   PubMed Web of Science ®Google Scholar
• Stitt AW. The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp. Mol. Pathol. 75(1), 95–108 (2003).
   PubMed Web of Science ®Google Scholar
• Lelkes PI, Hahn KL, Sukovich DA, Karmiol S, Schmidt DH. On the possible role of reactive oxygen species in angiogenesis. Adv. Exp. Med. Biol. 454, 295–310 (1998).
   PubMed Web of Science ®Google Scholar
• Buhimschi IA, Buhimschi CS, Weiner CP. Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation. Am. J. Obstet. Gynecol. 188(1), 203–208 (2003).
   PubMed Web of Science ®Google Scholar
• Saito Y, Uppal A, Byfield G, Budd S, Hartnett ME. Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model. Invest. Ophthalmol. Vis. Sci. 49(4), 1591–1598 (2008).
   PubMed Web of Science ®Google Scholar
• Ushio-Fukai M. Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc. Res. 71(2), 226–235 (2006).
   PubMed Web of Science ®Google Scholar
• Ushio-Fukai M, Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 266(1), 37–52 (2008).
   PubMed Web of Science ®Google Scholar
• Tawfik A, Sanders T, Kahook K, Akeel S, Elmarakby A, Al-Shabrawey M. Suppression of retinal peroxisome proliferator-activated receptor γ in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase. Invest. Ophthalmol. Vis. Sci. 50(2), 878–884 (2009).
   PubMed Web of Science ®Google Scholar
• Jang DS, Lee YM, Jeong IH, Kim JS. Constituents of the flowers of Platycodon grandiflorum with inhibitory activity on advanced glycation end products and rat lens aldose reductase in vitro. Arch. Pharm. Res. 33(6), 875–880 (2010).
   PubMed Web of Science ®Google Scholar
• Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic. Biol. Med. 36(7), 838–849 (2004).
   PubMed Web of Science ®Google Scholar
• Ansó E, Zuazo A, Irigoyen M, Urdaci MC, Rouzaut A, Martínez-Irujo JJ. Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism. Biochem. Pharmacol. 79(11), 1600–1609 (2010).
   PubMed Web of Science ®Google Scholar
• Park SW, Cho CS, Jun HO et al. Anti-angiogenic effect of luteolin on retinal neovascularization via blockade of reactive oxygen species production. Invest. Ophthalmol. Vis. Sci. 53(12), 7718–7726 (2012).
   PubMed Web of Science ®Google Scholar
• Akeel S, El-Awady A, Hussein K et al. Recombinant bone morphogenetic protein-2 induces up-regulation of vascular endothelial growth factor and interleukin 6 in human pre-osteoblasts: role of reactive oxygen species. Arch. Oral Biol. 57(5), 445–452 (2012).
   PubMed Web of Science ®Google Scholar
• Dong A, Shen J, Krause M et al. Superoxide dismutase 1 protects retinal cells from oxidative damage. J. Cell. Physiol. 208(3), 516–526 (2006).
   PubMed Web of Science ®Google Scholar
• Imamura Y, Noda S, Hashizume K et al. Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc. Natl Acad. Sci. USA 103(30), 11282–11287 (2006).
   PubMed Web of Science ®Google Scholar
• Dong A, Xie B, Shen J et al. Oxidative stress promotes ocular neovascularization. J. Cell. Physiol. 219(3), 544–552 (2009).
   PubMed Web of Science ®Google Scholar
• Cao Y, Cao R. Angiogenesis inhibited by drinking tea. Nature 398(6726), 381 (1999).
   Google Scholar
• Wang D, Wang H, Brown J et al. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J. Exp. Med. 203(4), 941–951 (2006).
   PubMed Web of Science ®Google Scholar
• Nie D, Hillman GG, Geddes T et al. Platelet-type 12-lipoxygenase in a human prostate carcinoma stimulates angiogenesis and tumor growth. Cancer Res. 58(18), 4047–4051 (1998).
   PubMed Web of Science ®Google Scholar
• Tang DG, Renaud C, Stojakovic S, Diglio CA, Porter A, Honn KV. 12(S)-HETE is a mitogenic factor for microvascular endothelial cells: its potential role in angiogenesis. Biochem. Biophys. Res. Commun. 211(2), 462–468 (1995).
   PubMed Web of Science ®Google Scholar
• Li Z, He T, Du K et al. Overexpression of 15-lipoxygenase-1 in oxygen-induced ischemic retinopathy inhibits retinal neovascularization via downregulation of vascular endothelial growth factor-A expression. Mol. Vis. 18, 2847–2859 (2012).
   PubMed Web of Science ®Google Scholar
• Yan Y, He T, Shen Y et al. Adenoviral 15-lipoxygenase-1 gene transfer inhibits hypoxia-induced proliferation of retinal microvascular endothelial cells in vitro. Int. J. Ophthalmol. 5(5), 562–569 (2012).
   PubMed Web of Science ®Google Scholar
• Connor KM, SanGiovanni JP, Lofqvist C et al. Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat. Med. 13(7), 868–873 (2007).
   PubMed Web of Science ®Google Scholar
• Sapieha P, Stahl A, Chen J et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids. Sci. Transl. Med. 3(69), 69ra12 (2011).
   PubMed Web of Science ®Google Scholar
• Al-Shabrawey M, Mussell R, Kahook K et al. Increased expression and activity of 12-lipoxygenase in oxygen-induced ischemic retinopathy and proliferative diabetic retinopathy: implications in retinal neovascularization. Diabetes 60(2), 614–624 (2011).
   PubMed Web of Science ®Google Scholar
• Othman A, Ahmad S, Megyerdi S et al. 12/15-lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase. PLoS ONE 8(2), e57254 (2013).
   PubMed Web of Science ®Google Scholar
• Joussen AM, Murata T, Tsujikawa A, Kirchhof B, Bursell SE, Adamis AP. Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am. J. Pathol. 158(1), 147–152 (2001).
   PubMed Web of Science ®Google Scholar
• Mahajan VB, Vallone JG, Lin JH et al. T-cell infiltration in autosomal dominant neovascular inflammatory vitreoretinopathy. Mol. Vis. 16, 1034–1040 (2010).
   PubMed Web of Science ®Google Scholar
• He C, Sun Y, Ren X et al. Angiogenesis mediated by toll-like receptor 4 in ischemic neural tissue. Arterioscler. Thromb. Vasc. Biol. 33(2), 330–338 (2013).
   PubMed Web of Science ®Google Scholar
• Tezel TH, Bodek E, Sönmez K et al. Targeting tissue factor for immunotherapy of choroidal neovascularization by intravitreal delivery of factor VII-Fc chimeric antibody. Ocul. Immunol. Inflamm. 15(1), 3–10 (2007).
   PubMed Web of Science ®Google Scholar
• Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res. Treat. 36(2), 127–137 (1995).
   PubMed Web of Science ®Google Scholar
• Gao G, Li Y, Gee S et al. Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5. J. Biol. Chem. 277(11), 9492–9497 (2002).
   PubMed Web of Science ®Google Scholar
• Lutty GA, Thompson DC, Gallup JY, Mello RJ, Patz A, Fenselau A. Vitreous: an inhibitor of retinal extract-induced neovascularization. Invest. Ophthalmol. Vis. Sci. 24(1), 52–56 (1983).
   PubMed Web of Science ®Google Scholar
• Lutty GA, Mello RJ, Chandler C, Fait C, Bennett A, Patz A. Regulation of cell growth by vitreous humour. J. Cell. Sci. 76, 53–65 (1985).
   PubMed Web of Science ®Google Scholar
• Gao G, Li Y, Fant J, Crosson CE, Becerra SP, Ma JX. Difference in ischemic regulation of vascular endothelial growth factor and pigment epithelium-derived factor in brown Norway and Sprague Dawley rats contributing to different susceptibilities to retinal neovascularization. Diabetes 51(4), 1218–1225 (2002).
   PubMed Web of Science ®Google Scholar
• Mohan N, Monickaraj F, Balasubramanyam M, Rema M, Mohan V. Imbalanced levels of angiogenic and angiostatic factors in vitreous, plasma and postmortem retinal tissue of patients with proliferative diabetic retinopathy. J. Diabetes Complicat. 26(5), 435–441 (2012).
   PubMed Web of Science ®Google Scholar
• Tombran-Tink J, Johnson LV. Neuronal differentiation of retinoblastoma cells induced by medium conditioned by human RPE cells. Invest. Ophthalmol. Vis. Sci. 30(8), 1700–1707 (1989).
   PubMed Web of Science ®Google Scholar
• Becerra SP, Sagasti A, Spinella P, Notario V. Pigment epithelium-derived factor behaves like a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop. J. Biol. Chem. 270(43), 25992–25999 (1995).
   PubMed Web of Science ®Google Scholar
• Tombran-Tink J, Chader GG, Johnson LV. PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp. Eye Res. 53(3), 411–414 (1991).
   PubMed Web of Science ®Google Scholar
• 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 90(4), 1526–1530 (1993).
   PubMed Web of Science ®Google Scholar
• Becerra SP. Structure–function studies on PEDF. A noninhibitory serpin with neurotrophic activity. Adv. Exp. Med. Biol. 425, 223–237 (1997).
   PubMed Web of Science ®Google Scholar
• Araki T, Taniwaki T, Becerra SP, Chader GJ, Schwartz JP. Pigment epithelium-derived factor (PEDF) differentially protects immature but not mature cerebellar granule cells against apoptotic cell death. J. Neurosci. Res. 53(1), 7–15 (1998).
   PubMed Web of Science ®Google Scholar
• Dawson DW, Volpert OV, Gillis P et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285(5425), 245–248 (1999).
   PubMed Web of Science ®Google Scholar
• Mori K, Duh E, Gehlbach P et al. Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J. Cell. Physiol. 188(2), 253–263 (2001).
   PubMed Web of Science ®Google Scholar
• Stellmach V, Crawford SE, Zhou W, Bouck N. Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor. Proc. Natl Acad. Sci. USA 98(5), 2593–2597 (2001).
   PubMed Web of Science ®Google Scholar
• Tombran-Tink J, Barnstable CJ. PEDF: a multifaceted neurotrophic factor. Nat. Rev. Neurosci. 4(8), 628–636 (2003).
   PubMed Web of Science ®Google Scholar
• Zhang SX, Ma JX, Sima J et al. Genetic difference in susceptibility to the blood-retina barrier breakdown in diabetes and oxygen-induced retinopathy. Am. J. Pathol. 166(1), 313–321 (2005).
   PubMed Web of Science ®Google Scholar
• Sheikpranbabu S, Haribalaganesh R, Lee KJ, Gurunathan S. Pigment epithelium-derived factor inhibits advanced glycation end products-induced retinal vascular permeability. Biochimie 92(8), 1040–1051 (2010).
   PubMed Web of Science ®Google Scholar
• Sheikpranbabu S, Ravinarayanan H, Elayappan B, Jongsun P, Gurunathan S. Pigment epithelium-derived factor inhibits vascular endothelial growth factor - and interleukin-1β-induced vascular permeability and angiogenesis in retinal endothelial cells. Vascul. Pharmacol. 52(1–2), 84–94 (2010).
   PubMed Web of Science ®Google Scholar
• Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am. J. Ophthalmol. 134(3), 348–353 (2002).
   PubMed Web of Science ®Google Scholar
• Boehm BO, Lang G, Volpert O et al. Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy. Diabetologia 46(3), 394–400 (2003).
   PubMed Web of Science ®Google Scholar
• Kim SY, Mocanu C, Mcleod DS et al. Expression of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in sickle cell retina and choroid. Exp. Eye Res. 77(4), 433–445 (2003).
   PubMed Web of Science ®Google Scholar
• Ogata N, Tombran-Tink J, Jo N, Mrazek D, Matsumura M. Upregulation of pigment epithelium-derived factor after laser photocoagulation. Am. J. Ophthalmol. 132(3), 427–429 (2001).
   PubMed Web of Science ®Google Scholar
• Spranger J, Osterhoff M, Reimann M et al. Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease. Diabetes 50(12), 2641–2645 (2001).
   PubMed Web of Science ®Google Scholar
• Yang J, Williams RS, Kelly DP. Bcl3 interacts cooperatively with peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α to coactivate nuclear receptors estrogen-related receptor α and PPARα. Mol. Cell. Biol. 29(15), 4091–4102 (2009).
   PubMed Web of Science ®Google Scholar
• Shalom-Barak T, Nicholas JM, Wang Y et al. Peroxisome proliferator-activated receptor γ controls Muc1 transcription in trophoblasts. Mol. Cell. Biol. 24(24), 10661–10669 (2004).
   PubMed Web of Science ®Google Scholar
• Muranaka K, Yanagi Y, Tamaki Y et al. Effects of peroxisome proliferator-activated receptor γ and its ligand on blood–retinal barrier in a streptozotocin-induced diabetic model. Invest. Ophthalmol. Vis. Sci. 47(10), 4547–4552 (2006).
   PubMed Web of Science ®Google Scholar
• Lee KS, Kim SR, Park SJ et al. Peroxisome proliferator activated receptor-γ modulates reactive oxygen species generation and activation of nuclear factor-κB and hypoxia-inducible factor 1α in allergic airway disease of mice. J. Allergy Clin. Immunol. 118(1), 120–127 (2006).
   PubMed Web of Science ®Google Scholar
• Sung B, Park S, Yu BP, Chung HY. Amelioration of age-related inflammation and oxidative stress by PPARγ activator: suppression of NF-κB by 2,4-thiazolidinedione. Exp. Gerontol. 41(6), 590–599 (2006).
   PubMed Web of Science ®Google Scholar
• Song MK, Roufogalis BD, Huang TH. Modulation of diabetic retinopathy pathophysiology by natural medicines through PPAR-γ-related pharmacology. Br. J. Pharmacol. 165(1), 4–19 (2012).
   PubMed Web of Science ®Google Scholar
• Stahl A, Sapieha P, Connor KM et al. Short communication: PPAR γ mediates a direct antiangiogenic effect of ω 3-PUFAs in proliferative retinopathy. Circ. Res. 107(4), 495–500 (2010).
   PubMed Web of Science ®Google Scholar
• Murata T, He S, Hangai M et al. Peroxisome proliferator-activated receptor-γ ligands inhibit choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 41(8), 2309–2317 (2000).
   PubMed Web of Science ®Google Scholar
• Dougherty TJ, Marcus SL. Photodynamic therapy. Eur. J. Cancer 28A(10), 1734–1742 (1992).
   PubMed Web of Science ®Google Scholar
• Kaplan MJ, Somers RG, Greenberg RH, Ackler J. Photodynamic therapy in the management of metastatic cutaneous adenocarcinomas: case reports from Phase 1/2 studies using tin ethyl etiopurpurin (SnET2). J. Surg. Oncol. 67(2), 121–125 (1998).
   PubMed Web of Science ®Google Scholar
• Ben-Hur E, Orenstein A. The endothelium and red blood cells as potential targets in PDT-induced vascular stasis. Int. J. Radiat. Biol. 60(1–2), 293–301 (1991).
   PubMed Web of Science ®Google Scholar
• Flower RW. Optimizing treatment of choroidal neovascularization feeder vessels associated with age-related macular degeneration. Am. J. Ophthalmol. 134(2), 228–239 (2002).
   PubMed Web of Science ®Google Scholar
• Ho T, Smiddy WE, Flynn HW Jr. Vitrectomy in the management of diabetic eye disease. Surv. Ophthalmol. 37(3), 190–202 (1992).
   PubMed Web of Science ®Google Scholar
• Arrigg PG, Cavallerano J. The role of vitrectomy for diabetic retinopathy. J. Am. Optom. Assoc. 69(11), 733–740 (1998).
   PubMedGoogle Scholar
• Sharma S, Brown GC, Brown MM, Hollands H, Shah GK. The cost–effectiveness of photodynamic therapy for fellow eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 108(11), 2051–2059 (2001).
   PubMed Web of Science ®Google Scholar
• Shinoda K, Ishida S, Kawashima S et al. Clinical factors related to the aqueous levels of vascular endothelial growth factor and hepatocyte growth factor in proliferative diabetic retinopathy. Curr. Eye Res. 21(2), 655–661 (2000).
   PubMed Web of Science ®Google Scholar
• Drolet DW, Nelson J, Tucker CE et al. Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm. Res. 17(12), 1503–1510 (2000).
   PubMed Web of Science ®Google Scholar
• Ruckman J, Green LS, Beeson J et al. 2′-fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. J. Biol. Chem. 273(32), 20556–20567 (1998).
   PubMed Web of Science ®Google Scholar
• Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351(27), 2805–2816 (2004).
   PubMed Web of Science ®Google Scholar
• Cunningham ET Jr, Adamis AP, Altaweel M et al.; Macugen Diabetic Retinopathy Study Group. A Phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 112(10), 1747–1757 (2005).
   PubMed Web of Science ®Google Scholar
• Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 248(7), 915–930 (2010).
   PubMed Web of Science ®Google Scholar
• Presta LG, Chen H, O’Connor SJ et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57(20), 4593–4599 (1997).
   PubMed Web of Science ®Google Scholar
• Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J. Clin. Oncol. 23(22), 4853–4855 (2005).
   PubMed Web of Science ®Google Scholar
• Miller KD, Chap LI, Holmes FA et al. Randomized Phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23(4), 792–799 (2005).
   PubMed Web of Science ®Google Scholar
• Yang JC, Sherry RM, Steinberg SM et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J. Clin. Oncol. 21(16), 3127–3132 (2003).
   PubMed Web of Science ®Google Scholar
• Abouammoh M, Sharma S. Ranibizumab versus bevacizumab for the treatment of neovascular age-related macular degeneration. Curr. Opin. Ophthalmol. 22(3), 152–158 (2011).
   PubMed Web of Science ®Google Scholar
• Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350(23), 2335–2342 (2004).
   PubMed Web of Science ®Google Scholar
• Arevalo JF, Fromow-Guerra J, Sanchez JG et al.; Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collaborative Retina Study Group at 12 months follow-up. Retina (Philadelphia, PA) 28(10), 1387–1394 (2008).
   PubMed Web of Science ®Google Scholar
• Willard AL, Herman IM. Vascular complications and diabetes: current therapies and future challenges. J. Ophthalmol. 2012, 209538 (2012).
   PubMed Web of Science ®Google Scholar
• Rosenfeld PJ, Brown DM, Heier JS et al.; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 355(14), 1419–1431 (2006).
   PubMed Web of Science ®Google Scholar
• Nguyen QD, Shah SM, Khwaja AA et al.; READ-2 Study Group. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 117(11), 2146–2151 (2010).
   PubMed Web of Science ®Google Scholar
• Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl Acad. Sci. USA 99(17), 11393–11398 (2002).
   PubMed Web of Science ®Google Scholar
• Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V. Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest. Ophthalmol. Vis. Sci. 46(2), 726–733 (2005).
   PubMed Web of Science ®Google Scholar
• Rakic JM, Zelinkova M, Comhaire-Poutchinian Y, Galand A, Duchateau E. Treatment of Graves macular edema with intravitreal injection of corticosteroids. Bull. Soc. Belge Ophtalmol. 288, 43–48 (2003).
   PubMedGoogle Scholar
• Brown DM, Kaiser PK, Michels M et al.; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 355(14), 1432–1444 (2006).
   PubMed Web of Science ®Google Scholar
• Kaiser PK; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with an open-label extension: TAP report no. 8. Graefes Arch. Clin. Exp. Ophthalmol. 244(9), 1132–1142 (2006).
   PubMed Web of Science ®Google Scholar
• Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am. J. Ophthalmol. 142(4), 660–668 (2006).
   PubMed Web of Science ®Google Scholar
• Essex RW, Tufail A, Bunce C, Aylward GW. Two-year results of surgical removal of choroidal neovascular membranes related to non-age-related macular degeneration. Br. J. Ophthalmol. 91(5), 649–654 (2007).
   PubMed Web of Science ®Google Scholar
• Xu H, Chen M, Forrester JV. Para-inflammation in the aging retina. Prog. Retin. Eye Res. 28(5), 348–368 (2009).
   PubMed Web of Science ®Google Scholar
• Leal EC, Santiago AR, Ambrósio AF. Old and new drug targets in diabetic retinopathy: from biochemical changes to inflammation and neurodegeneration. Curr. Drug Targets CNS Neurol. Disord. 4(4), 421–434 (2005).
   PubMedGoogle Scholar
• Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH. Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to Drusen formation and age-related macular degeneration. PLoS ONE 4(1), e4160 (2009).
   PubMed Web of Science ®Google Scholar
• Simó R, Hernández C. Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. Diabetologia 51(9), 1574–1580 (2008).
   PubMed Web of Science ®Google Scholar
• Wirostko B, Wong TY, Simó R. Vascular endothelial growth factor and diabetic complications. Prog. Retin. Eye Res. 27(6), 608–621 (2008).
   PubMed Web of Science ®Google Scholar
• Day S, Acquah K, Mruthyunjaya P, Grossman DS, Lee PP, Sloan FA. Ocular complications after anti-vascular endothelial growth factor therapy in Medicare patients with age-related macular degeneration. Am. J. Ophthalmol. 152(2), 266–272 (2011).
   PubMed Web of Science ®Google Scholar
• Wulff C, Wilson H, Wiegand SJ, Rudge JS, Fraser HM. Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinology 143(7), 2797–2807 (2002).
   PubMed Web of Science ®Google Scholar
• Ni Z, Hui P. Emerging pharmacologic therapies for wet age-related macular degeneration. Ophthalmologica 223(6), 401–410 (2009).
   PubMed Web of Science ®Google Scholar
• Danis RP, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCβ inhibition with LY333531. Invest. Ophthalmol. Vis. Sci. 39(1), 171–179 (1998).
   PubMed Web of Science ®Google Scholar
• Bursell SE, Clermont AC, Kinsley BT, Simonson DC, Aiello LM, Wolpert HA. Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 37(5), 886–897 (1996).
   PubMed Web of Science ®Google Scholar
• Aiello LP, Bursell SE, Clermont A et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform-selective inhibitor. Diabetes 46(9), 1473–1480 (1997).
   PubMed Web of Science ®Google Scholar
• Feke GT, Buzney SM, Ogasawara H et al. Retinal circulatory abnormalities in Type 1 diabetes. Invest. Ophthalmol. Vis. Sci. 35(7), 2968–2975 (1994).
   PubMed Web of Science ®Google Scholar
• Xu X, Zhu Q, Xia X, Zhang S, Gu Q, Luo D. Blood–retinal barrier breakdown induced by activation of protein kinase C via vascular endothelial growth factor in streptozotocin-induced diabetic rats. Curr. Eye Res. 28(4), 251–256 (2004).
   PubMed Web of Science ®Google Scholar
• Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ. Res. 90(1), 107–111 (2002).
   PubMed Web of Science ®Google Scholar
• Strøm C, Sander B, Klemp K, Aiello LP, Lund-Andersen H, Larsen M. Effect of ruboxistaurin on blood–retinal barrier permeability in relation to severity of leakage in diabetic macular edema. Invest. Ophthalmol. Vis. Sci. 46(10), 3855–3858 (2005).
   PubMed Web of Science ®Google Scholar
• Schwartz SG, Flynn HW Jr, Aiello LP. Ruboxistaurin mesylate hydrate for diabetic retinopathy. Drugs Today 45(4), 269–274 (2009).
   PubMed Web of Science ®Google Scholar
• Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669), 806–811 (1998).
   PubMed Web of Science ®Google Scholar
• Kaiser PK, Symons RC, Shah SM et al.; siRNA-027 Study Investigators. RNAi-based treatment for neovascular age-related macular degeneration by siRNA-027. Am. J. Ophthalmol. 150(1), 33.e2–39.e2 (2010).
   Web of Science ®Google Scholar
• Shen J, Samul R, Silva RL et al. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther. 13(3), 225–234 (2006).
   PubMed Web of Science ®Google Scholar
• Ceda GP, Hoffman AR, Silverberg GD, Wilson DM, Rosenfeld RG. Regulation of growth hormone release from cultured human pituitary adenomas by somatomedins and insulin. J. Clin. Endocrinol. Metab. 60(6), 1204–1209 (1985).
   PubMed Web of Science ®Google Scholar
• Smith LE, Kopchick JJ, Chen W et al. Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 276(5319), 1706–1709 (1997).
   PubMed Web of Science ®Google Scholar
• Gilbert RE, Kelly DJ, Cox AJ et al. Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes. Diabetologia 43(11), 1360–1367 (2000).
   PubMed Web of Science ®Google Scholar
• Williams B, Baker AQ, Gallacher B, Lodwick D. Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension 25(5), 913–917 (1995).
   PubMed Web of Science ®Google Scholar
• Chua CC, Hamdy RC, Chua BH. Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells. Biochim. Biophys. Acta 1401(2), 187–194 (1998).
   PubMed Web of Science ®Google Scholar
• Goa KL, Haria M, Wilde MI. Lisinopril. A review of its pharmacology and use in the management of the complications of diabetes mellitus. Drugs 53(6), 1081–1105 (1997).
   PubMed Web of Science ®Google Scholar
• Scatena R. Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor. A novel pharmacological approach for tissue remodelling-related diseases. Expert Opin. Investig. Drugs 9(9), 2159–2165 (2000).
   PubMed Web of Science ®Google Scholar
• Shalinsky DR, Brekken J, Zou H et al. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann. N. Y. Acad. Sci. 878, 236–270 (1999).
   PubMed Web of Science ®Google Scholar
• Garcia C, Bartsch DU, Rivero ME et al. Efficacy of prinomastat (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization. Curr. Eye Res. 24(1), 33–38 (2002).
   PubMed Web of Science ®Google Scholar
• Spandau UH, Sauder G, Schubert U, Hammes HP, Jonas JB. Effect of triamcinolone acetonide on proliferation of retinal endothelial cells in vitro and in vivo. Br. J. Ophthalmol. 89(6), 745–747 (2005).
   PubMed Web of Science ®Google Scholar
• Wang YS, Friedrichs U, Eichler W, Hoffmann S, Wiedemann P. Inhibitory effects of triamcinolone acetonide on bFGF-induced migration and tube formation in choroidal microvascular endothelial cells. Graefes Arch. Clin. Exp. Ophthalmol. 240(1), 42–48 (2002).
   PubMed Web of Science ®Google Scholar
• Koedam JA, Smink JJ, van Buul-Offers SC. Glucocorticoids inhibit vascular endothelial growth factor expression in growth plate chondrocytes. Mol. Cell. Endocrinol. 197(1–2), 35–44 (2002).
   PubMed Web of Science ®Google Scholar
• Gille J, Reisinger K, Westphal-Varghese B, Kaufmann R. Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes. J. Invest. Dermatol. 117(6), 1581–1587 (2001).
   PubMed Web of Science ®Google Scholar
• Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur. J. Pharmacol. 341(2–3), 309–315 (1998).
   PubMed Web of Science ®Google Scholar
• Jamrozy-Witkowska A, Kowalska K, Jankowska-Lech I, Terelak-Borys B, Nowosielska A, Grabska-Liberek I. Complications of intravitreal injections – own experience. Klin. Oczna 113(4–6), 127–131 (2011).
   PubMedGoogle Scholar
• Shah AM, Oster SF, Freeman WR. Viral retinitis after intravitreal triamcinolone injection in patients with predisposing medical comorbidities. Am. J. Ophthalmol. 149(3), 433.e1–440.e1 (2010).
   Web of Science ®Google Scholar
• Wilkinson-Berka JL, Alousis NS, Kelly DJ, Gilbert RE. COX-2 inhibition and retinal angiogenesis in a mouse model of retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 44(3), 974–979 (2003).
   PubMed Web of Science ®Google Scholar
• Carmo A, Cunha-Vaz JG, Carvalho AP, Lopes MC. Nitric oxide synthase activity in retinas from non-insulin-dependent diabetic Goto–Kakizaki rats: correlation with blood–retinal barrier permeability. Nitric Oxide 4(6), 590–596 (2000).
   PubMed Web of Science ®Google Scholar
• Takahashi K, Saishin Y, Saishin Y et al. Topical nepafenac inhibits ocular neovascularization. Invest. Ophthalmol. Vis. Sci. 44(1), 409–415 (2003).
   PubMed Web of Science ®Google Scholar
• Zheng Z, Schwab S, Grau A, Berger C. Neuroprotection by early and delayed treatment of acute stroke with high dose aspirin. Brain Res. 1186, 275–280 (2007).
   PubMed Web of Science ®Google Scholar
• Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc. Natl Acad. Sci. USA 96(23), 13496–13500 (1999).
   PubMed Web of Science ®Google Scholar
• Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC. Minocycline for short-term neuroprotection. Pharmacotherapy 26(4), 515–521 (2006).
   PubMed Web of Science ®Google Scholar
• Baptiste DC, Hartwick AT, Jollimore CA, Baldridge WH, Seigel GM, Kelly ME. An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death. Mol. Pharmacol. 66(5), 1113–1122 (2004).
   PubMed Web of Science ®Google Scholar
• Roychoudhury J, Herndon JM, Yin J, Apte RS, Ferguson TA. Targeting immune privilege to prevent pathogenic neovascularization. Invest. Ophthalmol. Vis. Sci. 51(7), 3560–3566 (2010).
   PubMed Web of Science ®Google Scholar
• Funatsu H, Yamashita H, Noma H et al. Outcome of vitreous surgery and the balance between vascular endothelial growth factor and endostatin. Invest. Ophthalmol. Vis. Sci. 44(3), 1042–1047 (2003).
   PubMed Web of Science ®Google Scholar
• Lai CC, Wu WC, Chen SL et al. Recombinant adeno-associated virus vector expressing angiostatin inhibits preretinal neovascularization in adult rats. Ophthalmic Res. 37(1), 50–56 (2005).
   PubMed Web of Science ®Google Scholar