{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:47:25Z","timestamp":1790621245235,"version":"4.1.0"},"reference-count":43,"publisher":"Pharmaceutical Society of Japan","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biological &amp; Pharmaceutical Bulletin","Biol. Pharm. Bull."],"published-print":{"date-parts":[[2017]]},"DOI":"10.1248\/bpb.b17-00475","type":"journal-article","created":{"date-parts":[[2017,11,30]],"date-time":"2017-11-30T22:16:15Z","timestamp":1512080175000},"page":"2045-2049","source":"Crossref","is-referenced-by-count":35,"title":["Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis"],"prefix":"10.1248","volume":"40","author":[{"given":"Tsutomu","family":"Nakahara","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akane","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rina","family":"Yagasaki","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asami","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"163","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"1) Saint-Geniez M, D\u2019Amore PA. Development and pathology of the hyaloid, choroidal and retinal vasculature. <i>Int. J. Dev. Biol.<\/i>, <b>48<\/b>, 1045\u20131058 (2004).","DOI":"10.1387\/ijdb.041895ms"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2) Alon T, Hemo I, Itin A, Pe\u2019er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. <i>Nat. Med.<\/i>, <b>1<\/b>, 1024\u20131028 (1995).","DOI":"10.1038\/nm1095-1024"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3) 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. <i>N. Engl. J. Med.<\/i>, <b>351<\/b>, 2805\u20132816 (2004).","DOI":"10.1056\/NEJMoa042760"},{"key":"4","unstructured":"4) Takeda AL, Colquitt J, Clegg AJ, Jones J. Pegaptanib and ranibizumab for neovascular age-related macular degeneration: a systematic review. <i>Br. J. Ophthalmol.<\/i>, <b>91<\/b>, 1177\u20131182 (2007)."},{"key":"5","doi-asserted-by":"crossref","unstructured":"5) Moradian S, Ahmadieh H, Malihi M, Soheilian M, Dehghan MH, Azarmina M. Intravitreal bevacizumab in active progressive proliferative diabetic retinopathy. <i>Graefes Arch. Clin. Exp. Ophthalmol.<\/i>, <b>246<\/b>, 1699\u20131705 (2008).","DOI":"10.1007\/s00417-008-0914-4"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6) Mintz-Hittner HA, Kennedy KA, Chuang AZ, BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. <i>N. Engl. J. Med.<\/i>, <b>364<\/b>, 603\u2013615 (2011).","DOI":"10.1056\/NEJMoa1007374"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7) Nishijima K, Ng YS, Zhong L, Bradley J, Schubert W, Jo N, Akita J, Samuelsson SJ, Robinson GS, Adamis AP, Shima DT. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. <i>Am. J. Pathol.<\/i>, <b>171<\/b>, 53\u201367 (2007).","DOI":"10.2353\/ajpath.2007.061237"},{"key":"8","unstructured":"8) Saint-Geniez M, Maharaj AS, Walshe TE, Tucker BA, Sekiyama E, Kurihara T, Darland DC, Young MJ, D\u2019Amore PA. Endogenous VEGF is required for visual function: evidence for a survival role on M\u00fcller cells and photoreceptors. <i>PLOS ONE<\/i>, <b>3<\/b>, e3554 (2008)."},{"key":"9","doi-asserted-by":"crossref","unstructured":"9) Yagasaki R, Nakahara T, Mori A, Sakamoto K, Ishii K. Effects of mTOR inhibition on normal retinal vascular development in the mouse. <i>Exp. Eye Res.<\/i>, <b>129<\/b>, 127\u2013134 (2014).","DOI":"10.1016\/j.exer.2014.11.005"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10) Yagasaki R, Nakahara T, Ushikubo H, Mori A, Sakamoto K, Ishii K. Anti-angiogenic effects of mammalian target of rapamycin inhibitors in a mouse model of oxygen-induced retinopathy. <i>Biol. Pharm. Bull.<\/i>, <b>37<\/b>, 1838\u20131842 (2014).","DOI":"10.1248\/bpb.b14-00487"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11) Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. <i>Proc. Natl. Acad. Sci. U.S.A.<\/i>, <b>98<\/b>, 7037\u20137044 (2001).","DOI":"10.1073\/pnas.121145898"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12) Laplante M, Sabatini DM. mTOR signaling in growth control and disease. <i>Cell<\/i>, <b>149<\/b>, 274\u2013293 (2012).","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13) Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. <i>Ann. Oncol.<\/i>, <b>16<\/b>, 525\u2013537 (2005).","DOI":"10.1093\/annonc\/mdi113"},{"key":"14","unstructured":"14) Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. <i>Nat. Med.<\/i>, <b>8<\/b>, 128\u2013135 (2002)."},{"key":"15","doi-asserted-by":"crossref","unstructured":"15) Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C, Sun J, Monahan-Earley RA, Shiojima I, Nagy JA, Lin MI, Walsh K, Dvorak AM, Briscoe DM, Neeman M, Sessa WC, Dvorak HF, Benjamin LE. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. <i>Cancer Cell<\/i>, <b>10<\/b>, 159\u2013170 (2006).","DOI":"10.1016\/j.ccr.2006.07.003"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16) Stahl A, Paschek L, Martin G, Gross NJ, Feltgen N, Hansen LL, Agostini HT. Rapamycin reduces VEGF expression in retinal pigment epithelium (RPE) and inhibits RPE-induced sprouting angiogenesis <i>in vitro<\/i>. <i>FEBS Lett.<\/i>, <b>582<\/b>, 3097\u20133102 (2008).","DOI":"10.1016\/j.febslet.2008.08.005"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17) Xue Q, Nagy JA, Manseau EJ, Phung TL, Dvorak HF, Benjamin LE. Rapamycin inhibition of the Akt\/mTOR pathway blocks select stages of VEGF-A164-driven angiogenesis, in part by blocking S6kinase. <i>Arterioscler. Thromb. Vasc. Biol.<\/i>, <b>29<\/b>, 1172\u20131178 (2009).","DOI":"10.1161\/ATVBAHA.109.185918"},{"key":"18","unstructured":"18) Dejneka NS, Kuroki AM, Fosnot J, Tang W, Tolentino MJ, Bennett J. Systemic rapamycin inhibits retinal and choroidal neovascularization in mice. <i>Mol. Vis.<\/i>, <b>10<\/b>, 964\u2013972 (2004)."},{"key":"19","doi-asserted-by":"crossref","unstructured":"19) Kwon YS, Kim JC. Inhibition of corneal neovascularization by rapamycin. <i>Exp. Mol. Med.<\/i>, <b>38<\/b>, 173\u2013179 (2006).","DOI":"10.1038\/emm.2006.21"},{"key":"20","unstructured":"20) Uemura A, Kusuhara S, Katsuta H, Nishikawa S. Angiogenesis in the mouse retina: a model system for experimental manipulation. <i>Exp. Cell Res.<\/i>, <b>312<\/b>, 676\u2013683 (2006)."},{"key":"21","doi-asserted-by":"crossref","unstructured":"21) Fruttiger M. Development of the retinal vasculature. <i>Angiogenesis<\/i>, <b>10<\/b>, 77\u201388 (2007).","DOI":"10.1007\/s10456-007-9065-1"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22) Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM, Seaward MR, Willett KL, Aderman CM, Guerin KI, Hua J, Lofqvist C, Hellstrom A, Smith LE. The mouse retina as an angiogenesis model. <i>Invest. Ophthalmol. Vis. Sci.<\/i>, <b>51<\/b>, 2813\u20132826 (2010).","DOI":"10.1167\/iovs.10-5176"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23) Ozaki H, Seo MS, Ozaki K, Yamada H, Yamada E, Okamoto N, Hofmann F, Wood JM, Campochiaro PA. Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. <i>Am. J. Pathol.<\/i>, <b>156<\/b>, 697\u2013707 (2000).","DOI":"10.1016\/S0002-9440(10)64773-6"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24) Uemura A, Kusuhara S, Wiegand SJ, Yu RT, Nishikawa S. Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes. <i>J. Clin. Invest.<\/i>, <b>116<\/b>, 369\u2013377 (2006).","DOI":"10.1172\/JCI25964"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25) Morita A, Nakahara T, Abe N, Kurauchi Y, Mori A, Sakamoto K, Nagamitsu T, Ishii K. Effects of pre- and post-natal treatment with KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, on retinal vascular development and patterning in mice. <i>Exp. Eye Res.<\/i>, <b>120<\/b>, 127\u2013137 (2014).","DOI":"10.1016\/j.exer.2014.01.009"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26) Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouch\u00e9 A, Yuce A, Fujisawa H, Hermans B, Shani M, Jansen S, Hicklin D, Anderson DJ, Gardiner T, Hammes HP, Moons L, Dewerchin M, Collen D, Carmeliet P, D\u2019Amore PA. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. <i>J. Clin. Invest.<\/i>, <b>109<\/b>, 327\u2013336 (2002).","DOI":"10.1172\/JCI200214362"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27) Okabe K, Kobayashi S, Yamada T, Kurihara T, Tai-Nagara I, Miyamoto T, Mukouyama YS, Sato TN, Suda T, Ema M, Kubota Y. Neurons limit angiogenesis by titrating VEGF in retina. <i>Cell<\/i>, <b>159<\/b>, 584\u2013596 (2014).","DOI":"10.1016\/j.cell.2014.09.025"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28) del Toro R, Prahst C, Mathivet T, Siegfried G, Kaminker JS, Larrivee B, Breant C, Duarte A, Takakura N, Fukamizu A, Penninger J, Eichmann A. Identification and functional analysis of endothelial tip cell-enriched genes. <i>Blood<\/i>, <b>116<\/b>, 4025\u20134033 (2010).","DOI":"10.1182\/blood-2010-02-270819"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29) Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. <i>Mol. Cell. Biol.<\/i>, <b>22<\/b>, 7004\u20137014 (2002).","DOI":"10.1128\/MCB.22.20.7004-7014.2002"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30) Vi\u00f1als F, Chambard JC, Pouyss\u00e9gur J. p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. <i>J. Biol. Chem.<\/i>, <b>274<\/b>, 26776\u201326782 (1999).","DOI":"10.1074\/jbc.274.38.26776"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31) Kasai A, Shintani N, Kato H, Matsuda S, Gomi F, Haba R, Hashimoto H, Kakuda M, Tano Y, Baba A. Retardation of retinal vascular development in apelin-deficient mice. <i>Arterioscler. Thromb. Vasc. Biol.<\/i>, <b>28<\/b>, 1717\u20131722 (2008).","DOI":"10.1161\/ATVBAHA.108.163402"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32) Kasai A, Ishimaru Y, Kinjo T, Satooka T, Matsumoto N, Yoshioka Y, Yamamuro A, Gomi F, Shintani N, Baba A, Maeda S. Apelin is a crucial factor for hypoxia-induced retinal angiogenesis. <i>Arterioscler. Thromb. Vasc. Biol.<\/i>, <b>30<\/b>, 2182\u20132187 (2010).","DOI":"10.1161\/ATVBAHA.110.209775"},{"key":"33","unstructured":"33) Siemerink MJ, Klaassen I, Van Noorden CJ, Schlingemann RO. Endothelial tip cells in ocular angiogenesis: potential target for anti-angiogenesis therapy. <i>J. Histochem. Cytochem.<\/i>, <b>61<\/b>, 101\u2013115 (2013)."},{"key":"34","unstructured":"34) Smith LE, Wesolowski E, McLellan A, Kostyk SK, D\u2019Amato R, Sullivan R, D\u2019Amore PA. Oxygen-induced retinopathy in the mouse. <i>Invest. Ophthalmol. Vis. Sci.<\/i>, <b>35<\/b>, 101\u2013111 (1994)."},{"key":"35","doi-asserted-by":"crossref","unstructured":"35) Tobe T, Ortega S, Luna JD, Ozaki H, Okamoto N, Derevjanik NL, Vinores SA, Basilico C, Campochiaro PA. Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. <i>Am. J. Pathol.<\/i>, <b>153<\/b>, 1641\u20131646 (1998).","DOI":"10.1016\/S0002-9440(10)65753-7"},{"key":"36","doi-asserted-by":"crossref","unstructured":"36) Lambert V, Lecomte J, Hansen S, Blacher S, Gonzalez ML, Struman I, Sounni NE, Rozet E, de Tullio P, Foidart JM, Rakic JM, Noel A. Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice. <i>Nat. Protoc.<\/i>, <b>8<\/b>, 2197\u20132211 (2013).","DOI":"10.1038\/nprot.2013.135"},{"key":"37","doi-asserted-by":"crossref","unstructured":"37) Nakano A, Nakahara T, Mori A, Ushikubo H, Sakamoto K, Ishii K. Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats. <i>Exp. Eye Res.<\/i>, <b>143<\/b>, 120\u2013131 (2016).","DOI":"10.1016\/j.exer.2015.10.016"},{"key":"38","doi-asserted-by":"crossref","unstructured":"38) Leibinger M, Andreadaki A, Fischer D. Role of mTOR in neuroprotection and axon regeneration after inflammatory stimulation. <i>Neurobiol. Dis.<\/i>, <b>46<\/b>, 314\u2013324 (2012).","DOI":"10.1016\/j.nbd.2012.01.004"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39) Park HY, Kim JH, Park CK. Activation of autophagy induces retinal ganglion cell death in a chronic hypertensive glaucoma model. <i>Cell Death Dis.<\/i>, <b>3<\/b>, e290 (2012).","DOI":"10.1038\/cddis.2012.26"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40) Ichikawa A, Nakahara T, Kurauchi Y, Mori A, Sakamoto K, Ishii K. Rapamycin prevents <i>N<\/i>-methyl-D-aspartate-induced retinal damage through an ERK-dependent mechanism in rats. <i>J. Neurosci. Res.<\/i>, <b>92<\/b>, 692\u2013702 (2014).","DOI":"10.1002\/jnr.23358"},{"key":"41","doi-asserted-by":"crossref","unstructured":"41) Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S. Potential role of microglia in retinal blood vessel formation. <i>Invest. Ophthalmol. Vis. Sci.<\/i>, <b>47<\/b>, 3595\u20133602 (2006).","DOI":"10.1167\/iovs.05-1522"},{"key":"42","doi-asserted-by":"crossref","unstructured":"42) Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH, Honor\u00e9 JC, Kermorvant-Duchemin E, Varma DR, Tremblay S, Leduc M, Rihakova L, Hardy P, Klein WH, Mu X, Mamer O, Lachapelle P, Di Polo A, Beaus\u00e9jour C, Andelfinger G, Mitchell G, Sennlaub F, Chemtob S. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. <i>Nat. Med.<\/i>, <b>14<\/b>, 1067\u20131076 (2008).","DOI":"10.1038\/nm.1873"},{"key":"43","doi-asserted-by":"crossref","unstructured":"43) Hayashi I, Aoki Y, Asano D, Ushikubo H, Mori A, Sakamoto K, Nakahara T, Ishii K. Protective effects of everolimus against <i>N<\/i>-methyl-D-aspartic acid-induced retinal damage in rats. <i>Biol. Pharm. Bull.<\/i>, <b>38<\/b>, 1765\u20131771 (2015).","DOI":"10.1248\/bpb.b15-00464"}],"container-title":["Biological &amp; Pharmaceutical Bulletin","Biological and Pharmaceutical Bulletin"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/bpb\/40\/12\/40_b17-00475\/_pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,7]],"date-time":"2019-10-07T05:38:17Z","timestamp":1570426697000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/bpb\/40\/12\/40_b17-00475\/_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017]]},"references-count":43,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1248\/bpb.b17-00475","relation":{},"ISSN":["0918-6158","1347-5215"],"issn-type":[{"value":"0918-6158","type":"print"},{"value":"1347-5215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017]]}}}