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Ocular neovascularization

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Abstract

Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss in developed countries. They can be divided into retinal vascular diseases, in which there is leakage and/or neovascularization (NV) from retinal vessels, and subretinal NV, in which new vessels grow into the normally avascular outer retina and subretinal space. The first category of diseases includes diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity, and the second category includes neovascular age-related macular degeneration (AMD), ocular histoplasmosis, pathologic myopia, and other related diseases. Retinal hypoxia is a key feature of the first category of diseases resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1) which stimulates expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGF-B), placental growth factor, stromal-derived growth factor-1 and their receptors, as well as other hypoxia-regulated gene products such as angiopoietin-2. Although hypoxia has not been demonstrated as part of the second category of diseases, HIF-1 is elevated and thus the same group of hypoxia-regulated gene products plays a role. Clinical trials have shown that VEGF antagonists provide major benefits for patients with subretinal NV due to AMD and even greater benefits are seen by combining antagonists of VEGF and PDGF-B. It is likely that addition of antagonists of other agents listed above will be tested in the future. Other appealing strategies are to directly target HIF-1 or to use gene transfer to express endogenous or engineered anti-angiogenic proteins. While substantial progress has been made, the future looks even brighter for patients with retinal and choroidal vascular diseases.

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References

  1. Michaelson I (1948) The mode of development of the vascular system of the retina with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK 68:137–180

    Google Scholar 

  2. Baird A, Esch F, Gospodarowicz D, Guillemin R (1985) Retina- and eye-derived endothelial cell growth factors: partial molecular characterization and identity with acidic and basic fibroblast growth factors. Biochemistry 24:7855–7860

    PubMed  CAS  Google Scholar 

  3. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845

    PubMed  CAS  Google Scholar 

  4. Plate KH, Breier G, Welch HA, Risau W (1992) Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature 359:845–848

    PubMed  CAS  Google Scholar 

  5. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    PubMed  CAS  Google Scholar 

  6. Patz A (1968) The role of oxygen in retrolental fibroplasia. Trans Am Opthalmol Soc 66:940–985

    CAS  Google Scholar 

  7. Patz A (1984) Current concepts of the effect of oxygen on the developing retina. Curr Eye Res 3:159–163

    PubMed  CAS  Google Scholar 

  8. Patz A, Eastham A, Higgenbotham DH, Kleh T (1953) Oxygen studies in retrolental figroplasia: production of the microscopic changes of retrolental fibroplasia in experimental animals. Am J Ophthalmol 36:1511–1522

    PubMed  CAS  Google Scholar 

  9. Smith LEH, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, D’Amore PA (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101–111

    PubMed  CAS  Google Scholar 

  10. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LEH (1995) 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 92:10457–10461

    PubMed  CAS  Google Scholar 

  11. Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Med 1:1024–1028

    PubMed  CAS  Google Scholar 

  12. Pierce EA, Foley ED, Smith LE (1996) Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 114:1219–1228

    PubMed  CAS  Google Scholar 

  13. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LEH (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 92:905–909

    PubMed  CAS  Google Scholar 

  14. Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90:4304–4308

    PubMed  CAS  Google Scholar 

  15. Wang GL, Jiang B-H, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    PubMed  CAS  Google Scholar 

  16. Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88:1474–1480

    PubMed  CAS  Google Scholar 

  17. Ozaki H, Yu A, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL et al (1999) Hypoxia inducible factor-1α is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci 40:182–189

    PubMed  CAS  Google Scholar 

  18. Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S, Rowan A, Yan Z, Campochiaro PA, Semenza GL (2003) Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res 93:1074–1081

    PubMed  CAS  Google Scholar 

  19. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H et al (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583

    PubMed  CAS  Google Scholar 

  20. Seo M-S, Okamoto N, Vinores MA, Vinores SA, Hackett SF, Yamada H, Yamada E, Derevjanik NL, LaRochelle W, Zack DJ et al (2000) Photoreceptor-specific expression of PDGF-B results in traction retinal detachment. Am J Pathol 157:995–1005

    PubMed  CAS  Google Scholar 

  21. Mori K, Gehlbach P, Ando A, Dyer G, Lipinsky E, Chaudhry AG, Hackett SF, Campochiaro PA (2002) Retina-specific expression of PDGF-B versus PDGF-A: vascular versus nonvascular proliferative retinopathy. Invest Ophthalmol Vis Sci 43:2001–2006

    PubMed  Google Scholar 

  22. Lima e Silva R, Shen J, Hackett SF, Kachi S, Akiyama H, Kiuchi K, Yokoi K, Hatara C, McLauer T, Aslam S (2007) The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J 21:3219–3230

    PubMed  CAS  Google Scholar 

  23. Diez H, Fischer A, Winkler A, Hu C-J, Hatzopoulos AK, Breier G, Gessler M (2007) Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res 313:1–9

    PubMed  CAS  Google Scholar 

  24. Hofmann JJ, Iruela-Arispe ML (2007) Notch expression patterns in the retina: an eye on receptor–ligand distribution during angiogenesis. Gene Expr Patterns 7:461–470

    PubMed  CAS  Google Scholar 

  25. Hellstrom M, Phing LK, Hofmman JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N et al (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 15:776–780

    Google Scholar 

  26. Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009) The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124–1135

    PubMed  CAS  Google Scholar 

  27. Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436:193–200

    PubMed  CAS  Google Scholar 

  28. Yannuzzi LA, Negrao S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter JS, Freund KB, Sorenson J, Orlock D, Borodoker N (2001) Retinal angiomatous proliferation in age-related macular degeneration. Retina 21:416–434

    PubMed  CAS  Google Scholar 

  29. Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, Zack DJ, Campochiaro PA (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 151:281–291

    PubMed  CAS  Google Scholar 

  30. Tobe T, Okamoto N, Vinores MA, Derevjanik NL, Vinores SA, Zack DJ, Campochiaro PA (1998) Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 39:180–188

    PubMed  CAS  Google Scholar 

  31. Heckenlively JR, Hawes NL, Friedlander M, Nusinowitz S, Hurd R, Davisson M, Chang B (2003) Mouse model of subretinal neovascularization with choroidal anastomosis. Retina 23:518–522

    PubMed  Google Scholar 

  32. Li C, Huang Z, Kingsley R, Zhou X, Li F, Parke DW 2nd, Cao W (2007) Biochemical alterations in the retinas of very low-density lipoprotein receptor knockout mice: an animal model of retinal angiomatous proliferation. Arch Ophthalmol 125:795–803

    PubMed  CAS  Google Scholar 

  33. Yamada H, Yamada E, Kwak N, Ando A, Suzuki A, Esumi N, Zack DJ, Campochiaro PA (2000) Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the retina. J Cell Physiol 185:135–142

    PubMed  CAS  Google Scholar 

  34. Ryan SJ (1982) Subretinal neovascularization: natural history of an experimental model. Arch Ophthalmol 100:1804–1809

    PubMed  CAS  Google Scholar 

  35. Tobe T, Ortega S, Luna JD, Ozaki H, Okamoto N, Derevjanik NL, Vinores SA, Basilico C, Campochiaro PA (1998) Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol 153:1641–1646

    PubMed  CAS  Google Scholar 

  36. Oshima Y, Oshima S, Nambu H, Kachi S, Takahashi K, Umeda N, Shen J, Dong A, Apte RS, Duh E et al (2005) Different effects of angiopoietin 2 in different vascular beds in the eye; new vessels are most sensitive. FASEB J 19:963–965

    PubMed  CAS  Google Scholar 

  37. Kwak N, Okamoto N, Wood JM, Campochiaro PA (2000) VEGF is an important stimulator in a model of choroidal neovascularization. Invest Ophthalmol Vis Sci 41:3158–3164

    PubMed  CAS  Google Scholar 

  38. Kryzstolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NM, Li W, Connolly E, O’Neill CA, Miller JW (2002) Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol 120:338–346

    Google Scholar 

  39. Baffi J, Byrnes G, Chan CC, Csaky KG (2000) Choroidal neovascularization in the rat induced by adenovirus mediated expression of vascular endothelial growth factor. Invest Ophthalmol Vis Sci 41:3582–3589

    PubMed  CAS  Google Scholar 

  40. Oshima Y, Oshima S, Nambu H, Kachi S, Hackett SF, Melia M, Kaleko M, Connelly S, Esumi N, Zack DJ et al (2004) Increased expression of VEGF in retinal pigmented epithelial cells is not sufficient to cause choroidal neovascularization. J Cell Physiol 201:393–400

    PubMed  CAS  Google Scholar 

  41. Vinores SA, Xiao WH, Aslam S, Shen J, Oshima Y, Nambu H, Liu H, Carmeliet P, Campochiaro PA (2006) Implication of the hypoxia response element of the VEGF promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development. J Cell Physiol 206:749–758

    PubMed  CAS  Google Scholar 

  42. Jo N, Mailhos C, Ju M, Cheung E, Bradley J, Nishijima K, Robinson GS, Adamis AP, Shima DT (2006) Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 168:2036–2053

    PubMed  CAS  Google Scholar 

  43. Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R et al (2008) Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci USA 105:19579–19586

    PubMed  CAS  Google Scholar 

  44. Yoshida T, Zhang H, Iwase T, Shen J, Semenza G, Campochiaro PA (2010) Digoxin inhibits retinal ischemia-induced HIF-1α expression and ocular neovascularization. FASEB J 24:1759–1767

    PubMed  CAS  Google Scholar 

  45. Chandel NS, Maltepe E, Godwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A 95:11715–11720

    PubMed  CAS  Google Scholar 

  46. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia. J Biol Chem 275:25130–21138

    PubMed  CAS  Google Scholar 

  47. Lu H, Dalgard CL, Mohyeldin A, McGate T, Tait AS, Verma A (2005) Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280:41928–41939

    PubMed  CAS  Google Scholar 

  48. Dong A, Xie B, Shen J, Yoshida T, Yokoi K, Hackett SF, Campochiaro PA (2009) Oxidative stress promotes ocular neovascularization. J Cell Physiol 219:544–552

    PubMed  CAS  Google Scholar 

  49. Age-Related Eye Disease Study Research Group (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch Ophthalmol 119:1417–1436

    Google Scholar 

  50. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343

    PubMed  CAS  Google Scholar 

  51. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Yung S, Chimenti S, Landsman L, Abramaovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189

    PubMed  CAS  Google Scholar 

  52. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438

    PubMed  CAS  Google Scholar 

  53. Otani A, Kinder K, Ewait K, Otero FJ, Schimmel P, Friedlander M (2002) Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis. Nat Med 8:1004–1010

    PubMed  CAS  Google Scholar 

  54. Grant MB, May WS, Caballero S, Brown GA, Guthrie SM, Mamee RN, Byrne BJ, Vaught T, Spoerri PE, Peck AB et al (2002) Adult hematopoietic stem cells provide functional hemangioblastic activity during retinal neovascularization. Nat Med 8:607–612

    PubMed  CAS  Google Scholar 

  55. Sengupta N, Calballero S, Mames RN, Butler JM, Scott EW, Grant MB (2003) The role of adult bone marrow-derived stem cells in choroidal neovascularization. Invest Ophthalmol Vis Sci 44:4908–4913

    PubMed  Google Scholar 

  56. Lang RA, Bishop MJ (1993) Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell 74:453–462

    PubMed  CAS  Google Scholar 

  57. Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Galss DA, Patel MS, Shu W et al (2005) WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437:417–421

    PubMed  CAS  Google Scholar 

  58. Apte RS, Richter J, Herndon J, Ferguson TA (2006) Macrophage inhibition of neovascularization in a murine model of age-related macular degeneration. PLoS Med 8:e310

    Google Scholar 

  59. Lu P, Li L, LIu G, van Rooijen N, Mukaida N, Zhang X (2009) Opposite roles of CCR2 and CX3CR1 macrophages in alkali-induced corneal neovascularization. Cornea 28:562–569

    PubMed  CAS  Google Scholar 

  60. Cousins SW, Esponosa-Heidmann DG, Miller DM, Pereira-Simon S, Hernandez EP, Chien H, Meier-jewett C, Dix RD (2012) Cytomegalovirus infection results in more severe experimental choroidal neovascularization. PLoS Pathog 8:e1002671

    PubMed  CAS  Google Scholar 

  61. Shen J, Xie B, Dong A, Swaim M, Hackett SF, Campochiaro PA (2007) In vivo immunostaining demonstrates macrophages associate with growing and regressing vessels. Invest Ophthalmol Vis Sci 48:4335–4341

    PubMed  Google Scholar 

  62. Outtz HH, Tattersall IW, Kofler NM, Steinbach N, Kitajewski J (2011) Notch 1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 118:3436–3439

    PubMed  CAS  Google Scholar 

  63. Stefater JAR, Lewkowich I, Rao S, Mariggi G, Carpenter AC, Burr AR, Fan J, Ajima R, Molkentin JD, Willimas BO (2011) Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature 474:511–515

    PubMed  CAS  Google Scholar 

  64. Knighton DR, Hunt TK, Scheuenstuhl H, Halliday BJ, Werb Z, Banda MJ (1983) Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science 221: 1283–1285

    Google Scholar 

  65. Kelly J, Khan AA, Yin J, Ferguson TA, Apte RS (2007) Senescence regulates macrophage activation and angiogenic fate at site of tissue injury in mice. J Clin Invest 117:3421–3426

    PubMed  CAS  Google Scholar 

  66. Espinosa-Heidmann DG, Suner IJ, Hernandez E, Monroy D, Csaky KG, Cousins SW (2003) Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3586–3592

    PubMed  Google Scholar 

  67. Tsutsumi C, Sonoda KH, Egashira K, Qiao H, Hisatomi T, Nakao S, Ishibashi M, Charo IF, Sakamoto T, Murata T et al (2003) The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization. J Leukoc Biol 74:25–32

    PubMed  CAS  Google Scholar 

  68. Noda K, She H, Nakazawa T, Hisatomi T, Nakao S, Almulki L, Zandi S, Miyahara S, Ito Y, Thomas KL et al (2008) Vascular adhesion protein-1 blockade suppresses choroidal neovascularization. FASEB J 22:2928–2935

    PubMed  CAS  Google Scholar 

  69. Xie B, Shen J, Dong A, Rashid A, Stoller G, Campochiaro PA (2009) Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J Cell Physiol 218:192–198

    PubMed  CAS  Google Scholar 

  70. Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T (2009) M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 206:1089–1102

    PubMed  CAS  Google Scholar 

  71. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–74

    PubMed  CAS  Google Scholar 

  72. Davis S, Aldrich TH, Jones P, Acheson A, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169

    PubMed  CAS  Google Scholar 

  73. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60

    PubMed  CAS  Google Scholar 

  74. Hackett SF, Ozaki H, Strauss RW, Wahlin K, Suri C, Maisonpierre P, Yancopoulos G, Campochiaro PA (2000) Angiopoietin 2 expression in the retina: upregulation during physiologic and pathologic neovascularization. J Cell Physiol 184:275–284

    PubMed  CAS  Google Scholar 

  75. Hackett SF, Wiegand SJ, Yancopoulos G, Campochiaro P (2002) Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol 192:182–187

    PubMed  CAS  Google Scholar 

  76. Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte M, Jackson D et al (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Devel Cell 3:411–423

    CAS  Google Scholar 

  77. Oshima Y, Deering T, Oshima S, Nambu H, Reddy PS, Kaleko M, Connelly S, Hackett SF, Campochiaro PA (2004) Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor. J Cell Physiol 199:412–417

    PubMed  CAS  Google Scholar 

  78. Nambu H, Nambu R, Oshima Y, Hackett SF, Wiegand SJ, Yancopoulos G, Zack DJ, Campochiaro PA (2004) Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood-retinal barrier. Gene Ther 11:865–873

    PubMed  CAS  Google Scholar 

  79. Nambu H, Umeda N, Kachi S, Oshima Y, Nambu R, Campochiaro PA (2005) Angiopoietin 1 prevents retinal detachment in an aggressive model of proliferative retinopathy, but has no effect on established neovascularization. J Cell Physiol 204:227–235

    PubMed  CAS  Google Scholar 

  80. Friedlander M, Theesfeld CL, Sugita M, Fruttiger M, Thomas MA, Chang S, Cheresh DA (1996) Involvement of integrins alpha-v beta-3 and alpha-v beta-5 in ocular neovascular diseases. Proc Natl Acad Sci USA 93:9764–9769

    PubMed  CAS  Google Scholar 

  81. Hammes H, Brownlee M, Jonczyk A, Sutter A, Preissner K (1996) Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat Med 2:529–533

    PubMed  CAS  Google Scholar 

  82. Luna J, Tobe T, Mousa SA, Reilly TM, Campochiaro PA (1996) Antagonists of integrin alpha-v beta-3 inhibit retinal neovascularization in a murine model. Lab Invest 75:563–573

    PubMed  CAS  Google Scholar 

  83. Umeda N, Kachi S, Akiyama H, Zahn G, Vossmeyer D, Stragies R, Campochiaro PA (2006) Suppression and regression of choroidal neovascularization by systemic administration of an Alpha5Beta1 integrin antagonist. Mol Pharmacol 69:1820–1828

    PubMed  CAS  Google Scholar 

  84. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birknead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285

    PubMed  Google Scholar 

  85. Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H, Knebelmann B, Sukhatme VP (1999) Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem Biophys Res Comm 255:735–739

    PubMed  CAS  Google Scholar 

  86. Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK et al (2000) Anti-angiogenic cues from vascular basement membrane collagen. Canc Res 60:2520–2526

    CAS  Google Scholar 

  87. Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torres A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R (2000) Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem 275:1209–1215

    PubMed  CAS  Google Scholar 

  88. Petitclerc C, Boutaud A, Prestayko A, Xu J, Sado Y, Ninomiya Y, Sarras MP Jr, Hudson BG, Brooks PC (2000) New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J Biol Chem 275:8051–8061

    PubMed  CAS  Google Scholar 

  89. Lima e Silva R, Kachi S, Akiyama H, Shen J, Aslam S, Gong YY, Khu NH, Hatara MC, Boutaud A, Peterson R et al (2006) Recombinant non-collagenous domain of α2(IV) collagen causes involution of choroidal neovascularization by inducing apoptosis. J Cell Physiol 208:161–166

    PubMed  Google Scholar 

  90. Mori K, Ando A, Gehlbach P, Nesbitt D, Takahashi K, Goldsteen D, Penn M, Chen CT, Melia M, Phipps S et al (2001) Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin. Am J Pathol 159:313–320

    PubMed  CAS  Google Scholar 

  91. Takahashi K, Saishin Y, Saishin Y, Lima Silva R, Oshima Y, Oshima S, Melia M, Paszkiet B, Zerby D, Kadan MJ et al (2003) Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment. FASEB J 17:896–898

    PubMed  CAS  Google Scholar 

  92. Mori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J, Mori K, Yang HS, Zack DJ, Ettyreddy D et al (2001) Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol 188:253–263

    PubMed  CAS  Google Scholar 

  93. Lai C-C, Wu W-C, Chen S-L, Xiao X, Tsai T-C, Huan S-J, Chen T-L, Tsai RJ-F, Tsao Y-P (2001) Suppression of choroidal neovascularization by adeno-associated virus vector expressing angiostatin. Invest Ophthalmol Vis Sci 42:2401–2407

    PubMed  CAS  Google Scholar 

  94. Lai C-M, Brankov M, Zaknich T, Lai YK-Y, Shen W-Y, Constable IJ, Kovesdi I, Rakoczy PE (2001) Inhibition of angiogenesis by adenovirus-mediated sFlt-1 expression in a rat model of corneal neovascularization. Human Gene Ther 12:1299–1310

    CAS  Google Scholar 

  95. Lai YK, Shen WY, Brankov M, Lai CM, Constable IJ, Rakoczy PE (2002) Potential long-term inhibition of ocular neovascularization by recombinant adeno-associated virus-mediated secretion gene therapy. Gene Ther 9:804–813

    PubMed  CAS  Google Scholar 

  96. Shen J, Yang XR, Xiao WH, Hackett SF, Sato Y, Campochiaro PA (2006) Vasohibin is up-regulated by VEGF in the retina and suppresses VEGF receptor 2 and retinal neovascularization. FASEB J 20:723–725

    PubMed  CAS  Google Scholar 

  97. Ferrara N, Damico L, Shams N, Lowman H, Kim R (2006) Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26:859–870

    PubMed  Google Scholar 

  98. Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V (2005) Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 46:726–733

    PubMed  Google Scholar 

  99. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, Group MS (2006) Ranibizumab for neovascular age-related macular degeneration. N Eng J Med 355:1419–1431

    CAS  Google Scholar 

  100. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S, Group AS (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Eng J Med 355:1432–1444

    CAS  Google Scholar 

  101. Saishin Y, Takahashi K, Lima Silva R, Hylton D, Rudge J, WS J, Campochiaro PA (2003) VEGF-TRAPR1R2 suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier. J Cell Physiol 195:241–248

    PubMed  CAS  Google Scholar 

  102. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD et al (2012) Intravitreal Aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 119:2537–2548

    PubMed  Google Scholar 

  103. CATT Research Group, Marin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Eng J Med 364:1897–1908

    Google Scholar 

  104. Boyer DS, Ophthotech Anti-PDGF in AMD Study Group (2009) Combined inhibition of platelet-derived (PDGF) and vascular endothelial (VEGF) growth factors for the treatment of neovascular age-related macular degeneration (NV-AMD). Results of a phase 1 study. Invest Ophthalmol Vis Sci Online ARVO abstract 1260

  105. Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, Saperstein DA, Gupta A, Stout JT, Macko J et al (2006) Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther 17:167–176

    PubMed  CAS  Google Scholar 

  106. Campochiaro PA (2011) Gene transfer for neovascular age-related macular degeneration. Hum Gene Ther 22:523–529

    PubMed  CAS  Google Scholar 

  107. Campochiaro PA (2012) Gene transfer for ocular neovascularization and macular edema. Gene Ther 19:121–126

    PubMed  CAS  Google Scholar 

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Disclosure

The author is consultant for Genentech, Regeneron, Allergan, and Aerpio for which Johns Hopkins University receives remuneration and receives research support for clinical trials from the above, Genzyme, and Oxford BioMedica.

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Correspondence to Peter A. Campochiaro.

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Campochiaro, P.A. Ocular neovascularization. J Mol Med 91, 311–321 (2013). https://doi.org/10.1007/s00109-013-0993-5

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  • DOI: https://doi.org/10.1007/s00109-013-0993-5

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