Journal of Molecular Medicine

, Volume 91, Issue 3, pp 311–321 | Cite as

Ocular neovascularization



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.


Angiogenesis Age-related macular degeneration Diabetic retinopathy Hypoxia-inducible factor-1 Vascular endothelial growth factor Platelet-derived growth factor 



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.


  1. 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 68:137–180Google Scholar
  2. 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 24:7855–7860PubMedGoogle Scholar
  3. 3.
    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845PubMedGoogle Scholar
  4. 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 359:845–848PubMedGoogle Scholar
  5. 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 331:1480–1487PubMedGoogle Scholar
  6. 6.
    Patz A (1968) The role of oxygen in retrolental fibroplasia. Trans Am Opthalmol Soc 66:940–985Google Scholar
  7. 7.
    Patz A (1984) Current concepts of the effect of oxygen on the developing retina. Curr Eye Res 3:159–163PubMedGoogle Scholar
  8. 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 36:1511–1522PubMedGoogle Scholar
  9. 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 35:101–111PubMedGoogle Scholar
  10. 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 92:10457–10461PubMedGoogle Scholar
  11. 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 1:1024–1028PubMedGoogle Scholar
  12. 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 114:1219–1228PubMedGoogle Scholar
  13. 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 92:905–909PubMedGoogle Scholar
  14. 14.
    Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90:4304–4308PubMedGoogle Scholar
  15. 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 92:5510–5514PubMedGoogle Scholar
  16. 16.
    Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88:1474–1480PubMedGoogle Scholar
  17. 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 40:182–189PubMedGoogle Scholar
  18. 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 93:1074–1081PubMedGoogle Scholar
  19. 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 7:575–583PubMedGoogle Scholar
  20. 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 157:995–1005PubMedGoogle Scholar
  21. 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 43:2001–2006PubMedGoogle Scholar
  22. 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 21:3219–3230PubMedGoogle Scholar
  23. 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 313:1–9PubMedGoogle Scholar
  24. 24.
    Hofmann JJ, Iruela-Arispe ML (2007) Notch expression patterns in the retina: an eye on receptor–ligand distribution during angiogenesis. Gene Expr Patterns 7:461–470PubMedGoogle Scholar
  25. 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 15:776–780Google Scholar
  26. 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 137:1124–1135PubMedGoogle Scholar
  27. 27.
    Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436:193–200PubMedGoogle Scholar
  28. 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 21:416–434PubMedGoogle Scholar
  29. 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 151:281–291PubMedGoogle Scholar
  30. 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 39:180–188PubMedGoogle Scholar
  31. 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 23:518–522PubMedGoogle Scholar
  32. 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 125:795–803PubMedGoogle Scholar
  33. 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 185:135–142PubMedGoogle Scholar
  34. 34.
    Ryan SJ (1982) Subretinal neovascularization: natural history of an experimental model. Arch Ophthalmol 100:1804–1809PubMedGoogle Scholar
  35. 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 153:1641–1646PubMedGoogle Scholar
  36. 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 19:963–965PubMedGoogle Scholar
  37. 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 41:3158–3164PubMedGoogle Scholar
  38. 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 120:338–346Google Scholar
  39. 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 41:3582–3589PubMedGoogle Scholar
  40. 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 201:393–400PubMedGoogle Scholar
  41. 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 206:749–758PubMedGoogle Scholar
  42. 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 168:2036–2053PubMedGoogle Scholar
  43. 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 105:19579–19586PubMedGoogle Scholar
  44. 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 24:1759–1767PubMedGoogle Scholar
  45. 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 95:11715–11720PubMedGoogle Scholar
  46. 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 275:25130–21138PubMedGoogle Scholar
  47. 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 280:41928–41939PubMedGoogle Scholar
  48. 48.
    Dong A, Xie B, Shen J, Yoshida T, Yokoi K, Hackett SF, Campochiaro PA (2009) Oxidative stress promotes ocular neovascularization. J Cell Physiol 219:544–552PubMedGoogle Scholar
  49. 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 119:1417–1436Google Scholar
  50. 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 87:3336–3343PubMedGoogle Scholar
  51. 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 124:175–189PubMedGoogle Scholar
  52. 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 5:434–438PubMedGoogle Scholar
  53. 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 8:1004–1010PubMedGoogle Scholar
  54. 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 8:607–612PubMedGoogle Scholar
  55. 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 44:4908–4913PubMedGoogle Scholar
  56. 56.
    Lang RA, Bishop MJ (1993) Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell 74:453–462PubMedGoogle Scholar
  57. 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 437:417–421PubMedGoogle Scholar
  58. 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:e310Google Scholar
  59. 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 28:562–569PubMedGoogle Scholar
  60. 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:e1002671PubMedGoogle Scholar
  61. 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 48:4335–4341PubMedGoogle Scholar
  62. 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 118:3436–3439PubMedGoogle Scholar
  63. 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 474:511–515PubMedGoogle Scholar
  64. 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: 1283–1285Google Scholar
  65. 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 117:3421–3426PubMedGoogle Scholar
  66. 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 44:3586–3592PubMedGoogle Scholar
  67. 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 74:25–32PubMedGoogle Scholar
  68. 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 22:2928–2935PubMedGoogle Scholar
  69. 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 218:192–198PubMedGoogle Scholar
  70. 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 206:1089–1102PubMedGoogle Scholar
  71. 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 376:70–74PubMedGoogle Scholar
  72. 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 87:1161–1169PubMedGoogle Scholar
  73. 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 277:55–60PubMedGoogle Scholar
  74. 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 184:275–284PubMedGoogle Scholar
  75. 75.
    Hackett SF, Wiegand SJ, Yancopoulos G, Campochiaro P (2002) Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol 192:182–187PubMedGoogle Scholar
  76. 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 3:411–423Google Scholar
  77. 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 199:412–417PubMedGoogle Scholar
  78. 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 11:865–873PubMedGoogle Scholar
  79. 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 204:227–235PubMedGoogle Scholar
  80. 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 93:9764–9769PubMedGoogle Scholar
  81. 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 2:529–533PubMedGoogle Scholar
  82. 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 75:563–573PubMedGoogle Scholar
  83. 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 69:1820–1828PubMedGoogle Scholar
  84. 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 88:277–285PubMedGoogle Scholar
  85. 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 255:735–739PubMedGoogle Scholar
  86. 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 60:2520–2526Google Scholar
  87. 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 275:1209–1215PubMedGoogle Scholar
  88. 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 275:8051–8061PubMedGoogle Scholar
  89. 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 208:161–166PubMedGoogle Scholar
  90. 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 159:313–320PubMedGoogle Scholar
  91. 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 17:896–898PubMedGoogle Scholar
  92. 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 188:253–263PubMedGoogle Scholar
  93. 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 42:2401–2407PubMedGoogle Scholar
  94. 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 12:1299–1310Google Scholar
  95. 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 9:804–813PubMedGoogle Scholar
  96. 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 20:723–725PubMedGoogle Scholar
  97. 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 26:859–870PubMedGoogle Scholar
  98. 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 46:726–733PubMedGoogle Scholar
  99. 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 355:1419–1431Google Scholar
  100. 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 355:1432–1444Google Scholar
  101. 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 195:241–248PubMedGoogle Scholar
  102. 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 119:2537–2548PubMedGoogle Scholar
  103. 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 364:1897–1908Google Scholar
  104. 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 1260Google Scholar
  105. 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 17:167–176PubMedGoogle Scholar
  106. 106.
    Campochiaro PA (2011) Gene transfer for neovascular age-related macular degeneration. Hum Gene Ther 22:523–529PubMedGoogle Scholar
  107. 107.
    Campochiaro PA (2012) Gene transfer for ocular neovascularization and macular edema. Gene Ther 19:121–126PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Departments of Ophthalmology and NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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