Skip to main content
Book cover

Angiogenesis pp 517–531Cite as

Ocular Neovascularization

  • Chapter

The molecular cascade leading to neovascularization is complex and can vary in different tissues and different disease processes. Each tissue has its own unique microenvironment with potential differences in blood vessels, surrounding cells, and extracellular matrix. These differences can result in differences in constitutive and induced- expression of neovascularization-related proteins or they can alter the effects of proteins; some proteins promote neovascularization in one setting and inhibit it in others. Proteins depend upon other molecules for their actions, and lack of expression of a binding partner in a tissue can have a major impact on the effect of a protein in that setting. In order to define the potential actions of a protein and its interactions with other proteins in neovascularization, it is useful to study its effects in several well-characterized vascular beds and different pathologic processes. The eye is an important organ in which to study neovascularization, because it has several useful features that facilitate such study, and also because neovascular diseases are prevalent causes of visual morbidity and blindness. The eye contains several vascular beds separated by avascular tissue. The vascular beds can be visualized in vivo, and the presence of neovascularization can be unequivocally identified and quantified because of the surrounding avascular tissue. Also, retina-specific promoters combined with inducible promoter systems provide a useful way to control expression of proteins of interest. By observing the different effects of proteins in different vascular beds in the eye, at different stages of development, and in different disease models, a more complete picture of the protein’s actions and interactions with other proteins can emerge.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987;325:253–257.

    Article  PubMed  CAS  Google Scholar 

  2. Watanabe T, Raff MC. Retinal astrocytes are immigrants from the optic nerve. Nature 1988;332:834–837.

    Article  PubMed  CAS  Google Scholar 

  3. Stone J, Itin A, Alon T, Pe’er J, Gnessin H, Chan-Ling T et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J. Neurosci. 1995;15:4738–4747.

    PubMed  CAS  Google Scholar 

  4. Stalmans I, Ng Y-S, Rohan R, Fruttiger M, Bouche A, Yuce A et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 2002;109:327–336.

    PubMed  CAS  Google Scholar 

  5. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol. 2003;161:1163–1177.

    Article  PubMed  CAS  Google Scholar 

  6. Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high affinity ligand-receptor pair. Cell 2004;116:883–895.

    Article  PubMed  CAS  Google Scholar 

  7. Alon T, Hemo I, Itin A, Pe’er 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. Nature Med. 1995;1:1024–1028.

    Article  PubMed  CAS  Google Scholar 

  8. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997;277:242–245.

    Article  PubMed  CAS  Google Scholar 

  9. Lang RA, Bishop MJ. Macrophages are reqired for cell death and tissue remodeling in the developing mouse eye. Cell 1993;74:453–462.

    Article  PubMed  CAS  Google Scholar 

  10. Kato M, Patel MS, Levasseur R, Lobov I, Chang BHJ, Glass DJ et al. Cbfa-1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J. Cell Biol. 2002;157:303–314.

    Article  PubMed  CAS  Google Scholar 

  11. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc. Natil. Acad. Sci. USA 2002;99:11205–11210.

    Article  CAS  Google Scholar 

  12. Oshima Y, Oshima S, Nambu H, Kachi S, Takahashi K, Umeda N et al. Different effects of angiopoietin 2 in different vascular beds in the eye; new vessels are most sensitive. FASEB J. 2005;19:963–965.

    PubMed  CAS  Google Scholar 

  13. Shimizu K, Kobayashi Y, Muraoka K. Midperipheral fundus involvement in diabetic retinopathy. Ophthalmology 1981;88:601–612.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  15. Penn JS, Tolman BL, Lowery LA. Variable oxygen exposure causes preretinal neovascularization in the newborn rat. Invest. Ophthalmol. Vis. Sci. 1993;34:576–585.

    PubMed  CAS  Google Scholar 

  16. Smith LEH, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R et al. Oxygen-induced retinopathy in the mouse. Invest. Ophthalmol. Vis. Sci. 1994;35:101–111.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Ozaki H, Yu A, Della N, Ozaki K, Luna JD, Yamada H et al. Hypoxia inducible factor-1a is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest. Ophthalmol. Vis. Sci. 1999;40:182–189.

    PubMed  CAS  Google Scholar 

  19. Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S et al. 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. 2003;93:1074–1081.

    Article  PubMed  CAS  Google Scholar 

  20. Engerman R, Bloodworth JMB, Nelson S. Relationship of microvascular disease in diabetes to metabolic control. Diabetes 1977;26:760–769.

    Article  PubMed  CAS  Google Scholar 

  21. Virdi P, Hayreh S. Ocular neovascularization with retinal vascular occlusion. I. Association with retinal vein occlusion. Arch. Ophthalmol. 1980;100:331–341.

    Google Scholar 

  22. Miller JW, Adamis AP, Shima DT, D’Amore PA, Moulton RS, O’Reilly MS et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am. J. Pathol. 1994;145:574–584.

    PubMed  CAS  Google Scholar 

  23. Pournaras C, Tsacopoulos M, Strommer K, Gilodi N, Leuenberger PM. Experimental retinal branch vein occlusion in miniature pigs induces local tissue hypoxia and vasoproliferative microangiopathy. Ophthalmology 1990;97:1321–1328.

    PubMed  CAS  Google Scholar 

  24. Pournaras CJ, Tsacopoulos M, Strommer K, Gilodi N, Leuenberger PM. Scatter photocoagulation restores tissue hypoxia in experimental vasoproliferative microangiopathy in miniature pigs. Ophthalmology 1990;97:1329–1333.

    PubMed  CAS  Google Scholar 

  25. Danis RP, Yang Y, Massicotte SJ, Boldt C. Preretinal and optic nerve head neovascularization induced by photodynamic venous thrombosis in domestic pigs. Arch Ophthalmol 1993;111:539–533.

    PubMed  CAS  Google Scholar 

  26. Danis RP, Bingaman DP, Yang Y, Ladd B. Inhibition of preretinal and optic nerve head neovascularization in pigs by intravitreal triamcinolone acetonide. Ophthalmology 1996;103:2099–2104.

    PubMed  CAS  Google Scholar 

  27. Klein R, Klein BEK, Linton KP. The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am. J. Epidemiol. 1993;137:190–200.

    PubMed  CAS  Google Scholar 

  28. Green WR, Wilson DJ. Choroidal neovascularization. Ophthalmology 1986;93:1169–1176.

    PubMed  CAS  Google Scholar 

  29. Yannuzzi LA, Negrao S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter JS et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21:416–434.

    Article  PubMed  CAS  Google Scholar 

  30. Ryan SJ. Subretinal neovascularization: natural history of an experimental model. Arch. Ophthalmol. 1982;100:1804–1809.

    PubMed  CAS  Google Scholar 

  31. Dobi ET, Puliafito CA, Destro M. A new model of choroidal neovascularization in the rat. Arch. Ophthalmol. 1989;107:264–269.

    PubMed  CAS  Google Scholar 

  32. Tobe T, Ortega S, Luna JD, Ozaki H, Okamoto N, Derevjanik NL et al. Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am. J. Pathol. 1998;153:1641–1646.

    PubMed  CAS  Google Scholar 

  33. Saishin Y, Lima Silva R, Saishin Y, Callahan K, Schoch C, Ahlheim M et al. Periocular injection of microspheres containing PKC412 inhibits choroidal neovascularization in a porcine model. Invest. Ophthalmol. Vis. Sci. 2003;44:4989–4993.

    Article  PubMed  Google Scholar 

  34. Saishin Y, Silva RL, Saishin Y, Kachi S, Aslam S, Gong YY et al. Periocular gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization in a human-sized eye. Hum. Gene Ther. 2005;16:473–478.

    Article  PubMed  CAS  Google Scholar 

  35. Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W et al. Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am. J. Pathol. 1997;151:281–291.

    PubMed  CAS  Google Scholar 

  36. Tobe T, Okamoto N, Vinores MA, Derevjanik NL, Vinores SA, Zack DJ et al. Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest. Ophthalmol. Vis. Sci. 1998;39:180–188.

    PubMed  CAS  Google Scholar 

  37. Ohno-Matsui K, Hirose A, Yamamoto S, Saikia J, Okamoto N, Gehlbach P et al. Inducible expression of vascular endothelial growth factor in photoreceptors of adult mice causes severe proliferative retinopathy and retinal detachment. Am. J. Pathol. 2002;160:711–719.

    PubMed  CAS  Google Scholar 

  38. Takahashi K, Saishin Y, Saishin Y, Lima Silva R, Oshima Y, Oshima S et al. Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment. FASEB J. 2003;17:896–898.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  40. Spilsbury K, Garrett KS, Shen WY, Constable IJ, Rakoczy PE. Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. Am. J. Pathol. 2000;157:135–144.

    PubMed  CAS  Google Scholar 

  41. Abraham JA, Whang JL, Tumolo A, Mergia A, Freidman J, Gospodarowicz D et al. Human basic fibroblast growth factor: nucleotide sequence and genomic organization. EMBO J. 1986;5:2523–2528.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. Ozaki H, Okamoto N, Ortega S, Chang M, Ozaki K, Sadda S et al. Basic fibroblast growth factor is neither necessary nor sufficient for the development of retinal neovascularization. Am. J. Pathol. 1998;153:757–765.

    PubMed  CAS  Google Scholar 

  44. Yamada H, Yamada E, Kwak N, Ando A, Suzuki A, Esumi N et al. Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the retina. J. Cell. Physiol. 2000;185:135–142.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  46. Plate KH, Breier G, Millauar B, Ullrich A, Risau W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Canc. Res. 1993;53:5822–5827.

    CAS  Google Scholar 

  47. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 1994;331:1480–1487.

    Article  PubMed  CAS  Google Scholar 

  48. Adamis AP, Miller JW, Bernal M-T, D’Amico DJ, Folkman J, Yeo T-K et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 1994;118:445–450.

    PubMed  CAS  Google Scholar 

  49. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L 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. U.S.A. 1995;92:10457–10461.

    Article  PubMed  CAS  Google Scholar 

  50. Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LES. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc. Natl. Acad. Sci. USA. 1996;93:4851–4856.

    Article  PubMed  CAS  Google Scholar 

  51. Ozaki H, Seo M-S, Ozaki K, Yamada H, Yamada E, Hofmann F et al. Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am. J. Pathol. 2000;156:679–707.

    Google Scholar 

  52. Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest. Ophthalmol. Vis. Sci. 1996; 37:1929–1934.

    PubMed  CAS  Google Scholar 

  53. 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. 1996;37:855–868.

    PubMed  CAS  Google Scholar 

  54. Amin R, Pulkin JE, Frank RN. Growth factor localization in choroidal neovascular membranes of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 1994;35:3178–3188.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  56. Kryzstolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NM et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch. Ophthalmol. 2002;120:338–346.

    Google Scholar 

  57. Gragoudas ES, Adamis AP, Cunningham ET, Jr., Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N. Eng. J. Med. 2004;351:2805–2816.

    Article  CAS  Google Scholar 

  58. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Eng. J. Med. 2006;355:1432–1444.

    Article  CAS  Google Scholar 

  59. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al. Ranibizumab for neovascular age-related macular degeneration. N. Eng. J. Med. 2006;355:1419–1431.

    Article  CAS  Google Scholar 

  60. Nguyen QD, Shah SM, Tatlipinar S, Do DV, Van Anden E, Campochiaro PA. Bevacizumab suppresses choroidal neovascularization due to pathologic myopia. Br. J. Ophthalmol. 2005;89:1368–1370.

    Article  PubMed  CAS  Google Scholar 

  61. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intavitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophtalmic Surg. Lasers Imaging 2005;36:331–335.

    Google Scholar 

  62. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–372.

    Article  PubMed  Google Scholar 

  63. Spaide RF, Laud K, Fine HF, Klancnik JM, Jr., Meyerle CB, Yannuzzi LA et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383–390.

    Article  PubMed  Google Scholar 

  64. Adamis AP, Altaweel M, Bressler NM, Cunningham ET, Jr., Davis MD, Goldbaum M et al. Changes in retinal neovacularization after pegaptanib (Macugen) therapy in diabetic retinopathy. Ophthalmology 2006;113:23–28.

    Article  PubMed  Google Scholar 

  65. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981;88:583–600.

    Google Scholar 

  66. Nguyen QD, Shah SM, Van Anden E, Sung JU, Vitale S, Campochiaro PA. Supplemental inspired oxygen improves diabetic macular edema; a pilot study. Invest. Ophthalmol. Vis. Sci. 2003;45:617–624.

    Article  Google Scholar 

  67. Ozaki H, Hayashi H, Vinores SA, Moromizato Y, Campochiaro PA, Oshima K. Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res 1997;64:505–517.

    Article  PubMed  CAS  Google Scholar 

  68. Derevjanik NL, Vinores SA, Xiao W-H, Mori K, Turon T, Hudish T et al. Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest. Ophthalmol. Vis. Sci. 2002;43:2462–2467.

    PubMed  Google Scholar 

  69. Campochiaro PA and the C99-PKC412–003 Study Group. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest. Ophthalmol. Vis. Sci. 2004;45:922–931.

    Article  PubMed  Google Scholar 

  70. Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am. J. Ophthalmol. 2006;142:161–169.

    Article  CAS  Google Scholar 

  71. Reichelt M, Shi S, Hayes M, Kay G, Batch J, Gole GA et al. Vascular endothelial growth factor-B and retinal vascular development in the mouse. Clin. Exp. Ophthalmol. 2003;31:61–65.

    Article  Google Scholar 

  72. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 2001;7:575–583.

    Article  PubMed  CAS  Google Scholar 

  73. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 2002;8:831–839.

    PubMed  CAS  Google Scholar 

  74. Holash J, Davis S, Papadoupoulos N, Croll SD, Ho L, Russell M et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:11393–11398.

    Article  PubMed  CAS  Google Scholar 

  75. Saishin Y, Saishin Y, Takahashi K, Lima Silva R, Hylton D, Rudge J et al. VEGF-TRAPR1R2 suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier. J. Cell. Physiol. 2003;195:241–248.

    Article  PubMed  CAS  Google Scholar 

  76. Nguyen QD, Shah SM, Hafiz G, Quinlan E, Sung J, Chu K et al. A phase 1 trial of intravenously administered VEGF trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006;113:1522e1521–1522e1514.

    Article  Google Scholar 

  77. Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). J. Biol. Chem. 2001;276:3222–3230.

    Article  PubMed  CAS  Google Scholar 

  78. Fong GH, Zhang L, Bryce DM, Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knockout mice. Development 1999;126: 3015–3025.

    PubMed  CAS  Google Scholar 

  79. Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding Flt-1 but not to Flk-1/KDR. J. Biol. Chem. 1994;269:25646–25654.

    PubMed  CAS  Google Scholar 

  80. Shen J, Samul R, Lima e Silva R, Akiyama H, Liu H, Saishin Y et al. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther. 2005;13:225–234.

    Article  CAS  Google Scholar 

  81. Klagsbrun M, Takashima S, Mamluk R. The role of neuropilin in vascular and tumor biology. Adv. Exp. Med. Biol. 2002;515:33–48.

    PubMed  CAS  Google Scholar 

  82. Neufeld G, Kessler O, Herzog Y. The interaction of neuropilin-1 and neuropilin-2 with tyrosine-kinase receptors for VEGF. Adv. Exp. Med. Biol. 2002;515:81–91.

    PubMed  CAS  Google Scholar 

  83. Oh H, Takagi H, Otani A, Koyama S, Kemmonchi S, Uemura A et al. Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis. Proc. Natl. Acad. Sci. USA 2002;99:383–388.

    Article  PubMed  CAS  Google Scholar 

  84. Shen J, Samul R, Zimmer J, Liu H, Liang X, Hackett SF et al. Deficiency of neuropilin 2 suppresses VEGF-induced retinal neovascularization. Mol. Med. 2004;10:12–18.

    Article  PubMed  CAS  Google Scholar 

  85. Akiyama H, Mohamedali K, Lima-Silva R, Kachi S, Shen J, Hatara C et al. Vascular targeting of ocular neovascularization with a VEGF121/Gelonin chmeric protein. Mol. Pharmacol. 2005;68:1543–1550.

    PubMed  CAS  Google Scholar 

  86. Dumont DJ, Gradwohl G, Fong G-H, Puri MC, Gerstenstein M, Auerbach A et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 1994;8:1897–1909.

    Article  PubMed  CAS  Google Scholar 

  87. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995;376:70–74.

    Article  PubMed  CAS  Google Scholar 

  88. Davis S, Aldrich TH, Jones P, Acheson A, Ryan TE, Bruno J et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996;87:1161–1169.

    Article  PubMed  CAS  Google Scholar 

  89. Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J. Cell Biol. 2005;169:239–243.

    Article  PubMed  CAS  Google Scholar 

  90. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277:55–60.

    Article  PubMed  CAS  Google Scholar 

  91. Hackett SF, Ozaki H, Strauss RW, Wahlin K, Suri C, Maisonpierre P et al. Angiopoietin 2 expression in the retina: upregulation during physiologic and pathologic neovascularization. J. Cell. Physiol. 2000;184:275–284.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  93. Oshima Y, Takahashi K, Oshima S, Saishin Y, Saishin Y, Silva RL et al. Intraocular gutless adenoviral vectored VEGF stimulates anterior segment but not retinal neovascularization. J. Cell. Physiol. 2004;199:399–411.

    Article  PubMed  CAS  Google Scholar 

  94. Oshima Y, Deering T, Oshima S, Nambu H, Reddy PS, Kaleko M et al. Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor. J. Cell. Physiol. 2004;199:412–417.

    Article  PubMed  CAS  Google Scholar 

  95. Oshima Y, Oshima S, Nambu H, Kachi S, Hackett SF, Melia M et al. Increased expression of VEGF in retinal pigmented epithelial cells is not sufficient to cause choroidal neovascularization. J. Cell. Physiol. 2004;201:393–400.

    Article  PubMed  CAS  Google Scholar 

  96. Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH et al. Increased vascularization in mice overexpressing angiopoietin-1. Science 1998;282:468–471.

    Article  PubMed  CAS  Google Scholar 

  97. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999;286: 2511–2515.

    Article  PubMed  CAS  Google Scholar 

  98. Nambu H, Nambu R, Oshima Y, Hackett SF, Wiegand SJ, Yancopoulos G et al. Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood-retinal barrier. Gene Ther. 2004;11:865–873.

    Article  PubMed  CAS  Google Scholar 

  99. Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW. Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am. J. Pathol. 2005;166:637–644.

    PubMed  CAS  Google Scholar 

  100. Vinores SA, Xiao WH, Shen J, Campochiaro PA. TNFalpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage. J. Neuroimmunol. 2007;182:73–79.

    Article  PubMed  CAS  Google Scholar 

  101. Ilg RC, Davies MH, Powers MR. Altered retinal neovascularization in TNF receptor-deficient mice. Curr. Eye Res. 2005;30:1003–1013.

    Article  PubMed  CAS  Google Scholar 

  102. Smith LEH, Kopchick JJ, Chen W, Knapp J, Kinose F, Daley D et al. Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 1997;276:1706–1709.

    Article  PubMed  CAS  Google Scholar 

  103. Smith LEH, Shen W, Perruzzi C, Soker S, Kinose F, Xu X et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat. Med. 1999;5:1390–1395.

    Article  PubMed  CAS  Google Scholar 

  104. Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M et al. Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J. Clin. Invest. 2003;111:1835–1842.

    PubMed  CAS  Google Scholar 

  105. Ruberte J, Ayuso E, Navarro M, Carretero A, Nacher V, Haurigot V et al. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J. Clin. Invest. 2004;113:1149–1157.

    PubMed  CAS  Google Scholar 

  106. Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL. Insulin-like growth factor 1 induces hypoxia-inducible factor-1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J. Biol. Chem. 2002;277:38205–38211.

    Article  PubMed  CAS  Google Scholar 

  107. Seo M-S, Okamoto N, Vinores MA, Vinores SA, Hackett SF, Yamada H et al. Photoreceptor-specific expression of PDGF-B results in traction retinal detachment. Am. J. Pathol. 2000;157:995–1005.

    PubMed  CAS  Google Scholar 

  108. Campochiaro PA, Glaser BM. Platelet-derived growth factor is chemotactic for human retinal pigment epithelial cells. Arch. Ophthalmol. 1985;103:576–579.

    PubMed  CAS  Google Scholar 

  109. Bergers G, Song S, Meyer-Morse N, Bersland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 2003;111:1287–1295.

    PubMed  CAS  Google Scholar 

  110. Seo M-S, Kwak N, Ozaki H, Yamada H, Okamoto N, Fabbro D et al. Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor. Am. J. Pathol. 1999;154:1743–1753.

    PubMed  CAS  Google Scholar 

  111. Grant MB, May WS, Caballero S, Brown GA, Guthrie SM, Mamee RN et al. Adult hematopoietic stem cells provide functional hemangioblastic activity during retinal neovascularization. Nat. Med. 2002;8:607–612.

    Article  PubMed  CAS  Google Scholar 

  112. Espinosa-Heidmann DG, Caicado A, Hernandez EP, Csaky KG, Cousins SW. Bone marrow-derived progenitor cells contribute to experimental choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2003;44:4914–4919.

    Article  PubMed  Google Scholar 

  113. Chan-Ling T, Baxter L, Afzal A, Sengupta N, Caballero S, Rosinova E et al. Hematopoietic stem cells provide repair functions after laser-induced Bruch’s membrane rupture model of choroidal neovascularization. Am. J. Pathol. 2006;168:1031–1044.

    Article  PubMed  CAS  Google Scholar 

  114. Amoaku WMK, Archer DB. Cephalic radiation and retinal vasculopathy. Eye 1990;4:195–203.

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  116. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Yung S et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006;124:175–189.

    Article  PubMed  CAS  Google Scholar 

  117. Lima e Silva R, Shen J, Hackett SF, Kachi S, Akiyama H, Kiuchi K, Yokoi K, Hatara MC, Lauer T, Aslam S, Gong YY, Xiao WH, Khu NH, Thut C, Campochiaro PA. The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J. 2007;21:3219–3230.

    Article  PubMed  CAS  Google Scholar 

  118. Smalley W, DuBois RN. Colorectal cancer and nonsteroidal anti-inflammatory drugs. Adv. Pharmacol. 1997;39:1–20.

    Article  PubMed  CAS  Google Scholar 

  119. Kawamori T, Rao CV, Seibert K, Reddy BS. Chemopreventive activity of celecoxib, a specific cyclooxigenase-2 inhibitor, against colon carcinogenesis. Cancer Res. 1998;58: 409–412.

    PubMed  CAS  Google Scholar 

  120. Williams CS, Mann M, DuBois RN. The role of cyclooxigenases in inflammation, cancer, and development. Oncogene 1999;18:7908–7916.

    Article  PubMed  CAS  Google Scholar 

  121. Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN. Host cyclooxygenase-2 modulates carcinoma growth. J. Clin. Invest. 2000;105:1589–1594.

    Article  PubMed  CAS  Google Scholar 

  122. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998;93:705–716.

    Article  PubMed  CAS  Google Scholar 

  123. Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing. Nat. Med. 1999;5:1418–1423.

    Article  PubMed  CAS  Google Scholar 

  124. Takahashi K, Saishin Y, Saishin Y, Mori K, Ando A, Yamamoto S et al. Topical nepafenac inhibits ocular neovascularization. Invest. Ophthalmol. Vis. Sci. 2003;44:409–415.

    Article  PubMed  Google Scholar 

  125. Gamache DA, Graff G, Brady MT, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. Assessment of anti-inflammatory efficacy. Inflammation 2000;24:357–370.

    Article  PubMed  CAS  Google Scholar 

  126. Ke T-L, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers. Inflammation 2000;24:371–384.

    Article  PubMed  CAS  Google Scholar 

  127. Dike LE, Ingber DE. Integrin-dependent induction of early growth response genes in capillary endothelial cells. J. Cell Sci. 1996;109:2855–2863.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  129. Umeda N, Kachi S, Akiyama H, Zahn G, Vossmeyer D, Stragies R et al. Suppression and regression of choroidal neovascularization by systemic administration of an Alpha5Beta1 integrin antagonist. Mol. Pharmacol. 2006;69:1820–1828.

    Article  PubMed  CAS  Google Scholar 

  130. Vlodavsky I, Folkman J, Sullivan R, Fridman R, Rivka I-M, Sasse J et al. Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc. Natl. Acad. Sci. USA 1987;84:2292–2296.

    Article  PubMed  CAS  Google Scholar 

  131. Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z. Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. Cancer Metastasis Rev. 1990;9:203–226.

    Article  PubMed  CAS  Google Scholar 

  132. Park JE, Keller G-A, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix. Mol. Biol. Cell 1993;4:1317–1326.

    PubMed  CAS  Google Scholar 

  133. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88:277–285.

    Article  PubMed  Google Scholar 

  134. Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H et al. Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem. Biophys. Res. Comm. 1999;255:735–739.

    Article  PubMed  CAS  Google Scholar 

  135. Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K et al. Anti-angiogenic cues from vascular basement membrane collagen. Canc. Res. 2000;60:2520–2526.

    CAS  Google Scholar 

  136. Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torres A et al. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J. Biol. Chem. 2000;275:1209–1215.

    Article  PubMed  CAS  Google Scholar 

  137. Petitclerc C, Boutaud A, Prestayko A, Xu J, Sado Y, Ninomiya Y et al. New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J. Biol. Chem. 2000;275:8051–8061.

    Article  PubMed  CAS  Google Scholar 

  138. Maeshima Y, Colorado PC, Torre A, Holthaus KA, Grankemeyer JA, Ericksen MB et al. Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J. Biol. Chem. 2000;275:21340–21348.

    Article  PubMed  CAS  Google Scholar 

  139. Maeshima Y, Colorado PC, Kalluri R. Two RGD-independent alphavbeta3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. J. Biol. Chem. 2000;275:23745–23750.

    Article  PubMed  CAS  Google Scholar 

  140. Shahan T, Grant D, Tootell M, Ziaie Z, Ohno N, Mousa SA et al. Oncothanin, a peptide from the alpha 3 chain of type IV collagen, modifies endothelial cell function and inhibits angiogenesis. Connect. Tissue Res. 2004;45:151–163.

    Article  PubMed  CAS  Google Scholar 

  141. Oberbaumer I, Wiedemann H, Timpl R, Kuhn K. Shape and assembly of type IV procollagen obtained from cell culture. EMBO J. 1982;1:805–810.

    PubMed  CAS  Google Scholar 

  142. Sundaramoorty M, Meiyappan M, Todd P, Hudson BG. Crystal structure of NC1 domains. Structural basis for type IV collagen assembly in basement membranes. J. Biol. Chem. 2002;277:31142–31153.

    Article  CAS  Google Scholar 

  143. Ortega N, Werb Z. New functional roles for noncollagenous domains of basement membrane collagens. J. Cell Sci. 2002;115:4201–4214.

    Article  PubMed  CAS  Google Scholar 

  144. Shen GQ, Butkowski R, Cheng T, Wieslander J, Katz A, Cass J et al. Comparison of non-collagenous type IV collagen subunits in human glomerular basement membrane, alveolar basement membrane, and placenta. Connect. Tissue Res. 1990;24:289–301.

    Article  PubMed  CAS  Google Scholar 

  145. Hudson BG, Reeders ST, Tryggvason K. Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport sydromes and diffuse leiomyomatosis. J. Biol. Chem. 1993;268:26033–26036.

    PubMed  CAS  Google Scholar 

  146. Miner JH, Sanes JR. Collagen IV alpha 3, alpha 4, and alpha 5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches. J. Cell Biol. 1994;127:879–891.

    Article  PubMed  CAS  Google Scholar 

  147. Tanaka K, Iyama K, Kitaoka M, Ninomiya Y, Oohashi T, Sado Y et al. Differential expression of alpha 1(IV), alpha 2 (IV), alpha 5(IV), and alpha 6 (IV) collagen chains in the basement membrane of basal cell carcinoma. Histochem. J. 1997;29:563–570.

    Article  PubMed  CAS  Google Scholar 

  148. Fleischmajer R, Kuhn K, Sato Y, MacDonald EDn, Perlish JS, Pan TC et al. There is temporal and spatial expression of alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) collagen chains and beta 1 integrins during the development of the basal lamina in an “in vitro” skin model. J. Invest. Dermatol. 1997;109:527–533.

    Article  PubMed  CAS  Google Scholar 

  149. Lima e Silva R, Kachi S, Akiyama H, Shen J, Aslam S, Gong YY et al. Recombinant non-collagenous domain of alpha2(IV) collagen causes involution of choroidal neovascularization by inducing apoptosis. J. Cell. Physiol. 2006;208:161–166.

    Article  PubMed  CAS  Google Scholar 

  150. Mori K, Ando A, Gehlbach P, Nesbitt D, Takahashi K, Goldsteen D et al. Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin. Am J Pathol 2001;159:313–320.

    PubMed  CAS  Google Scholar 

  151. Mori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J et al. Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J. Cell. Physiol. 2001;188:253–263.

    Article  PubMed  CAS  Google Scholar 

  152. Mori K, Gehlbach P, Ando A, McVey D, Wei L, A. CP. Regression of ocular neovascularization by increased expression of pigment epithelium-derived factor. Invest. Ophthalmol. Vis. Sci. 2001;43:2428–2434.

    Google Scholar 

  153. Mori K, Gehlbach P, Yamamoto S, Duh E, Zack DJ, Li Q et al. AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2002;43:1994–2000.

    PubMed  Google Scholar 

  154. Auricchio A, Behling KC, Maguire AM, O’Conner EM, Bennett J, Wilson JM et al. Inhibition of retinal neovascularization by intraocular viral-mediated delivery of anti-angiogenic agents. Mol. Ther. 2002;6:490–494.

    Article  PubMed  CAS  Google Scholar 

  155. Lai C-C, Wu W-C, Chen S-L, Xiao X, Tsai T-C, Huan S-J et al. Suppression of choroidal neovascularization by adeno-associated virus vector expressing angiostatin. Invest. Ophthalmol. Vis. Sci. 2001;42:2401–2407.

    PubMed  CAS  Google Scholar 

  156. Takahashi T, Nakamura T, Hayashi A, Kamei M, Nakabayashi M, Okada AA et al. Inhibition of experimental choroidal neovascularization by overexpression of tissue inhibitor of metalloproteinases-3 in retinal pigment epithelium. Amer. J. Ophthalmol. 2000;130:774–781.

    Article  CAS  Google Scholar 

  157. Hangai M, Moon YS, Kitaya N, Chan CK, Wu D-Y, Peters KG et al. Systemically expressed soluble Tie2 inhibits intraocular neovascularization. Human Gene Ther. 2001;12:1311–1321.

    Article  CAS  Google Scholar 

  158. Honda M, Sakamoto T, Ishibashi T, Inomata H, Ueno H. Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF.flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration. Gene Ther. 2000;7:978–985.

    Article  PubMed  CAS  Google Scholar 

  159. Lai C-M, Brankov M, Zaknich T, Lai YK-Y, Shen W-Y, Constable IJ et al. Inhibition of angiogenesis by adenovirus-mediated sFlt-1 expression in a rat model of corneal neovascularization. Human Gene Ther. 2001;12:1299–1310.

    Article  CAS  Google Scholar 

  160. Gehlbach P, Demetriades AM, Yamamoto S, Deering T, Xiao WH, Duh EJ et al. Periocular gene transfer of sFlt-1 suppresses ocular neovascularization and VEGF-induced breakdown of the blood-retinal barrier. Hum. Gene Ther. 2003;14:129–141.

    Article  PubMed  CAS  Google Scholar 

  161. Watanabe K, Hasegawa Y, Yamashita H, Shimizu K, Ding Y, Abe M et al. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J. Clin. Invest. 2004;114:898–907.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  163. Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN et al. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum. Gene Ther. 2006;17:167–176.

    Article  PubMed  CAS  Google Scholar 

  164. Lima e Silva R, Saishin Y, Saishin Y, Akiyama H, Kachi S, Aslam S et al. Suppression and regression of choroidal neovascularization by polyamine analogs. Invest. Ophthalmol. Vis. Sci. 2005;46:3323–3330.

    Article  PubMed  Google Scholar 

  165. Lima e Silva R, Kachi S, Akiyama H, Shen J, Hatara MC, Aslam S et al. Trans-scleral delivery of polyamine analogs for ocular neovascularization. Exp. Eye Res. 2006;83:1260–1267.

    Article  PubMed  CAS  Google Scholar 

  166. Hill SA, Sonergan SJ, Denekamp J, Chaplin DJ. Vinca alkaloids: anti-vascular effects in a murine tumor. Eur. J. Cancer 1993;29A:1320–1324.

    Article  PubMed  CAS  Google Scholar 

  167. Seed S, Slaughter DP, Limarzi LR. Effect of colchicine on human carcinoma. Surgery 1940;7:696–709.

    Google Scholar 

  168. Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS, Garia-Kendall D. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A4. Experientia 1989;45:205–211.

    Article  Google Scholar 

  169. Woods JA, Hatfield JA, Pettit GR, Fox BW, McGown AT. The interaction with tubulin of a series of stilbenes based on combrestastatin A-4. Br. J. Cancer 1995;71:705–711.

    PubMed  CAS  Google Scholar 

  170. Dark GD, Hill SA, Prise VE, Tozer GM, Pettit GR, Chaplin DJ. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Canc. Res. 1997;57:1829–1834.

    CAS  Google Scholar 

  171. Pettit GR, Temple C, Narayanan VL, Varma R, Simpson MJ, Boyd MR et al. Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs. Anti-Cancer Drug Design 1995;10:299–309.

    PubMed  CAS  Google Scholar 

  172. Nambu H, Nambu R, Melia M, Campochiaro PA. Combretastatin A-4 Phosphate Suppresses Development and Induces Regression of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2003;44:3650–3655.

    Article  PubMed  Google Scholar 

  173. Ando A, Mori K, Yamada H, Yamada E, Takahashi K, Saikia J et al. Nitric oxide is proangiogenic in retina and choroid. J. Cell Physiol. 2001;191:116–124.

    Article  Google Scholar 

  174. Ando A, Yang A, Nambu H, Campochiaro PA. Blockade of nitric-oxide synthase reduces choroidal neovascularization. Mol. Pharmacol. 2002;62:539–544.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Campochiaro, P.A. (2008). Ocular Neovascularization. In: Figg, W.D., Folkman, J. (eds) Angiogenesis. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-71518-6_44

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-71518-6_44

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-71517-9

  • Online ISBN: 978-0-387-71518-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics