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Mechanisms of Pathological VEGF Production in the Retina and Modification with VEGF-Antagonists

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Studies on Retinal and Choroidal Disorders

Abstract

The production of Vascular Endothelial Growth Factor (VEGF) in the retina is important to maintain the vasculature in the choroid and has protective function on the retinal pigment epithelium and the neuroretina. The expression of VEGF is mainly regulated by the presence of oxygen, a decline of oxygen partial pressure resulting in an activation of Hypoxia Inducible Factor 1α (HIF-1α), inducing the expression of VEGF. A plethora of other factors are also involved, including oxidative stress, hyperglycemia, or inflammatory cytokines. An increase in VEGF secretion can lead to pathological vascularization in the retina, as seen in exudative age-related macular degeneration (AMD), retinopathy of prematurity or in diabetic retinopathy. In order to treat pathological neovascularizations in the retina, VEGF antagonists have been introduced into the clinic and approved for the treatment of wet AMD. Recently, VEGF-antagonists have also been approved for the treatment of diabetic macular edema. New products are developed, e.g., VEGF-Trap Eye or VEGF receptor antagonists which are currently being tested in clinical trials. VEGF siRNAs are also being tested. VEGF-antagonists neutralize secreted VEGF by inhibiting the binding of VEGF to its receptor. Additional pathways are possible, e.g., interfering with autoregulatory pathways. VEGF-receptor antagonists inhibit the signal transduction induced by VEGF binding. Anti-VEGF-siRNA intracellularly inhibits the expression of VEGF and might also exert an RNA specific, VEGF-independent effect.

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Abbreviations

AGE:

Advanced glycation end products

AMD:

Age-related macular degeneration

ARE:

AU-rich elements

CLK1:

CDC-like kinase

CNV:

Choroidal neovascularization

PlGF:

Placental growth factor

ECM:

Extracellular matrix

ER:

Endoplasmic reticulum

IGF:

Insulin-like growth factor

IRES:

Internal ribosome entry site

MAPK:

Mitogen activated kinase

MMP:

Matrix metalloprotease

NMDA:

N-methyl-d-aspartate

NP:

Neuropilin

PI3K:

Phosphoinositide 3-kinase

PKC:

Protein kinase C

PLC:

Phospholipase

PlGF:

Placental growth factor

RISC:

RNA-inducing silencing complex

ROP:

Retinopathy of prematurity

RPE:

Retinal pigment epithelium

SELEX:

Systematic evolution of ligands by exponential enrichments

SH-2:

Src homology-2

Shh:

Sonic hedgehog

SR:

Serine–arginine rich proteins

TGFβ:

Transforming growth factor beta

TLR:

Toll-like receptor

UPR:

Unfolded protein response

UTR:

Untranslated region

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

References

  1. Carmeliet P, Ferriera V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    PubMed  CAS  Google Scholar 

  2. Miquerol L, Langille BL, Nagy A (2000) Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 127:3941–3946

    PubMed  CAS  Google Scholar 

  3. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985

    PubMed  CAS  Google Scholar 

  4. Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Comm 161:851–858

    PubMed  CAS  Google Scholar 

  5. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    PubMed  CAS  Google Scholar 

  6. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266:11947–11954

    PubMed  CAS  Google Scholar 

  7. Poltorak Z, Cohen T, Sivan R, Kandelis Y, Spira G, Vlodavsky I, Keshet E, Neufeld G (1997) VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 272:7151–7158

    PubMed  CAS  Google Scholar 

  8. Whittle C, Gillespie K, Harrison R, Mathieson PW, Harper SJ (1999) Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant. Clin Sci 97:303–312

    PubMed  CAS  Google Scholar 

  9. Lei J, Jiang A, Pei D (1998) Identification and characterization of a new splicing variant of vascular endothelial growth factor: VEGF183. Biochim Biophys Acta 1443:400–406

    PubMed  CAS  Google Scholar 

  10. Mineur P, Colige AC, Deroanne CF, Dubail J, Kesteloot F, Habraken Y, Noel A, Vöö S, Waltenberger J, Lapiere CM, Nusgens BV, Lambert CA (2007) Newly identified biologically active and proteolysis-resistant VEGF-A isoform VEGF111 is induced by genotoxic agents. J Cell Biol 179:1261–1273

    PubMed  CAS  Google Scholar 

  11. Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML (2005) Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169:681–691

    PubMed  CAS  Google Scholar 

  12. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267:26031–26037

    PubMed  CAS  Google Scholar 

  13. Park JE, Keller GA, Ferrara N (1993) The vascular endothelial growth factor isoforms (VEGF): differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix bound VEGF. Mol Biol Cell 4:1317–1326

    PubMed  CAS  Google Scholar 

  14. Ferrara A (2010) Binding to the expracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell 21:687–690

    PubMed  CAS  Google Scholar 

  15. Klettner A, Roider J (2009) Treating age-related macular degeneration—interaction of VEGF-antagonists with their target. Mini Rev Med Chem 9:1127–1135

    PubMed  CAS  Google Scholar 

  16. Kim I, Ryan AM, Rohan R, Amano S, Agular S, Miller JW, Adamis AP (1999) Constitutive expression of VEGF, VEGFR-1, and VEGF-2 in normal eyes. Invest Ophthalmol Vis Sci 40:2115–2121

    PubMed  CAS  Google Scholar 

  17. Gerhardinger C, Brown LF, Roy S, Mizutani M, Zucker CL, Lorenzi M (1998) Expression of vascular endothelial growth factor in the human retina and in nonproliferative diabetic retinopathy. Am J Pathol 152:1453–1462

    PubMed  CAS  Google Scholar 

  18. Jingjing L, Xue Y, Agarwal N, Roque RS (1999) Human Müller cells express VEGF183, a novel spliced variant of vascular endothelial growth factor. Invest Ophthalmol Vis Sci 40:752–759

    PubMed  CAS  Google Scholar 

  19. Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD, Peat D, Gillatt DA, Haper SJ (2002) VEGF165b, an inhibitory splice variant of VEGF, is down regulated in renal cell carcinoma. Canc Res 62:4123–4131

    CAS  Google Scholar 

  20. Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones R, Cui TG, Sugiono M, Waine E, Perring R, Foster R, Digby-Bell J, Shields JD, Whittles CE, Mushens RE, Gillatt DA, Ziche M, Harper SJ, Bates DO (2004) VEGF165b, an inhibitory VEGF splice variant: mechanisms of action, in vivo effects on angiogenesis and endogenous protein expression. Cancer Res 64:7822–7835

    CAS  Google Scholar 

  21. Hua J, Spee C, Kase S, Rennel ES, Magnussen AL, Qui Y, Varey A, Dhayade S, Churchill AJ, Harper SJ, Bates DO, Hinton DR (2010) Recombinant human VEGF165b inhibits experimental choriodal neovascularization. Invest Ophthalmol Vis Sci 51:4282–4288

    PubMed  Google Scholar 

  22. Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, Ladomery MR, Harper SJ, Bates DO (2008) Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factor. J Cell Sci 121:3487–3495

    PubMed  CAS  Google Scholar 

  23. Giacca M (2010) Non-redundant functions of the protein isoforms arising from alternative splicing of the VEGF-A pre-mRNA. Transcription 1:149–153

    Google Scholar 

  24. Elias AP, Dias S (2008) Microenviroment changes (in pH) affect VEGF alternative splicing. Cancer Microenviron 1:131–139

    PubMed  Google Scholar 

  25. Qin G, Kishore R, Dolan CM, Silver M, Wecker A, Luedemann CN, Thorne T, Hanley A, Curry C, Heyd L, Dinesh D, Kearney M, Martelli F, Murayama T, Goukassian DA, Zhu Y, Losorde DW (2006) Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF. Proc Natl Acad Sci USA 103:11015–11020

    PubMed  CAS  Google Scholar 

  26. Merdzhanova G, Gout S, Keramidas M, Edmond V, Coll JL, Brambilla C, Brambilla E, Gazzeri S, Eymin B (2010) The transcription factor E2F1 and the SR protein SC35 control the ratio of pro-angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo. Oncogene 29:5392–5403

    PubMed  CAS  Google Scholar 

  27. Bastide A, Karaa Z, Bornes S, Hieblot C, Lacazette E, Prats H, Touriol C (2008) An upstream open reading frame with an IRES control expression of a specific VEGF-A isoform. Nucleic Acids Res 36:2434–2445

    PubMed  CAS  Google Scholar 

  28. Gogat K, Le Gat L, Van Den Berghe L, Marchant D, Kobetz A, Gadin S, Gasser B, Quere I, Abitbol M, Menasche M (2004) VEGF and KDR gene expression during human embryonic and fetal eye development. Invest Ophthalmol Vis Sci 45:7–14

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  30. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273:30336–30343

    PubMed  CAS  Google Scholar 

  31. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D’Amore PA (2009) An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci USA 106:18751–18756

    PubMed  CAS  Google Scholar 

  32. Gora-Kupilas K, Josko J (2005) The neuroprotective function of vascular endothelial growth factor (VEGF). Folia Neuropathol 43:31–39

    PubMed  CAS  Google Scholar 

  33. Zachary I (2005) Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function and therapeutic potential. Neurosignals 14:207–221

    PubMed  CAS  Google Scholar 

  34. Nishijima K, Ng YS, Zhong L, Bradley J, Schubert W, Jo N, Akita J, Samuelsson SJ, Robinson GS, Adamis AP, Shima DT (2007) Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 171:53–67

    PubMed  CAS  Google Scholar 

  35. Byeon SH, Lee SC, Choi SH, Lee HK, Lee JH, Chu YK, Kwon OW (2010) Vascular endothelial growth factor as an autocrine survival factor for retinal pigment epithelial cells under oxidative stress via the VEGF-R2/PI3K/Akt. Invest Ophthalmol Vis Sci 51:1190–1197

    PubMed  Google Scholar 

  36. Kilic Ü, Kilic E, Järve A, Guo Z, Spudich A, Bieber K, Barzena U, Bassetti CL, Marti HH, Hermann DM (2006) Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating Erk1/2 and Akt pathways. J Neurosci 26:12439–12446

    PubMed  CAS  Google Scholar 

  37. Saint-Geniez M, Maharaj ASR, Walshe TE, Tucker BA, Sekiyama E, Kurihara T, Darland DC, Young MJ, D’Amore PA (2008) Endogenous VEGF is required for visual function: evidence for a survival role on Müller cells and photoreceptors. PloS One 3:e3554

    PubMed  Google Scholar 

  38. Ueno S, Pease ME, Wersinger DM, Masuda T, Vinores SA, Licht T, Zack DJ, Quigley H, Keshet E, Campochiaro PA (2008) Prolonged blockade of VEGF family members does not cause identifiable damage to retinal neurons or vessels. J Cell Physiol 217:13–22

    PubMed  CAS  Google Scholar 

  39. Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, Pan YC, Olander JV, Connolly DT, Stern D (1990) Vascular permability factor: a tumor derived polypeptide that induces endothelia cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 172:1535–1545

    PubMed  CAS  Google Scholar 

  40. Ishida U, Usui T, Yamashiro K, Kaji Y, Amano S, Ogura Y, Hida T, Oguchi Y, Ambati J, Miller JW, Gragoudas ES, Ng YS, D’Amore PA, Shima DT, Adamis AP (2003) VEGF164-mediated inflammation is required for pathological, but not physiological ischemia-induced retinal neovascularization. J Exp Med 198:483–489

    PubMed  CAS  Google Scholar 

  41. Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, Olsen BR (2005) Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 167:1451–1459

    PubMed  CAS  Google Scholar 

  42. Le YZ, Bai Y, Zhu M, Zheng L (2010) Temporal requirement of RPE-derived VEGF in the development of choroidal vasculature. J Neurochem 112:1584–1592

    PubMed  CAS  Google Scholar 

  43. Bai Y, Ma JX, Guo J, Wang J, Zhu M, Chen Y, Le YZ (2009) Müller cell-derived VEGF is a significant contributor to retinal neovascularization. J Pathol 219:446–454

    PubMed  CAS  Google Scholar 

  44. Cervantes-Villagrana AR, Garcia-Roman J, Gonzales-Espinosa C, Lamas M (2010) Pharmacological inhibition of N-methyl d-aspartate receptor promotes secretion of vascular endothelial growth factor in müller cells: effects of hyperglycemia and hypoxia. Curr Eye Res 35:733–741

    PubMed  CAS  Google Scholar 

  45. Mowat FM, Luhmann UFO, Smith AJ, Lange C, Duran Y, Harten S, Shukla D, Maxwell PH, Ali RR, Bainbridge JWB (2010) HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischemia. PloS One 5:e11103

    PubMed  Google Scholar 

  46. Schrufer TL, Antonetti DA, Sonenberg N, Kimball S, Gardner TW, Jefferson LS (2010) Ablation of 4E-BP1/2 prevents hyperglycemia-mediated induction of VEGF expression in the rodent retina and in Müller cells in culture. Diabetes 59:2107–2116

    PubMed  CAS  Google Scholar 

  47. Scott A, Powner MB, Gandhi P, Clarkin C, Gutmann DH, Johnson RS, Ferrara N, Fruttiger M (2010) Astrocyte-derived vascular endothelial growth factor stabilizes vessels in the developing retinal vasculature. PloS One 5:e11863

    PubMed  Google Scholar 

  48. Weidemann A, Krohne TU, Aguilar E, Kurihara T, Takeda N, Dorrell MI, Simon MC, Haase VH, Friedlander M, Johnson RS (2010) Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia 58:1177–1185

    PubMed  Google Scholar 

  49. Darland DC, Massingham LJ, Smith SR, Piek E, Saint-Geniez M, D’Amore PA (2003) Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 264:275–288

    PubMed  CAS  Google Scholar 

  50. Yamagishi S, Amano S, Inagaki Y, Okamoto T, Koga K, Sasaki N, Yamamoto H, Takeuchi M, Makita Z (2002) Advanced glycation end products-induced apoptosis and overexpression of vascular endothelial growth factor in bovine retinal pericytes. Biochem Biophys Res Commun 290:973–978

    PubMed  CAS  Google Scholar 

  51. Vidro EK, Gee S, Unda R, Ma JX, Tsin A (2008) Glucose and TGFbeta2 modulate the viability of cultured human retinal pericytes and their VEGF release. Curr Eye Res 33:984–993

    PubMed  CAS  Google Scholar 

  52. Amadio M, Bucolo C, Leggio GM, Drago F, Govoni S, Pascale A (2010) The PKCß/HuR/VEGF pathway in diabetic retinopathy. Biochem Pharmacol 80:1230–1237

    PubMed  CAS  Google Scholar 

  53. Cao R, Xue Y, Hedlund EM, Zhong Z, Trisaris K, Tondelli B, Lucchini F, Zhu Z, Dissing S, Cao Y (2010) VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. Proc Nat Acad Sci 107:856–861

    PubMed  CAS  Google Scholar 

  54. Muller YA, Christinger HW, Keyt BA, de Vos AM (1997) The crystal structure of VEGF refined to 1.93 Angstrom resolution: multiple copy flexibility and receptor binding. Structure 5:1325–1338

    PubMed  CAS  Google Scholar 

  55. Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709

    PubMed  CAS  Google Scholar 

  56. Ebos JM, Bocci G, Man S, Thorpe PE, Hicklin DJ, Zhou D, Jia X, Kerbel RS (2004) A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Cancer Res 2:315–326

    PubMed  CAS  Google Scholar 

  57. Schenone S, Bondavalli F, Botta M (2007) Antiangiogenic agents: an update on small molecule VEGFR inhibitors. Curr Med Chem 14:2495–2516

    PubMed  CAS  Google Scholar 

  58. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995

    PubMed  CAS  Google Scholar 

  59. Rahimi N (2006) VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front Biosci 11:818–829

    PubMed  CAS  Google Scholar 

  60. Schwartz JD, Rowinski EK, Youssoufian H, Pytowski B, Wu Y (2010) Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (human antiobody targeting vascular endothelial growth factor receptor-1). Cancer 116:1027–1032

    PubMed  CAS  Google Scholar 

  61. 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 

  62. Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Eye Res 312:549–560

    CAS  Google Scholar 

  63. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravastation in pathological conditions. Nat Med 7:575–583

    PubMed  CAS  Google Scholar 

  64. Gille H, Kowaslki J, Li B, LeCouter J, Moffat B, Zioncheck TF, Pelletier N, Ferrara N (2001) Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 276:3222–3230

    PubMed  CAS  Google Scholar 

  65. Schlessinger J, Lemmon MA (2003) SH2 and PTB domains in tyrosine kinase signaling. Sci STKE 2003(191):R12

    Google Scholar 

  66. Ehrlich R, Harris A, Ciulla TA, Kheradiya N, Winston DM, Wirostko B (2010) Diabetic macula oedema: physical, physiological and molecular factors contribute to this pathological process. Acta Ophthalmol 88:279–291

    PubMed  CAS  Google Scholar 

  67. Chen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M (1997) Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 19:547–559

    PubMed  CAS  Google Scholar 

  68. Muraga M, Fernandez-Capetillo O, Tosato G (2005) Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelia growth factor receptor-2. Blood 105:1992–1999

    Google Scholar 

  69. Bachelder RE, Crago A, Chung J, Wendt MA, Shao LM, Robinson G, Mercurio AM (2001) Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res 61:5736–5740

    PubMed  CAS  Google Scholar 

  70. Wang L, Zeng H, Wang P, Soker S, Mukhopadhyay D (2003) Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-dependent endothelial cell migration. J Biol Chem 278:48848–48860

    PubMed  CAS  Google Scholar 

  71. Grünewald FS, Prota AE, Giese A, Ballmer-Hofer K (2010) Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiongenic signaling. Biochim Biophys Acta 1804:567–580

    PubMed  Google Scholar 

  72. Gitay-Goren H, Soker S, Vlodavsky I, Neufeld G (1992) The binding of vascular endothelial growth factor to its receptor is dependent on cell surface-associated heparin-like molecules. J Biol Chem 267:6093–6098

    PubMed  CAS  Google Scholar 

  73. Gitay-Goren H, Cohen T, Tessler S, Soker S, Gengrinovitch S, Rockwell P, Klagsbrun M, Levi BZ, Neufeld G (1996) Selective binding of VEGF121 to one of the three vascular endothelial growth factor receptors of vascular endothelial cells. J Biol Chem 271:5519–5523

    PubMed  CAS  Google Scholar 

  74. Cohen T, Gitay-Goren H, Sharon R, Shibuya M, Halaban R, Levi BU, Neufeld G (1995) VEGF121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell-surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells. J Biol Chem 270:11322–11326

    PubMed  CAS  Google Scholar 

  75. Hamma-Kourbali Y, Vassy R, Starzec A, Le Meuth-Metzinger V, Oudar O, Bagheri-Yarmand R, Perret G, Crepin M (2001) Vascular endothelial growth factor 165 (VEGF165) activities are inhibited by carboxymethyl benzylamide dextran that competes for heparin binding to VEGF165 and VEGF165 KDR complexes. J Biol Chem 276:39748–39754

    PubMed  CAS  Google Scholar 

  76. Mamluk R, Gechtman Z, Kucher ME, Gasiunas N, Gallagher J, Klagsbrun M (2002) Neuropilin-1 binds vascular endothelial growth factor 165, placental growth factor-2 and heparin via its b1b2 domain. J Biol Chem 277:24818–24825

    PubMed  CAS  Google Scholar 

  77. Soker S, Svahn CM, Neufeld G (1993) Vascular endothelial growth factor is inactivated by binding to alpha 2-macroglobulin and the binding is inhibited by heparin. J Biol Chem 268:7685–7691

    PubMed  CAS  Google Scholar 

  78. Gengrinovitch S, Berman B, David G, Witte L, Neufeld G, Ron D (1999) Glypican-1 is a VEGF165 binding proteoglycan that acts as an extracellular chaperone for VEGF165. J Biol Chem 274:10816–10822

    PubMed  CAS  Google Scholar 

  79. Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C, Shima DT (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vesel branching morphogenesis. Genes Dev 16:2684–2698

    PubMed  CAS  Google Scholar 

  80. Akiri G, Nahari D, Finkelstein Y, Le SH, Elroy-Stein O, Levi BZ (1998) Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription. Oncogene 17:227–236

    PubMed  CAS  Google Scholar 

  81. Pages G, Pouyssegur J (2005) Transcriptional regulation of the vascular endothelial growth factor gene—a concert of activating factors. Cardiovasc Res 65:564–573

    PubMed  CAS  Google Scholar 

  82. Hanson J, Gorman J, Reese J, Fraizer G (2007) Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1. Front Biosci 12:2279–2290

    PubMed  CAS  Google Scholar 

  83. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    PubMed  CAS  Google Scholar 

  84. Milanini-Mongiat J, Pouyssegur J, Pages G (2002) Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J Biol Chem 277:20631–20639

    PubMed  CAS  Google Scholar 

  85. Pages G (2007) Sp3-mediated VEGF regulation is dependent on phosphorylation by extra-cellular signals regulated kinases (Erk). J Cell Physiol 213:454–463

    PubMed  CAS  Google Scholar 

  86. Schäfer G, Cramer T, Suske G, Kemmner W, Wiedenmann B, Höcker M (2003) Oxidative stress regulates vascular endothelial growth factor-A gene transcription through Sp1- and Sp3-dependent activation of two proximal GC-rich promoter elements. J Biol Chem 278:8190–8198

    PubMed  Google Scholar 

  87. Yoo PS, Mulkeen AL, Cha CH (2006) Post-transcriptional regulation of vascular endothelial growth factor: implications for tumor angiogenesis. World J Gastroenterol 12:4937–4942

    PubMed  CAS  Google Scholar 

  88. Jang SK, Kräusslich HG, Nicklin MJ, Duke GM, Palmenberg AC, Wimmer E (1988) A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directes internal entry of ribosomes during in vitro translation. J Virol 62:2636–2643

    PubMed  CAS  Google Scholar 

  89. Wouters BG, van den Beucken T, Magagnin MG, Koritzinsky M, Fels D, Koumenis C (2005) Control of the hypoxic response through regulation of mRNA translation. Semin Cell Dev Biol 16:487–501

    PubMed  CAS  Google Scholar 

  90. van der Velden AW, Thomas AA (1999) The role of the 5′ untranslated region of an mRNA in translation regulation during development. Int J Biochem Cell Biol 31:87–106

    PubMed  Google Scholar 

  91. Huez I, Bornes S, Bresson D, Creancier L, Prats H (2001) New vascular endothelial growth factor isoform generated by internal ribosome entry site-driven CUG translation initiation. Mol Endocrinol 15:2197–2210

    PubMed  CAS  Google Scholar 

  92. Huez I, Creancier L, Audigier S, Gensac MC, Prats AC, Prats H (1998) Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol 18:6178–6190

    PubMed  CAS  Google Scholar 

  93. Mole DR, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for cellular oxygen sensing. IUBMB Life 52:43–47

    PubMed  CAS  Google Scholar 

  94. Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5:343–354

    PubMed  CAS  Google Scholar 

  95. Wang GL, Semenza GI (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270:1230–1237

    PubMed  CAS  Google Scholar 

  96. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J (1999) p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible facotr 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 274:32631–32637

    PubMed  CAS  Google Scholar 

  97. Zhang P, Zhang X, Hao X, Wang Y, Hui Y, Wang H, Hu D, Zhou J (2009) Rac1 activated HIF-1 in retinal pigment epithelium cells under hypoxia. Graefes Arch Clin Exp Ophthalmol 247:633–639

    PubMed  CAS  Google Scholar 

  98. Guma M, Rius J, Duong-Polk KX, Haddad GG, Lindsey JD, Karin M (2009) Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression. Proc Natl Acad Sci USA 106:8760–8765

    PubMed  CAS  Google Scholar 

  99. Levy NS, Chung S, Furneaux H, Levy AP (1998) Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem 273:6417–6423

    PubMed  CAS  Google Scholar 

  100. Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME (2008) Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 27:331–371

    PubMed  CAS  Google Scholar 

  101. Levy AP, Levy NS, Goldberg MA (1996) Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271:2746–2753

    PubMed  CAS  Google Scholar 

  102. Fan XC, Steitz JA (1998) HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci USA 95:15293–15298

    PubMed  CAS  Google Scholar 

  103. Amadio M, Scapagnini G, Lupo G, Drago F, Govoni S, Pascale A (2008) PKCßII/HuR/VEGF: a new molecular cascade in retinal pericytes for the regulation of VEGF gene expression. Pharmacol Res 57:60–66

    PubMed  CAS  Google Scholar 

  104. Iida K, Kawakami Y, Sone H, Suzuki H, Yatoh S, Isobe K, Takekoshi K, Yamada N (2002) Vascular endothelial growth factor gene expression in a retinal pigmented cell is up-regulated by glucose deprivation through 3′ UTR. Life Sci 71:1607–1614

    PubMed  CAS  Google Scholar 

  105. Ozawa K, Tsukamoto Y, Hori O, Kitao Y, Yanagi H, Stern DM, Ogawa S (2001) Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmatic reticulum chaperone. Cancer Res 61:4206–4213

    CAS  Google Scholar 

  106. Abcouwer SF, Marjon PI, Loper RK, Vander Jagt DL (2002) Response of VEGF expression to amino acid deprivation and inducers of endoplasmatic reticulum stress. Invest Ophthalmol Vis Sci 43:2791–2798

    PubMed  Google Scholar 

  107. Kase S, He S, Sonoda S, Kitamura M, Spee C, Wawrousek E, Ryan SJ, Kannan R, Hinton DR (2010) αB-crystallin regulation of angiogenesis by modulation of VEGF. Blood 115:3398–3406

    PubMed  CAS  Google Scholar 

  108. Deudero JJ, Caramelo C, Castellanos MC, Neria F, Fernandez-Sanchez R, Calabia O, Penate S, Gonzalez-Pacheco FR (2008) Induction of hypoxia-inducible factor 1 alpha gene expression by vascular endothelial growth factor. J Biol Chem 283:11435–11444

    PubMed  CAS  Google Scholar 

  109. Klettner A, Roider J (2008) Comparison of Bevacizumab, Ranibizumab and Pegaptanib in vitro: efficiency and possible additional pathways. Invest Ophthalmol Vis Sci 49:4523–4527

    PubMed  Google Scholar 

  110. Garrett TA, Van Buul JD, Burridge K (2007) VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. Exp Cell Res 313:3285–3297

    PubMed  CAS  Google Scholar 

  111. Handa JT, Verzijl N, Matrsunaga H, Aotaki-Keen A, Lutty GA, te Koppele JM, Miyata T, Hjemeland LM (1999) Increase in the advanced glycation end product pentosidine in Bruch’s membrane with age. Invest Ophthalmol Vis Sci 40:775–779

    PubMed  CAS  Google Scholar 

  112. Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, Bucala R, Adamis AP (1998) Advanced glycation end products increases retinal vascular endothelial growth factor expression. J Clin Invest 101:1219–1224

    PubMed  CAS  Google Scholar 

  113. Yokota T, Utsunomiya K, Taniguchi K, Gojo A, Kurata H, Tajima N (2007) Involvement of the Rho/Rho kinase signaling pathway in platelet-derived growth factor BB-induced vascular endothelial growth factor expression in diabetic rat retina. Jpn J Ophthalmol 51:424–430

    PubMed  CAS  Google Scholar 

  114. Ye X, Xu G, Chang Q, Fan J, Sun Z, Qin Y, Jiang AC (2010) Erk1/2 signaling pathways involved in VEGF release in diabetic rat retina. Invest Ophthalmol Vis Sci 51:5226–5233

    PubMed  Google Scholar 

  115. Treins C, Giorgetti-Peraldi S, Murdaca J, Van Obberghen E (2001) Regulation of vascular endothelial growth factor expression by advanced glycation end products. J Biol Chem 276:43836–43841

    PubMed  CAS  Google Scholar 

  116. Yanni SE, McCollum GW, Penn JS (2010) Genetic deletion of COX-2 diminishes VEGF production in mouse retinal Müller cells. Exp Eye Res 91:34–41

    PubMed  CAS  Google Scholar 

  117. Madsen-Bouterse SA, Kowluri RA (2008) Oxidative stress and diabetic retinopathy: pathophysiological mechanism and treatments perspectives. Rev Endocr Metab Disord 9:315–327

    PubMed  CAS  Google Scholar 

  118. Ding X, Patel M, Chan CC (2009) Molecular pathology of age-related macular degeneration. Prog Retin Eye Res 28:1–18

    PubMed  CAS  Google Scholar 

  119. Hartnett ME (2010) The effects of oxygen stresses on the development of feature of severe retinopathy of prematurity: knowledge from 50/10 OIR model. Doc Ophthalmol 120:25–39

    PubMed  Google Scholar 

  120. Klettner A, Roider J (2009) Constitutive and oxidative-stress-induced expression of VEGF in the RPE are differently regulated by different Mitogen-activated protein kinases. Graefes Arch Clin Exp Ophthalmol 247:1487–1492

    PubMed  Google Scholar 

  121. Kannan R, Zhang N, Sreekumar P, Spee C, Rodriguez A, Barron E, Hinton D (2006) Stimulation of apical and basolateral vascular endothelial growth factor-A and vascular endothelial growth factor-C secretion by oxidative stress in polarized retinal pigment epithelial cells. Mol Vis 12:1649–1659

    PubMed  CAS  Google Scholar 

  122. Wang H, Geisen P, Wittchen E, King B, Burridge K, D’Amore PA, Hartnett ME (2011) The role of RPE cell-associated VEGF189 in choroidal endothelial cell transmigration in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 52:570–578

    PubMed  CAS  Google Scholar 

  123. Sreekumar P, Kannan R, de Silva A, Burton R, Ryan R, Hinton D (2006) Thiol regulation of vascular endothelial growth factor-A and its receptors in human retinal pigment epithelial cells. Biochem Biophys Res Commun 346:1200–1206

    PubMed  CAS  Google Scholar 

  124. Platt DH, Bartoli M, El-Remessy AB, Al-Shabrawey M, Lemtalsi T, Fulton D, Caldwell RB (2005) Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3. Free Radic Biol Med 39:1353–1361

    PubMed  CAS  Google Scholar 

  125. Al-Shabrawey M, Bartoli M, El-Remessy AB, Ma G, Matragoon S, Lemtalsi T, Caldwell RW, Caldwell RB (2008) Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy. Invest Ophthalmol Vis Sci 49:3231–3238

    PubMed  Google Scholar 

  126. Caldwell RB, Zhang W, Romero MJ, Caldwell RW (2010) Vascular dysfunction in retinopathy—an emerging role for arginase. Brain Res Bull 81:303–309

    PubMed  CAS  Google Scholar 

  127. Nagineni CN, Kommineni VK, Willian A, Detrick B, Hooks JJ (2012) Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration. J Cell Physiol 227(1):116–126

    PubMed  CAS  Google Scholar 

  128. Yingchuan F, Chuntao L, Hui C, Jianbin H (2010) Increased Expression of TGF-beta1 and Smad 4 on oxygen-induced retinopathy in neonatal mice. Adv Exp Med Biol 664:71–77

    PubMed  Google Scholar 

  129. Nagineni CN, Samuel W, Nagineni S, Pardhasaradhi K, Wiggert B, Detrick B, Hooks JJ (2003) Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J Cell Physiol 197:453–462

    PubMed  CAS  Google Scholar 

  130. Wilkinson-Berka JL, Wraight C, Werther G (2006) The role of growth homone, insulin-like growth factor and somatostatin in diabetic retinopathy. Curr Med Chem 13:3307–3317

    PubMed  CAS  Google Scholar 

  131. Economou MA, Wu J, Vasilcanu D, Rosengren L, All-Ericsson C, van der Ploeg I, Menu E, Girnita L, Axelson M, Larsson O, Seregard S, Kvanta A (2008) Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor. Acta Ophthalmol 86:42–49

    PubMed  Google Scholar 

  132. Weng CY, Kothary PC, Verkade AJ, Reed DM, Del Monte MA (2009) MAP kinase pathway is involved in IGF-1-stimulated proliferation of human retinal pigment epithelial cell (hRPE). Curr Eye Res 34:867–876

    PubMed  CAS  Google Scholar 

  133. Cordeiro S, Seyler S, Stindl J, Milenkovic VM, Strauss O (2010) Heat-sensitive TRPV channels in retinal pigment epithelial cells: regulation of VEGF-A secretion. Invest Ophthalmol Vis Sci 51:6001–6008

    PubMed  Google Scholar 

  134. Salimen A, Kauppinen A, Hyttinen JMT, Toropainen E, Kaarniranta K (2010) Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med 16:535–542

    Google Scholar 

  135. Roybal CN, Yang S, Sun CW, Hurtado D, Vander Jagt DL, Townes TM, Abcouwer SF (2004) Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem 279:14844–14852

    PubMed  CAS  Google Scholar 

  136. Lucas N, Naiv AJ, Day ML (2009) The therapeutic potential of ADAM15. Curr Pharm Des 15:2311–2318

    PubMed  CAS  Google Scholar 

  137. Xie B, Shen J, Dong A, Swaim M, Hackett SF, Wyder L, Worpenberg S, Barbieri S, Campochiaro PA (2008) An Adam15 amplification loop promotes vascular endothelial growth factor-induced ocular neovascularization. FASEB J 22:2775–2783

    PubMed  CAS  Google Scholar 

  138. Surace EM, Balaggan KS, Tessitore A, Mussolino C, Cotugno G, Bonetti C, Vitale A, Ali RR, Auricchio A (2006) Inhibition of ocular neovascularisation by hedgehog blockade. Mol Ther 13:573–579

    PubMed  CAS  Google Scholar 

  139. He H, Zhang H, Li B, Li G, Wang Z (2010) Blockade of the sonic hedgehog signalling pathway inhibits choroidal neovascularization in a laser-induced rat model. J Huazhong Univ Sci Technolog Med Sci 30:659–665

    PubMed  CAS  Google Scholar 

  140. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Gyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Study Group (2004) Pepagtanib for neovascular age-related macular degeneration. N Eng J Med 351:2805–2816

    CAS  Google Scholar 

  141. Lee JH, Canny MD, De Erkenez A, Krilleke D, Ng YH, Shima DT, Pardi A, Jucker F (2005) A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165. Proc Natl Acad Sci USA 102:18902–18907

    PubMed  CAS  Google Scholar 

  142. Zhang HT, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, Harris AL, Ziche M, Bicknell R (2000) The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo. Br J Cancer 83:63–68

    PubMed  CAS  Google Scholar 

  143. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng G, Krummen L, Winkler M, Ferrara N (1997) Humanization of an anti-VEGF monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  145. Kim KH, Li B, Houck K, Winer J, Ferrara N (1992) The VEGF proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors 7:53–64

    PubMed  CAS  Google Scholar 

  146. Fuh G, Wu P, Liang WC, Ultsch M, Lee CV, Moffat B, Wiesmann C (2006) Structure-function studies of two synthetic anti-VEGF Fabs and comparison with Avastin Fab. J Biol Chem 281:6625–6631

    PubMed  CAS  Google Scholar 

  147. Yu L, Wu X, Cheng Z, Lee CV, LeCouter J, Campa C, Fuh G, Lowman H, Ferrara N (2008) Interaction between Bevacizumab and murine VEGF-A: a reassessment. Invest Ophthalmol Vis Sci 49:522–527

    PubMed  Google Scholar 

  148. Lowe J, Araujo J, Yang J, Reich M, Oldendorp A, Shiu V, Qarmby V, Lowman H, Lien S, Gaudreault J, Maia M (2007) Ranibizumab inhibits multiple forms of biologically active vascular endothelial growth factor in vitro and in vivo. Exp Eye Res 85:425–430

    PubMed  CAS  Google Scholar 

  149. Ziemssen F, Grisanti S, Bartz-Schmidt KU, Spitzer MS (2009) Off-label use of bevacizumab for the treatment of age-related macular degeneration: what is the evidence? Drugs Aging 26:295–320

    PubMed  CAS  Google Scholar 

  150. Miura Y, Klettner A, Roider J (2010) VEGF antagonists decrease barrier function of retinal pigment epithelium in vitro: possible participation of intracellular glutathione. Invest Ophthalmol Vis Sci 51:4848–4855

    PubMed  Google Scholar 

  151. Klettner A, Möhle F, Roider J (2010) Intracellular bevacizumab reduces phagocytotic uptake in RPE cells. Graefes Arch Clin Exp Ophthalmol 248:819–824

    PubMed  CAS  Google Scholar 

  152. Klettner AK, Kruse ML, Meyer T, Wesch D, Kabelitz D, Roider J (2009) Different properties of VEGF-antagonists: Bevacizumab but not Ranibizumab accumulates in RPE cells. Graefes Arch Clin Exp Ophthalmol 247:1601–1608

    PubMed  CAS  Google Scholar 

  153. Spitzer MS, Yoeruek K, Sierra A, Wallenfels-Thilo B, Schraermeyer U, Spitzer B, Bartz-Schmidt KU, Szurman P (2007) Comparative antiproliferative and cytotoxic profile of bevacizumab (Avastin), pegaptanib (Macugen) and ranibizumab (Lucentis) on different ocular cells. Graefes Arch Clin Exp Ophthalmol 245:1837–1842

    PubMed  CAS  Google Scholar 

  154. Brar VS, Sharma RK, Murthy RK, Chalam KV (2010) Bevacizumab neutralizes the protective effect of vascular endothelial growth factor on retinal gangion cells. Mol Vis 16:1848–1853

    PubMed  CAS  Google Scholar 

  155. Peters S, Heiduschka P, Julien S, Ziemssen F, Fietz H, Bartz-Schmidt KU, Tübingen Bevacizumab Study Group, Schraermeyer U (2007) Ultrastructural findings in the primate eye after intravitrial injection of bevacizumab. Am J Ophthalmol 143:995–1002

    PubMed  CAS  Google Scholar 

  156. Muller YA, Chen Y, Christinger HW, Cunningham BC, Lowman HB, de Vos AM (1998) VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 A resolution and mutational analysis of the interface. Structure 6:1153–1167

    PubMed  CAS  Google Scholar 

  157. Holash J, Davis S, Papadopoulos N, Croll S, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe W, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS (2002) VEGF-trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci 99:11393–11398

    PubMed  CAS  Google Scholar 

  158. Rudge JS, Holash J, Hylton D, Russell M, Jiang S, Leidich R, Papadopoulos N, Pyles EA, Torri A, Wiegand SJ, Thurston G, Stahl N, Yancopoulos GD (2007) VEGF trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci USA 104:18363–18370

    PubMed  CAS  Google Scholar 

  159. Dixon JA, Oliver S, Olson JL, Mandava N (2009) VEGF trap-eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drug 18:1573–1580

    CAS  Google Scholar 

  160. Dykxhoorn DM, Novina CD, Sharp PA (2003) Killing the messenger: short RNAs that silence gene expression. Nat Rev Cell Biol 4:457–467

    CAS  Google Scholar 

  161. Reich SJ, Fosnot J, Kuroki A, Tang W, Yang X, Maguire AM, Bennett J, Tolentino MJ (2003) Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularisation in a mouse model. Mol Vis 9:210–216

    PubMed  CAS  Google Scholar 

  162. Shen J, Samul R, Silva RL, Akiyama H, Liu H, Saishin Y, Hackett SF, Zinnen S, Kossen K, Fosnaugh K, Vargeese C, Gomez A, Bouhana K, Aitchison R, Pavco P, Campochiaro PA (2006) Suppression of ocular neovascularisation with siRNA targeting VEGF receptor 1. Gene Ther 13:225–234

    PubMed  CAS  Google Scholar 

  163. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozika M, Barri JZ, Albuquerque RJ, Yamasaki S, Itava M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Kariko K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597

    PubMed  CAS  Google Scholar 

  164. Kaiser PK, Symons RCA, Shah SM, Quinlan EJ, Tabendeh H, Do DV, Reisen G, Lockridge JA, Short B, Guerciolini R, Nguyen QD (2010) RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am J Ophthalmol 150:33–39

    PubMed  CAS  Google Scholar 

  165. Friday BB, Adjei AA (2008) Advances in targeting the Ras/Raf/MEK/Erk mitogen activated protein cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 14:342–346

    PubMed  CAS  Google Scholar 

  166. Gotink KJ, Verheul HMW (2010) Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 13:1–14

    PubMed  CAS  Google Scholar 

  167. Johnson LN (2009) Protein kinase inhibitors: contributions from structure to clinical compounds. Q Rev Biophys 42:1–40

    PubMed  CAS  Google Scholar 

  168. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670

    PubMed  CAS  Google Scholar 

  169. Jarvis A, Allerston CK, Jia H, Herzog B, Garza-Garcia A, Winfield N, Ellard K, Aqil R, Lynch R, Chapman C, Hartzoulakis B, Nally J, Stewart M, Cheng L, Menon M, Tickner M, Djordjevic S, Driscoll PC, Zachary I, Selwood DL (2010) Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem 53:2215–2226

    PubMed  CAS  Google Scholar 

  170. Giordano RJ, Cardo-Vila M, Lahdentranth J, Pasqualini R, Arap W (2001) Biopanning and rapid analysis of selective interactive ligands. Nat Med 7:1249–1253

    PubMed  CAS  Google Scholar 

  171. Giordano RJ, Cardo-Vila M, Salameh A, Anobom CD, Zeitlin BD, Hawke DH, Valente A, Almeida FCL, Nör JE, Sidman RL, Pasqualini R, Arap W (2010) From combinatorial peptide selection to drug prototype (I): targeting the vascular endothelial growth factor receptor pathway. Proc Natl Acad Sci USA 107:5112–5117

    PubMed  CAS  Google Scholar 

  172. Nagpal M, Nagpal K, Nagpal PN (2007) A comparative debate on the various anti-vascular endothelial growth factor drugs: pegaptanib sodium (Macugen), ranibizumab (Lucentis) and bevacizumab (Avastin). Indian J Ophthalmol 55:437–439

    PubMed  Google Scholar 

  173. Bian ZM, Elner SG, Elner VM (2007) Regulation of VEGF mRNA expression and protein secretion by TGF-ß2 in human retinal pigment epithelial cells. Exp Eye Res 84:812–822

    PubMed  CAS  Google Scholar 

  174. Varey AH, Rennel ES, Qiu Y, Bevan HS, Perrin RM, Raffy S, Dixon AR, Paraskeva C, Zaccheo O, Hassan AB, Haprer SJ, Bates DO (2008) VEGF165b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer 98:1366–1379

    PubMed  CAS  Google Scholar 

  175. Konopatskava O, Churchill AJ, Harper SJ, Bates DO, Gardiner TA (2006) VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice. Mol Vis 12:626–632

    Google Scholar 

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  1. Department of Ophthalmology, University of Kiel, University Medical Center, Arnold Heller-Str. 3, 24105, Kiel, Germany

    Alexa Klettner & Johann Roider

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    Thomas W. Gardner

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Klettner, A., Roider, J. (2012). Mechanisms of Pathological VEGF Production in the Retina and Modification with VEGF-Antagonists. In: Stratton, R., Hauswirth, W., Gardner, T. (eds) Studies on Retinal and Choroidal Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press. https://doi.org/10.1007/978-1-61779-606-7_13

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