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VEGF Splicing and the Role of VEGF Splice Variants: From Physiological-Pathological Conditions to Specific Pre-mRNA Splicing

  • Protocol
Book cover VEGF Signaling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1332))

Abstract

During this past decade, the vascular endothelial growth factor (VEGF) pathway has been extensively studied. VEGF is a paradigm of molecular regulation since its expression is controlled at all possible steps including transcription, mRNA stability, translation, and pre-mRNA splicing. The latter form of molecular regulation is probably the least studied. This field has been neglected; yet different forms of VEGF with different sizes and different physiological properties issued from alternative splicing have been described a long time ago. Recently a new level of complexity was added to the field of splicing of VEGF pre-mRNA. Whereas thousands of publications have described VEGF as a pro-angiogenic factor, an alternative splicing event generates specific anti-angiogenic forms of VEGF that only differ from the others by a modification in the last six amino acids of the protein. According to the scientists who discovered these isoforms, which are indistinguishable from the pro-angiogenic ones with pan VEGF antibodies, some of the literature on VEGF is at least inexact if not completely false. Moreover, the presence of anti-angiogenic forms of VEGF may explain the disappointing efficacy of anti-VEGF therapies on the overall survival of patients with different forms of cancers and with wet age-related macular degeneration. This review focuses on the existence of the different alternative splice variants of VEGF and the molecular mechanisms associated with their expression and function.

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References

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Plouet J, Schilling J, Gospodarowicz D (1989) Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J 8:3801–3806

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Gospodarowicz D, Abraham JA, Schilling J (1989) Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A 86:7311–7315

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312

    CAS  PubMed  Google Scholar 

  6. Connolly DT, Olander JV, Heuvelman D, Nelson R, Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J (1989) Human vascular permeability factor. Isolation from U937 cells. J Biol Chem 264:20017–20024

    CAS  PubMed  Google Scholar 

  7. Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD, Peat D, Gillatt D, Harper SJ (2002) VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 62:4123–4131

    CAS  PubMed  Google Scholar 

  9. Wu Q, Krainer AR (1999) AT-AC pre-mRNA splicing mechanisms and conservation of minor introns in voltage-gated ion channel genes. Mol Cell Biol 19:3225–3236

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Bonnal S, Vigevani L, Valcarcel J (2012) The spliceosome as a target of novel antitumour drugs. Nat Rev Drug Discov 11:847–859

    CAS  PubMed  Google Scholar 

  11. Matlin AJ, Clark F, Smith CW (2005) Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 6:386–398

    CAS  PubMed  Google Scholar 

  12. Ng B, Yang F, Huston DP, Yan Y, Yang Y, Xiong Z, Peterson LE, Wang H, Yang XF (2004) Increased noncanonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes. J Allergy Clin Immunol 114:1463–1470

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Gallego ME, Gattoni R, Stevenin J, Marie J, Expert-Bezancon A (1997) The SR splicing factors ASF/SF2 and SC35 have antagonistic effects on intronic enhancer-dependent splicing of the beta-tropomyosin alternative exon 6A. EMBO J 16:1772–1784

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Schaal TD, Maniatis T (1999) Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein-specific enhancer sequences. Mol Cell Biol 19:1705–1719

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Schaal TD, Maniatis T (1999) Multiple distinct splicing enhancers in the protein-coding sequences of a constitutively spliced pre-mRNA. Mol Cell Biol 19:261–273

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Krecic AM, Swanson MS (1999) hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol 11:363–371

    CAS  PubMed  Google Scholar 

  17. Hastings ML, Wilson CM, Munroe SH (2001) A purine-rich intronic element enhances alternative splicing of thyroid hormone receptor mRNA. RNA 7:859–874

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Simard MJ, Chabot B (2002) SRp30c is a repressor of 3′ splice site utilization. Mol Cell Biol 22:4001–4010

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Fairbrother WG, Yeh RF, Sharp PA, Burge CB (2002) Predictive identification of exonic splicing enhancers in human genes. Science 297:1007–1013

    CAS  PubMed  Google Scholar 

  20. Zhong XY, Wang P, Han J, Rosenfeld MG, Fu XD (2009) SR proteins in vertical integration of gene expression from transcription to RNA processing to translation. Mol Cell 35:1–10

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Huang Y, Steitz JA (2005) SRprises along a messenger’s journey. Mol Cell 17:613–615

    CAS  PubMed  Google Scholar 

  22. Eisenreich A, Rauch U (2010) Regulation and differential role of the tissue factor isoforms in cardiovascular biology. Trends Cardiovasc Med 20:199–203

    CAS  PubMed  Google Scholar 

  23. Giannakouros T, Nikolakaki E, Mylonis I, Georgatsou E (2011) Serine-arginine protein kinases: a small protein kinase family with a large cellular presence. FEBS J 278:570–586

    CAS  PubMed  Google Scholar 

  24. Ghosh G, Adams JA (2011) Phosphorylation mechanism and structure of serine-arginine protein kinases. FEBS J 278:587–597

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Jang SW, Yang SJ, Ehlen A, Dong S, Khoury H, Chen J, Persson JL, Ye K (2008) Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1. Cancer Res 68:4559–4570

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Edmond V, Brambilla C, Brambilla E, Gazzeri S, Eymin B (2011) SRSF2 is required for sodium butyrate-mediated p21(WAF1) induction and premature senescence in human lung carcinoma cell lines. Cell Cycle 10:1968–1977

    CAS  PubMed  Google Scholar 

  27. Woolard J, Bevan HS, Harper SJ, Bates DO (2009) Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation 16:572–592

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814

    CAS  PubMed  Google Scholar 

  29. 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

    CAS  PubMed  Google Scholar 

  30. Keyt BA, Berleau LT, Nguyen HV, Chen H, Heinsohn H, Vandlen R, Ferrara N (1996) The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency. J Biol Chem 271:7788–7795

    CAS  PubMed  Google Scholar 

  31. 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

    CAS  PubMed  Google Scholar 

  32. Mineur P, Colige AC, Deroanne CF, Dubail J, Kesteloot F, Habraken Y, Noel A, Voo 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 Central  CAS  PubMed  Google Scholar 

  33. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745

    CAS  PubMed  Google Scholar 

  34. Cao Y, Wang L, Nandy D, Zhang Y, Basu A, Radisky D, Mukhopadhyay D (2008) Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes. Cancer Res 68:8667–8672

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, Klagsbrun M (2000) Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: in vivo expression and antitumor activity. Proc Natl Acad Sci U S A 97:2573–2578

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442

    CAS  PubMed  Google Scholar 

  37. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vanderhoeck 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

    CAS  PubMed  Google Scholar 

  38. Carmeliet P, Ng YS, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I, Ehler E, Kakkar VV, Stalmans I, Mattot V, Perriard JC, Dewerchin M, Flameng W, Nagy A, Lupu F, Moons L, Collen D, D’Amore PA, Shima DT (1999) Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 5:495–502

    CAS  PubMed  Google Scholar 

  39. 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

    CAS  PubMed  Google Scholar 

  40. Meiron M, Anunu R, Scheinman EJ, Hashmueli S, Levi BZ (2001) New isoforms of VEGF are translated from alternative initiation CUG codons located in its 5′UTR. Biochem Biophys Res Commun 282:1053–1060

    CAS  PubMed  Google Scholar 

  41. Tee MK, Jaffe RB (2001) A precursor form of vascular endothelial growth factor arises by initiation from an upstream in-frame CUG codon. Biochem J 359:219–226

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Rosenbaum-Dekel Y, Fuchs A, Yakirevich E, Azriel A, Mazareb S, Resnick MB, Levi BZ (2005) Nuclear localization of long-VEGF is associated with hypoxia and tumor angiogenesis. Biochem Biophys Res Commun 332:271–278

    CAS  PubMed  Google Scholar 

  43. 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 Central  CAS  PubMed  Google Scholar 

  44. Takahashi H, Shibuya M (2005) The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 109:227–241

    CAS  Google Scholar 

  45. Rapisarda A, Melillo G (2012) Role of the VEGF/VEGFR axis in cancer biology and therapy. Adv Cancer Res 114:237–267

    CAS  PubMed  Google Scholar 

  46. Hofstaetter JG, Saad FA, Sunk IG, Bobacz K, Friehs I, Glimcher MJ (2007) Age-dependent expression of VEGF isoforms and receptors in the rabbit anterior cruciate ligament. Biochim Biophys Acta 1770:997–1002

    CAS  PubMed  Google Scholar 

  47. Kondo S, Matsumoto T, Yokoyama Y, Ohmori I, Suzuki H (1995) The shortest isoform of human vascular endothelial growth factor/vascular permeability factor (VEGF/VPF121) produced by Saccharomyces cerevisiae promotes both angiogenesis and vascular permeability. Biochim Biophys Acta 1243:195–202

    PubMed  Google Scholar 

  48. 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 vessel branching morphogenesis. Genes Dev 16:2684–2698

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouche A, Yuce A, Fujisawa H, Hermans B, Shani M, Jansen S, Hicklin D, Anderson DJ, Gardiner T, Hammes HP, Moons L, Dewerchin M, Collen D, Carmeliet P, D’Amore PA (2002) Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109:327–336

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Smith SK (2000) Angiogenesis and implantation. Hum Reprod 15(Suppl 6):59–66

    PubMed  Google Scholar 

  51. Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PG (2004) Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online 9:692–715

    PubMed  Google Scholar 

  52. Lam PM, Haines C (2005) Vascular endothelial growth factor plays more than an angiogenic role in the female reproductive system. Fertil Steril 84:1775–1778

    CAS  PubMed  Google Scholar 

  53. Breen EC (2007) VEGF in biological control. J Cell Biochem 102:1358–1367

    CAS  PubMed  Google Scholar 

  54. Sung HK, Michael IP, Nagy A (2010) Multifaceted role of vascular endothelial growth factor signaling in adult tissue physiology: an emerging concept with clinical implications. Curr Opin Hematol 17:206–212

    CAS  PubMed  Google Scholar 

  55. Katoh O, Tauchi H, Kawaishi K, Kimura A, Satow Y (1995) Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res 55:5687–5692

    CAS  PubMed  Google Scholar 

  56. Favard C, Moukadiri H, Dorey C, Praloran V, Plouet J (1991) Purification and biological properties of vasculotropin, a new angiogenic cytokine. Biol Cell 73:1–6

    CAS  PubMed  Google Scholar 

  57. Guerrin M, Moukadiri H, Chollet P, Moro F, Dutt K, Malecaze F, Plouet J (1995) Vasculotropin/vascular endothelial growth factor is an autocrine growth factor for human retinal pigment epithelial cells cultured in vitro. J Cell Physiol 164:385–394

    CAS  PubMed  Google Scholar 

  58. Sondell M, Lundborg G, Kanje M (1999) Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res 846:219–228

    CAS  PubMed  Google Scholar 

  59. Foster RR, Saleem MA, Mathieson PW, Bates DO, Harper SJ (2005) Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes. Am J Physiol Renal Physiol 288:F48–F57

    CAS  PubMed  Google Scholar 

  60. Ferrara N (1999) Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 56:794–814

    CAS  PubMed  Google Scholar 

  61. Carmeliet P, Collen D (2000) Transgenic mouse models in angiogenesis and cardiovascular disease. J Pathol 190:387–405

    CAS  PubMed  Google Scholar 

  62. Zygalaki E, Kaklamanis L, Nikolaou NI, Kyrzopoulos S, Houri M, Kyriakides Z, Lianidou ES, Kremastinos DT (2008) Expression profile of total VEGF, VEGF splice variants and VEGF receptors in the myocardium and arterial vasculature of diabetic and non-diabetic patients with coronary artery disease. Clin Biochem 41:82–87

    CAS  PubMed  Google Scholar 

  63. Herve MA, Buteau-Lozano H, Mourah S, Calvo F, Perrot-Applanat M (2005) VEGF189 stimulates endothelial cells proliferation and migration in vitro and up-regulates the expression of Flk-1/KDR mRNA. Exp Cell Res 309:24–31

    CAS  PubMed  Google Scholar 

  64. Hutchings H, Ortega N, Plouet J (2003) Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration, and survival through integrin ligation. FASEB J 17:1520–1522

    CAS  PubMed  Google Scholar 

  65. Maes C, Stockmans I, Moermans K, Van Looveren R, Smets N, Carmeliet P, Bouillon R, Carmeliet G (2004) Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J Clin Invest 113:188–199

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Faure C, Linossier MT, Malaval L, Lafage-Proust MH, Peyroche S, Vico L, Guignandon A (2008) Mechanical signals modulated vascular endothelial growth factor-A (VEGF-A) alternative splicing in osteoblastic cells through actin polymerisation. Bone 42:1092–1101

    CAS  PubMed  Google Scholar 

  67. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31

    CAS  PubMed  Google Scholar 

  68. Uthoff SM, Duchrow M, Schmidt MH, Broll R, Bruch HP, Strik MW, Galandiuk S (2002) VEGF isoforms and mutations in human colorectal cancer. Int J Cancer 101:32–36

    CAS  PubMed  Google Scholar 

  69. Catena R, Muniz-Medina V, Moralejo B, Javierre B, Best CJ, Emmert-Buck MR, Green JE, Baker CC, Calvo A (2007) Increased expression of VEGF121/VEGF165-189 ratio results in a significant enhancement of human prostate tumor angiogenesis. Int J Cancer 120:2096–2109

    CAS  PubMed  Google Scholar 

  70. Kawai H, Minamiya Y, Ito M, Saito H, Ogawa J (2008) VEGF121 promotes lymphangiogenesis in the sentinel lymph nodes of non-small cell lung carcinoma patients. Lung Cancer 59:41–47

    PubMed  Google Scholar 

  71. Li Z, Zhang Y, Ying MJ, Kapoun AM, Shao Q, Kerr I, Lam A, O’Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, Protter AA, Pollitt NS (2007) Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension 50:686–692

    CAS  PubMed  Google Scholar 

  72. Woods AK, Hoffmann DS, Weydert CJ, Butler SD, Zhou Y, Sharma RV, Davisson RL (2011) Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice. Hypertension 57:94–102

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Rosengart TK, Lee LY, Patel SR, Sanborn TA, Parikh M, Bergman GW, Hachamovitch R, Szulc M, Kligfield PD, Okin PM, Hahn RT, Devereux RB, Post MR, Hackett NR, Foster T, Grasso TM, Lesser ML, Isom OW, Crystal RG (1999) Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 100:468–474

    CAS  PubMed  Google Scholar 

  74. Rosengart TK, Bishawi MM, Halbreiner MS, Fakhoury M, Finnin E, Hollmann C, Shroyer AL, Crystal RG (2013) Long-term follow-up assessment of a phase 1 trial of angiogenic gene therapy using direct intramyocardial administration of an adenoviral vector expressing the VEGF121 cDNA for the treatment of diffuse coronary artery disease. Hum Gene Ther 24:203–208

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Suga S, Kim YG, Joly A, Puchacz E, Kang DH, Jefferson JA, Abraham JA, Hughes J, Johnson RJ, Schreiner GF (2001) Vascular endothelial growth factor (VEGF121) protects rats from renal infarction in thrombotic microangiopathy. Kidney Int 60:1297–1308

    CAS  PubMed  Google Scholar 

  76. Zhang Y, Matsuo H, Morita E (2005) Vascular endothelial growth factor 121 is the predominant isoform in psoriatic scales. Exp Dermatol 14:758–764

    CAS  PubMed  Google Scholar 

  77. Ciulla TA, Rosenfeld PJ (2009) Antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. Curr Opin Ophthalmol 20:158–165

    PubMed  Google Scholar 

  78. Wells JA, Murthy R, Chibber R, Nunn A, Molinatti PA, Kohner EM, Gregor ZJ (1996) Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br J Ophthalmol 80:363–366

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Lai CM, Dunlop SA, May LA, Gorbatov M, Brankov M, Shen WY, Binz N, Lai YK, Graham CE, Barry CJ, Constable IJ, Beazley LD, Rakoczy EP (2005) Generation of transgenic mice with mild and severe retinal neovascularisation. Br J Ophthalmol 89:911–916

    PubMed Central  PubMed  Google Scholar 

  80. Karvinen H, Pasanen E, Rissanen TT, Korpisalo P, Vahakangas E, Jazwa A, Giacca M, Yla-Herttuala S (2011) Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle. Gene Ther 18:1166–1172

    CAS  PubMed  Google Scholar 

  81. Ferraro B, Cruz YL, Coppola D, Heller R (2009) Intradermal delivery of plasmid VEGF(165) by electroporation promotes wound healing. Mol Ther 17:651–657

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Mittermayr R, Morton T, Hofmann M, Helgerson S, van Griensven M, Redl H (2008) Sustained (rh)VEGF(165) release from a sprayed fibrin biomatrix induces angiogenesis, up-regulation of endogenous VEGF-R2, and reduces ischemic flap necrosis. Wound Repair Regen 16:542–550

    PubMed  Google Scholar 

  83. Zacchigna S, Papa G, Antonini A, Novati F, Moimas S, Carrer A, Arsic N, Zentilin L, Visintini V, Pascone M, Giacca M (2005) Improved survival of ischemic cutaneous and musculocutaneous flaps after vascular endothelial growth factor gene transfer using adeno-associated virus vectors. Am J Pathol 167:981–991

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Enestvedt CK, Hosack L, Winn SR, Diggs BS, Uchida B, O’Rourke RW, Jobe BA (2008) VEGF gene therapy augments localized angiogenesis and promotes anastomotic wound healing: a pilot study in a clinically relevant animal model. J Gastrointest Surg 12:1762–1770, discussion 1771–1762

    PubMed  Google Scholar 

  85. Ye L, Haider H, Esa WB, Su L, Law PK, Zhang W, Lim Y, Poh KK, Sim EK (2010) Liposome-based vascular endothelial growth factor-165 transfection with skeletal myoblast for treatment of ischaemic limb disease. J Cell Mol Med 14:323–336

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Leong-Poi H, Kuliszewski MA, Lekas M, Sibbald M, Teichert-Kuliszewska K, Klibanov AL, Stewart DJ, Lindner JR (2007) Therapeutic arteriogenesis by ultrasound-mediated VEGF165 plasmid gene delivery to chronically ischemic skeletal muscle. Circ Res 101:295–303

    CAS  PubMed  Google Scholar 

  87. Yano A, Shingo T, Takeuchi A, Yasuhara T, Kobayashi K, Takahashi K, Muraoka K, Matsui T, Miyoshi Y, Hamada H, Date I (2005) Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia. J Neurosurg 103:104–114

    CAS  PubMed  Google Scholar 

  88. Guerrero M, Athota K, Moy J, Mehta LS, Laguens R, Crottogini A, Borrelli M, Corry P, Schoenherr D, Gentry R, Boura J, Grines CL, Raff GL, Shanley CJ, O’Neill WW (2008) Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction. J Interv Cardiol 21:242–251

    PubMed  Google Scholar 

  89. Ripa RS, Wang Y, Jorgensen E, Johnsen HE, Hesse B, Kastrup J (2006) Intramyocardial injection of vascular endothelial growth factor-A165 plasmid followed by granulocyte-colony stimulating factor to induce angiogenesis in patients with severe chronic ischaemic heart disease. Eur Heart J 27:1785–1792

    CAS  PubMed  Google Scholar 

  90. Cheng SY, Nagane M, Huang HS, Cavenee WK (1997) Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF121 and VEGF165 but not VEGF189. Proc Natl Acad Sci U S A 94:12081–12087

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Salven P, Perhoniemi V, Tykka H, Maenpaa H, Joensuu H (1999) Serum VEGF levels in women with a benign breast tumor or breast cancer. Breast Cancer Res Treat 53:161–166

    CAS  PubMed  Google Scholar 

  92. Jacobsen J, Rasmuson T, Grankvist K, Ljungberg B (2000) Vascular endothelial growth factor as prognostic factor in renal cell carcinoma. J Urol 163:343–347

    CAS  PubMed  Google Scholar 

  93. Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, Gatter KC, Harris AL (2001) Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer 85:881–890

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Stimpfl M, Tong D, Fasching B, Schuster E, Obermair A, Leodolter S, Zeillinger R (2002) Vascular endothelial growth factor splice variants and their prognostic value in breast and ovarian cancer. Clin Cancer Res 8:2253–2259

    CAS  PubMed  Google Scholar 

  95. Harlozinska A, Sedlaczek P, Kulpa J, Grybos M, Wojcik E, Van Dalen A, Einarsson R (2004) Vascular endothelial growth factor (VEGF) concentration in sera and tumor effusions from patients with ovarian carcinoma. Anticancer Res 24:1149–1157

    CAS  PubMed  Google Scholar 

  96. Li Q, Xu B, Fu L, Hao XS (2006) Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma. J Exp Clin Cancer Res 25:403–409

    CAS  PubMed  Google Scholar 

  97. Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, Koller C, Estrov Z, O’Brien S, Keating M, Freireich E, Albitar M (2000) Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96:2240–2245

    CAS  PubMed  Google Scholar 

  98. Legros L, Bourcier C, Jacquel A, Mahon FX, Cassuto JP, Auberger P, Pages G (2004) Imatinib mesylate (STI571) decreases the vascular endothelial growth factor plasma concentration in patients with chronic myeloid leukemia. Blood 104:495–501

    CAS  PubMed  Google Scholar 

  99. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18

    CAS  PubMed  Google Scholar 

  100. Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1998) Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 77:998–1002

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Tomisawa M, Tokunaga T, Oshika Y, Tsuchida T, Fukushima Y, Sato H, Kijima H, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1999) Expression pattern of vascular endothelial growth factor isoform is closely correlated with tumour stage and vascularisation in renal cell carcinoma. Eur J Cancer 35:133–137

    CAS  PubMed  Google Scholar 

  102. Oshika Y, Nakamura M, Tokunaga T, Ozeki Y, Fukushima Y, Hatanaka H, Abe Y, Yamazaki H, Kijima H, Tamaoki N, Ueyama Y (1998) Expression of cell-associated isoform of vascular endothelial growth factor 189 and its prognostic relevance in non-small cell lung cancer. Int J Oncol 12:541–544

    CAS  PubMed  Google Scholar 

  103. Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, Yang PC, Lee YC (2001) Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 19:432–441

    CAS  PubMed  Google Scholar 

  104. Herve MA, Buteau-Lozano H, Vassy R, Bieche I, Velasco G, Pla M, Perret G, Mourah S, Perrot-Applanat M (2008) Overexpression of vascular endothelial growth factor 189 in breast cancer cells leads to delayed tumor uptake with dilated intratumoral vessels. Am J Pathol 172:167–178

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Cao Y, E G, Wang E, Pal K, Dutta SK, Bar-Sagi D, Mukhopadhyay D (2012) VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res 72:3912–3918

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Wang H, Geisen P, Wittchen ES, King B, Burridge K, D’Amore PA, Hartnett ME (2011) The role of RPE cell-associated VEGF(1)(8)(9) in choroidal endothelial cell transmigration across the RPE. Invest Ophthalmol Vis Sci 52:570–578

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  109. Farah SE (2008) Treatment of neovascular age-related macular degeneration with pegaptanib and boosting with bevacizumab or ranibizumab as needed. Ophthalmic Surg Lasers Imaging 39:294–298

    PubMed  Google Scholar 

  110. Barakat MR, Kaiser PK (2009) VEGF inhibitors for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs 18:637–646

    CAS  PubMed  Google Scholar 

  111. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    CAS  PubMed  Google Scholar 

  112. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    CAS  PubMed  Google Scholar 

  113. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111

    PubMed  Google Scholar 

  114. Burger RA (2007) Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol 25:2902–2908

    CAS  PubMed  Google Scholar 

  115. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729

    CAS  PubMed  Google Scholar 

  116. Masellis AM, Sielaff TD, Bender GP (2009) Successful treatment of metastatic pancreatic adenocarcinoma with combination chemotherapy regimens. Int J Clin Oncol 14:478–481

    CAS  PubMed  Google Scholar 

  117. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    CAS  PubMed  Google Scholar 

  118. Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B (2008) Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 26:127–131

    CAS  PubMed  Google Scholar 

  119. Al-Marrawi MY, Rini B (2011) Pazopanib for the treatment of renal cancer. Expert Opin Pharmacother 12:1171–1189

    PubMed  Google Scholar 

  120. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239

    CAS  PubMed  Google Scholar 

  122. Qiu Y, Hoareau-Aveilla C, Oltean S, Harper SJ, Bates DO (2009) The anti-angiogenic isoforms of VEGF in health and disease. Biochem Soc Trans 37:1207–1213

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Claffey KP, Senger DR, Spiegelman BM (1995) Structural requirements for dimerization, glycosylation, secretion, and biological function of VPF/VEGF. Biochim Biophys Acta 1246:1–9

    PubMed  Google Scholar 

  124. Varey AH, Rennel ES, Qiu Y, Bevan HS, Perrin RM, Raffy S, Dixon AR, Paraskeva C, Zaccheo O, Hassan AB, Harper SJ, Bates DO (2008) VEGF 165 b, 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 Central  CAS  PubMed  Google Scholar 

  125. Perrin RM, Konopatskaya O, Qiu Y, Harper S, Bates DO, Churchill AJ (2005) Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia 48:2422–2427

    CAS  PubMed  Google Scholar 

  126. Konopatskaya 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

    CAS  PubMed  Google Scholar 

  127. Bevan HS, van den Akker NM, Qiu Y, Polman JA, Foster RR, Yem J, Nishikawa A, Satchell SC, Harper SJ, Gittenberger-de Groot AC, Bates DO (2008) The alternatively spliced anti-angiogenic family of VEGF isoforms VEGFxxxb in human kidney development. Nephron Physiol 110:p57–p67

    PubMed Central  CAS  PubMed  Google Scholar 

  128. Ladomery MR, Harper SJ, Bates DO (2007) Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm. Cancer Lett 249:133–142

    CAS  PubMed  Google Scholar 

  129. Cui TG, Foster RR, Saleem M, Mathieson PW, Gillatt DA, Bates DO, Harper SJ (2004) Differentiated human podocytes endogenously express an inhibitory isoform of vascular endothelial growth factor (VEGF165b) mRNA and protein. Am J Physiol Renal Physiol 286:F767–F773

    CAS  PubMed  Google Scholar 

  130. 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 factors. J Cell Sci 121:3487–3495

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Qiu Y, Bevan H, Weeraperuma S, Wratting D, Murphy D, Neal CR, Bates DO, Harper SJ (2008) Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF165b. FASEB J 22:1104–1112

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  133. Pritchard-Jones RO, Dunn DB, Qiu Y, Varey AH, Orlando A, Rigby H, Harper SJ, Bates DO (2007) Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 97:223–230

    PubMed Central  CAS  PubMed  Google Scholar 

  134. Bates DO, MacMillan PP, Manjaly JG, Qiu Y, Hudson SJ, Bevan HS, Hunter AJ, Soothill PW, Read M, Donaldson LF, Harper SJ (2006) The endogenous anti-angiogenic family of splice variants of VEGF, VEGFxxxb, are down-regulated in pre-eclamptic placentae at term. Clin Sci (Lond) 110:575–585

    CAS  Google Scholar 

  135. Bills VL, Salmon AH, Harper SJ, Overton TG, Neal CR, Jeffery B, Soothill PW, Bates DO (2011) Impaired vascular permeability regulation caused by the VEGF(1)(6)(5)b splice variant in pre-eclampsia. BJOG 118:1253–1261

    CAS  PubMed  Google Scholar 

  136. Schumacher VA, Jeruschke S, Eitner F, Becker JU, Pitschke G, Ince Y, Miner JH, Leuschner I, Engers R, Everding AS, Bulla M, Royer-Pokora B (2007) Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome. J Am Soc Nephrol 18:719–729

    CAS  PubMed  Google Scholar 

  137. Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah-Zadeh M, Welsh GI, Cheung MK, Ni L, Kase S, Rennel ES, Symonds KE, Nowak DG, Royer-Pokora B, Saleem MA, Hagiwara M, Schumacher VA, Harper SJ, Hinton DR, Bates DO, Ladomery MR (2011) WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell 20:768–780

    PubMed Central  CAS  PubMed  Google Scholar 

  138. Ergorul C, Ray A, Huang W, Darland D, Luo ZK, Grosskreutz CL (2008) Levels of vascular endothelial growth factor-A165b (VEGF-A165b) are elevated in experimental glaucoma. Mol Vis 14:1517–1524

    PubMed Central  CAS  PubMed  Google Scholar 

  139. Manetti M, Guiducci S, Romano E, Ceccarelli C, Bellando-Randone S, Conforti ML, Ibba-Manneschi L, Matucci-Cerinic M (2011) Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circ Res 109:e14–e26

    CAS  PubMed  Google Scholar 

  140. Cebe Suarez S, Pieren M, Cariolato L, Arn S, Hoffmann U, Bogucki A, Manlius C, Wood J, Ballmer-Hofer K (2006) A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci 63:2067–2077

    CAS  PubMed  Google Scholar 

  141. Kawamura H, Li X, Harper SJ, Bates DO, Claesson-Welsh L (2008) Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res 68:4683–4692

    CAS  PubMed  Google Scholar 

  142. Ruch C, Skiniotis G, Steinmetz MO, Walz T, Ballmer-Hofer K (2007) Structure of a VEGF-VEGF receptor complex determined by electron microscopy. Nat Struct Mol Biol 14:249–250

    CAS  PubMed  Google Scholar 

  143. Catena R, Larzabal L, Larrayoz M, Molina E, Hermida J, Agorreta J, Montes R, Pio R, Montuenga LM, Calvo A (2010) VEGF(1)(2)(1)b and VEGF(1)(6)(5)b are weakly angiogenic isoforms of VEGF-A. Mol Cancer 9:320

    PubMed Central  CAS  PubMed  Google Scholar 

  144. Rennel E, Waine E, Guan H, Schuler Y, Leenders W, Woolard J, Sugiono M, Gillatt D, Kleinerman E, Bates D, Harper S (2008) The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice. Br J Cancer 98:1250–1257

    PubMed Central  CAS  PubMed  Google Scholar 

  145. Rennel ES, Hamdollah-Zadeh MA, Wheatley ER, Magnussen A, Schuler Y, Kelly SP, Finucane C, Ellison D, Cebe-Suarez S, Ballmer-Hofer K, Mather S, Stewart L, Bates DO, Harper SJ (2008) Recombinant human VEGF165b protein is an effective anti-cancer agent in mice. Eur J Cancer 44:1883–1894

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Rennel ES, Varey AH, Churchill AJ, Wheatley ER, Stewart L, Mather S, Bates DO, Harper SJ (2009) VEGF(121)b, a new member of the VEGF(xxx)b family of VEGF-A splice isoforms, inhibits neovascularisation and tumour growth in vivo. Br J Cancer 101:1183–1193

    PubMed Central  CAS  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  148. Ranpura V, Hapani S, Wu S (2011) Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 305:487–494

    CAS  PubMed  Google Scholar 

  149. Bates DO, Catalano PJ, Symonds KE, Varey AH, Ramani P, O’Dwyer PJ, Giantonio BJ, Meropol NJ, Benson AB, Harper SJ (2012) Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab. Clin Cancer Res 18:6384–6391

    PubMed Central  CAS  PubMed  Google Scholar 

  150. Harris S, Craze M, Newton J, Fisher M, Shima DT, Tozer GM, Kanthou C (2012) Do anti-angiogenic VEGF (VEGFxxxb) isoforms exist? A cautionary tale. PLoS One 7, e35231

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Artac RA, McFee RM, Smith RA, Baltes-Breitwisch MM, Clopton DT, Cupp AS (2009) Neutralization of vascular endothelial growth factor antiangiogenic isoforms is more effective than treatment with proangiogenic isoforms in stimulating vascular development and follicle progression in the perinatal rat ovary. Biol Reprod 81:978–988

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Institut National pour la Santé et la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), the National Institute of Cancer (INCA), the Association for Cancer Research (ARC), the Fondation de France, the Fondation pour la Recherche Médicale (FRM), the «Association pour la Recherche sur les Tumeurs du Rein (ARTuR)», and ROCHE France. We thank Dr M Christiane Brahimi-Horn for editorial assistance. The other authors declare that they have no conflicts of interest.

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  1. Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Centre Antoine Lacassagne 33 Avenue de Valombrose, UMR CNRS 7284/INSERM U 1081, Nice, 06189, France

    Mélanie Guyot & Gilles Pagès

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  1. Mélanie Guyot
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  2. Gilles Pagès
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Correspondence to Gilles Pagès .

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    Lorna Fiedler

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Guyot, M., Pagès, G. (2015). VEGF Splicing and the Role of VEGF Splice Variants: From Physiological-Pathological Conditions to Specific Pre-mRNA Splicing. In: Fiedler, L. (eds) VEGF Signaling. Methods in Molecular Biology, vol 1332. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2917-7_1

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  • DOI: https://doi.org/10.1007/978-1-4939-2917-7_1

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