Skip to main content
SpringerLink
Log in

Vascular Endothelial Growth Factor: Molecular and Biological Aspects

  • Chapter
Vascular Growth Factors and Angiogenesis

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 237))

Abstract

The development of a vascular supply is a fundamental requirement for organ development and differentiation during embryogenesis as well as for wound healing and reproductive functions in the adult (Folkman 1995). Angiogenesis is also implicated in the pathogenesis of a variety of disorders: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis and psoriasis (Folkman 1995; Garner 1994).

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, Yeo KT (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 118:445–450.

    PubMed  CAS  Google Scholar 

  • Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D’Amore PA, Miller JW (1996) Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 114:66–71.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE (1995) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 92:10457–10461.

    PubMed  CAS  Google Scholar 

  • Albini A, Benelli R, Presta M, Rusnati M, Ziehe M, Rubartelli A, Paglialunga G, Bussolino F, Noonan D (1996a) HIV-tat protein is a heparin-binding angiogenic growth factor. Oncogene 12:289–297.

    PubMed  CAS  Google Scholar 

  • Albini A, Soldi R, Giunciuglio D, Giraudo E, Benelli R, Primo L, Noonan D, Salio M, Camussi G, Rockl W, Bussolino F (1996b) The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nat Med 2:1371–1375.

    PubMed  CAS  Google Scholar 

  • Algire GH, Chalkley HW (1945) Vascular reactions of normal and malignant tissues in vivo. I. Vascular recations of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 6:73–85.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Asahara T, Bauters C, Pastore C, Kearney M, Rossow S, Bunting S, Ferrara N, Symes JF, Isner JM (1995) Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery (see comments). Circulation 91:2793–2801.

    PubMed  CAS  Google Scholar 

  • Asano M, Yukita A, Matsumoto T, Kondo S, Suzuki H (1995) Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121. Cancer Res 55:5296–5301.

    PubMed  CAS  Google Scholar 

  • Banai S, Jaktlish MT, Shou M, Lazarous D, Scheinowitz M, Biro S, Epstein S, Unger E (1994a) Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor. Circulation 89:2183–2189.

    PubMed  CAS  Google Scholar 

  • Banai S, Shweiki D, Pinson A, Chandra M, Lazarovich G, Keshet E (1994b) Upregulation of vascular endothelial growth factor expression induced by myocardial ischemia: implications for coronary angiogenesis. Cardiovasc Res 28:1176–1179.

    PubMed  CAS  Google Scholar 

  • 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 

  • Bauters C, Asahara T, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM (1994) Physiological assessment of augmented vascularity induced by VEGF in ischemic rabbit hindlimb. Am J Physiol 267:H1263–H1271.

    PubMed  CAS  Google Scholar 

  • Bauters C, Asahara T, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM (1995) Recovery of disturbed endothelium-dependent flow in the collateral-perfused rabbit ischemic hindlimb after administration of vascular endothelial growth factor. Circulation 91:2802–2809.

    PubMed  CAS  Google Scholar 

  • Ben-Av P, Crofford LJ, Wilder RL, Hla T (1995) Induction of vascular endothelial growth factor expression in synovial fibroblasts. FEBS Lett 372:83–87.

    PubMed  CAS  Google Scholar 

  • Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, Robertson JT, Ali IU, Oldfield EH (1993) Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91:153–159.

    PubMed  CAS  Google Scholar 

  • Borgstrom P, Hillan KJ, Sriramarao P, Ferrara N (1996) Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res 56:4032–4039.

    PubMed  CAS  Google Scholar 

  • Borgstrom P, Hillan K, Sriramarao P, Ferrara N (1998a) Anti-Vascular endothelial growth factor antibody inhibits angiogenesis and growth of human prostate cancer in vivo. Prostate (in press)

    Google Scholar 

  • Borgstrom P, Hillan KJ, Sriraramao P, Ferrara N (1998)b Combination treatment with anti-vascular endothelial growth factor antibody and doxorubicin suppresses growth of breast carcinoma cells (submitted)

    Google Scholar 

  • Brandon EP, Idzerda RL, McKnight GS (1995) Targeting the mouse genome: a compendium of knockouts (part III). Curr Biol 5:873–881.

    PubMed  CAS  Google Scholar 

  • Breier G, Albrecht U, Sterrer S, Risau W (1992) Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114:521–532.

    PubMed  CAS  Google Scholar 

  • Brogi E, Schatteman G, Wu T, Kim EA, Varticovski L, Keyt B, Isner JM (1996) Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest 97:469–476.

    PubMed  CAS  Google Scholar 

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, Senger DR (1993a) Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 143:1255–1262.

    PubMed  CAS  Google Scholar 

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF (1993b) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 53:4727–4735.

    PubMed  CAS  Google Scholar 

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ (1995a) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 26:86–91

    PubMed  CAS  Google Scholar 

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ (1995a) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 26:86–91.

    PubMed  CAS  Google Scholar 

  • Brown LF, Harrist TJ, Yeo KT, Stahle-Backdahl M, Jackman RW, Berse B, Tognazzi K, Dvorak HF, Detmar M (1995b) Increased expression of vascular permeability factor (vascular endothelial growth factor) in bullous pemphigoid, dermatitis herpetiformis, and erythema multiforme. J Invest Dermatol 104:744–749.

    PubMed  CAS  Google Scholar 

  • Broxmeyer HE, Cooper S, Li ZH, Lu L, Song HY, Kwon BS, Warren RE, Donner DB (1995) Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. Int J Hematol 62:203–215.

    PubMed  CAS  Google Scholar 

  • Callow AD, Choi ET, Trachtenberg JD, Stevens SL, Connolly DT, Rodi C, Ryan US (1994) Vascular permeability factor accelerates endothelial regrowth following balloon angioplasty. Growth Factors 10:223–228.

    PubMed  CAS  Google Scholar 

  • Carmeliet P, Collen D (1997) Genetic analysis of blood vessel formation: role of endothelial versus smooth muscle cells. Trends Cardiovasc Med 8:271–281.

    Google Scholar 

  • Carmeliet P, Ferreira 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 

  • Chamow SM, Ashkenazi A (1996) Immunoadhesins: principles and applications. Trends Biotechnol 14:52–60.

    PubMed  CAS  Google Scholar 

  • Claffey KP, Wilkison WO, Spiegelman BM (1992) Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem 267:16317–16322.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ (1996) Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 271:736–741.

    PubMed  CAS  Google Scholar 

  • Conn G, Bayne ML, Soderman DD, Kwok PW, Sullivan KA, Palisi TM, Hope DA, Thomas KA (1990) Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci USA 87:2628–2632.

    PubMed  CAS  Google Scholar 

  • Cuevas P, Carceller F, Ortega S, Zazo M, Nieto I, Gimenez-Gallego G (1991) Hypotensive activity of fibroblast growth factor. Science 254:1208–1210.

    PubMed  CAS  Google Scholar 

  • Cuevas P, Garcia-Calvo M, Carceller F, Reimers D, Zazo M, Cuevas B, Munoz-Willery I, Martinez-Coso V, Lamas S, Gimenez-Gallego G (1996) Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats. Proc Natl Acad Sci USA 93:11996–12001.

    PubMed  CAS  Google Scholar 

  • Cullinan-Bove K, Koos RD (1993) Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 133:829–837.

    PubMed  CAS  Google Scholar 

  • Cunningham SA, Waxham MN, Arrate PM, Brock TA (1995) Interaction of the Flt-1 tyrosine kinase receptor with the p85 subunit of phosphatidylinositol 3-kinase. Mapping of a novel site involved in binding. J Biol Chem 270:20254–20257.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Davis-Smyth T, Chen H, Park J, Presta LG, Ferrara N (1996) The second immunoglobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade. EMBO J 15:4919–4927.

    PubMed  CAS  Google Scholar 

  • de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991.

    PubMed  Google Scholar 

  • Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, Berse B, Dvorak HF (1994) Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 180:1141–1146.

    PubMed  CAS  Google Scholar 

  • DiPietro LA (1997) Thrombospondin as a regulator of angiogenesis. In: Rosen E, Goldberh I (eds) Regulation of angiogenesis. Springer, Berlin Heidelberg New York, pp 295–314.

    Google Scholar 

  • Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659.

    CAS  Google Scholar 

  • Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039.

    PubMed  CAS  Google Scholar 

  • Dvorak HF, Harvey VS, Estrella P, Brown LF, McDonagh J, Dvorak AM (1987) Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest 57:673–686.

    CAS  Google Scholar 

  • Essed CD, Brand MVD, Becker AE (1983) Transluminal coronary angioplasty and early restenosis. Br Heart J 49:393–402.

    PubMed  CAS  Google Scholar 

  • Fassbender HJ, Simling-Annenfeld M (1983) The potential aggressiveness of synovial tissue in rheumatoid arthritis. J Pathol 10:845–851.

    Google Scholar 

  • Fava RA, Olsen NJ, Spencer-Green G, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF (1994) Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180:341–346.

    PubMed  CAS  Google Scholar 

  • Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Ferrara N, Clapp C, Weiner R (1991) The 16 K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 129:896–900.

    PubMed  CAS  Google Scholar 

  • Ferrara N, Houck K, Jakeman L, Leung DW (1992) Molecular and biological properties of the vascular endothelial growth family of proteins. Endocr Rev 13:18–32.

    PubMed  CAS  Google Scholar 

  • Ferrara N, Winer J, Burton T, Rowland A, Siegel M, Phillips HS, Terrell T, Keller GA, Levinson AD (1993) Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells. J Clin Invest 91:160–170.

    PubMed  CAS  Google Scholar 

  • 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 380:439–142.

    PubMed  CAS  Google Scholar 

  • Ferrara N, Chen H, Davis-Smyth T, Gerber H-P, Nguyen T-N, Peers D, Chisholm V, Hillan KJ, Schwall RH (1998) Vascular endothelial growth factor is essential for corpus luteum angiogenesis (submitted)

    Google Scholar 

  • Finnerty H, Kelleher K, Morris GE, Bean K, Merberg DM, Kriz R, Morris JC, Sookdeo H, Turner KJ, Wood CR (1993) Molecular cloning of murine FLT and FLT4. Oncogene 8:2293–2298.

    PubMed  CAS  Google Scholar 

  • Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    PubMed  CAS  Google Scholar 

  • Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186 Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31.

    PubMed  CAS  Google Scholar 

  • Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934.

    PubMed  CAS  Google Scholar 

  • Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70.

    PubMed  CAS  Google Scholar 

  • 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 

  • Frank S, Hubner G, Breier G, Longaker MT, Greenhalg DG, Werner S (1995) Regulation of VEGF expression in cultured keratinocytes. Implications for normal and impaited wound healing. J Biol Chem 270:12607–12613.

    CAS  Google Scholar 

  • Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA (1995) Definition of two angiogenic pathways by distinct alpha v integrins. Science 270:1500–1502.

    PubMed  CAS  Google Scholar 

  • Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103.

    PubMed  CAS  Google Scholar 

  • Galland F, Karamysheva A, Mattei MG, Rosnet O, Marchetto S, Birnbaum D (1992) Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Genomics 13:475–478.

    PubMed  CAS  Google Scholar 

  • Garner A (1994) Vascular diseases. Pathobiology of ocular disease. Dekker, New York.

    Google Scholar 

  • Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, Matsubara I, Vinante O, Bonoldi E, Boracchi P, Gatti C, Suzuki H, Tominaga T (1997) Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 89:139–147.

    PubMed  CAS  Google Scholar 

  • Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two VEGF receptor genes. Flt-1, but not Flk-l/KDR, is up-regulated by hypoxia. J Biol Chem 272:23659–23667.

    PubMed  CAS  Google Scholar 

  • Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, Oldfield EH, Klausner RD, Linehan WM (1996) Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 93:10589–10594.

    PubMed  CAS  Google Scholar 

  • Goldberg MA, Schneider TJ (1994) Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J Biol Chem 269:4355–4361.

    PubMed  CAS  Google Scholar 

  • Goldman C, Kim J, Wonf W-L, King V, Brock T, Gillespie Y (1993) Epidermal growth factor stimulates vascular endothelial growth factor production by malignant glioma cells. A model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4:121–133.

    CAS  Google Scholar 

  • Good D, Polverini P, Rastinejad F, Beau M, Lemons R, Frazier W, Bouck N (1990) A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospaondin. Proc Natl Acad Sci USA 87:6624–6628.

    PubMed  CAS  Google Scholar 

  • Graor RA, Gray BH (1991) Interventional treatment of peripheral vascular disease. Peripheral vascular diseases. Mosby, St Louis.

    Google Scholar 

  • Grugel S, Finkenzeller G, Weindel K, Barleon B, Marme D (1995) Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J Biol Chem 270:25915–25919.

    PubMed  CAS  Google Scholar 

  • Guidi AJ, Abu-Jawdeh G, Berse B, Jackman RW, Tognazzi K, Dvorak HF, Brown LF (1995) Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst 87:1237–1245.

    PubMed  CAS  Google Scholar 

  • Guidi AJ, Abu Jawdeh G, Tognazzi K, Dvorak HF, Brown LF (1996) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma. Cancer 78:454–460.

    PubMed  CAS  Google Scholar 

  • Guo D, Jia Q, Song HY, Warren RS, Donner DB (1995) Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. J Biol Chem 270:6729–6733.

    CAS  Google Scholar 

  • Harada K, Friedman M, Lopez J J, Wang SY, Li J, Prasad PV, Pearlman JD, Edelman ER, Sellke FW, Simons M (1996) Vascular endothelial growth factor administration in chronic myocardial ischemia. Am J Physiol 270:H1791–H1802.

    PubMed  CAS  Google Scholar 

  • Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kira Y (1994) Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol 267:H1948–H1954.

    PubMed  CAS  Google Scholar 

  • Hashimoto M, Ohsawa M, Ohnishi A, Naka N, Hirota S, Kitamura Y, Aozasa K (1995) Expression of vascular endothelial growth factor and its receptor mRNA in angiosarcoma. Lab Invest 73:859–863.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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 

  • Ikeda E, Achen MG, Breier G, Risau W (1995) Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270:19761–19766.

    PubMed  CAS  Google Scholar 

  • Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA (1996) Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 93:10595–10599.

    PubMed  CAS  Google Scholar 

  • Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T, Rosenfield K, Razvi S, Walsh K, Symes JF (1996a) Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb (see comments). Lancet 348:370–374.

    PubMed  CAS  Google Scholar 

  • Isner JM, Walsh K, Symes J, Pieczek A, Takeshita S, Lowry J, Rosenfield K, Weir L, Brogi E, Jurayj D (1996b) Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease. Hum Gene Ther 7:959–988.

    PubMed  CAS  Google Scholar 

  • Jakeman LB, Winer J, Bennett GL, Altar CA, Ferrara N (1992) Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest 89:244–253.

    PubMed  CAS  Google Scholar 

  • Jakeman LB, Armanini M, Philips HS, Ferrara N (1993) Developmental expression of binding sites and mRNA for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis. Endocrinology 133:848–859.

    PubMed  CAS  Google Scholar 

  • Kamat BR, Brown LF, Manseau EJ, Senger DR, Dvorak HF (1995) Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am J Pathol 146:157–165.

    CAS  Google Scholar 

  • Kendall RL, Wang G, Thomas KA (1996) Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 226:324–328.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Keyt BA, Nguyen HV, Berleau LT, Duarte CM, Park J, Chen H, Ferrara N (1996b) Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. J Biol Chem 271:5638–5646.

    CAS  Google Scholar 

  • Kieser A, Weich H, Brandner G, Marme, D, Kolch W (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963–969.

    PubMed  CAS  Google Scholar 

  • Kim KJ, Li B, Houck K, Winer J, Ferrara N (1992) The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors 7:53–64.

    PubMed  CAS  Google Scholar 

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362:841–844.

    PubMed  CAS  Google Scholar 

  • Koch AE, Harlow L, Haines GK, Amento EP, Unemori EN, Wong W-L, Pope RM, Ferrara N (1994) Vascular endothelial growth factor: a cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 152:4149–4156.

    PubMed  CAS  Google Scholar 

  • Kondo S, Asano M, Matsuo K, Ohmori I, Suzuki H (1994) Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim Biophys Acta 1221:211–214.

    PubMed  CAS  Google Scholar 

  • Ku DD, Zaleski JK, Liu S, Brock TA (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265:H586–H592.

    PubMed  CAS  Google Scholar 

  • Kuhn R, Schwenk F, Aguet M, Rajewsky K (1995) Inducible gene targeting in mice. Science 269:1427–1429.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 

  • Levy AP, Levy NS, Wegner S, Goldberg MA (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333–13340.

    PubMed  CAS  Google Scholar 

  • 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 

  • Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, Patterson C, Endego WO, Zhou F, Lee M (1995) Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem 270:308–312.

    PubMed  CAS  Google Scholar 

  • Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, Simons M (1996) VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270:H1803–H1811.

    PubMed  CAS  Google Scholar 

  • Liu Y, Cox SR, Morita T, Kourembanas S (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5’ enhancer. Circ Res 77:638–643.

    PubMed  CAS  Google Scholar 

  • Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR (1996) Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 37:855–868.

    PubMed  CAS  Google Scholar 

  • Madan A, Curtin PT (1993) A 24-base-pair sequence 3’ to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer. Proc Natl Acad Sci USA 90:3928–3932.

    PubMed  CAS  Google Scholar 

  • Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77:858–863.

    PubMed  CAS  Google Scholar 

  • Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegend SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie-2 that disrupts in vivo angiogenesis. Science 277:55–60.

    PubMed  CAS  Google Scholar 

  • Malecaze F, Clemens S, Simorer-Pinotel V, Mathis A, Chollet P, Favard P, Bayard F, Plouet J (1994) Detection of vascular endothelial growth factor mRNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch Ophthalmol 112:1476–1482.

    PubMed  CAS  Google Scholar 

  • Mandriota SJ, Seghezzi G, Vassalli JD, Ferrara N, Wasi S, Mazzieri R, Mignatti P, Pepper MS (1995) Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J Biol Chem 270:9709–9716.

    PubMed  CAS  Google Scholar 

  • Mandriota SJ, Menoud PA, Pepper MS (1996) Transforming growth factor beta 1 down-regulates vascular endothelial growth factor receptor 2/flk-l expression in vascular endothelial cells. J Biol Chem 271:11500–11505.

    PubMed  CAS  Google Scholar 

  • Matthews W, Jordan CT, Gavin M, Jenkins NA, Copeland NG, Lemischka IR (1991) A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci USA 88:9026–9030.

    PubMed  CAS  Google Scholar 

  • Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ (1996) Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res 56:3436–3440.

    PubMed  CAS  Google Scholar 

  • McLaren J, Prentice A, Charnock-Jones DS, Smith SK (1996) Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod 11:220–223.

    PubMed  CAS  Google Scholar 

  • Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK (1996) During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium (see comments). Nat Med 2:992–997.

    PubMed  CAS  Google Scholar 

  • Melnyk O, Shuman MA, Kim KJ (1996) Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary tumor growth. Cancer Res 56:921–924.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Millauer B, Wizigmann Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846.

    PubMed  CAS  Google Scholar 

  • Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579.

    PubMed  CAS  Google Scholar 

  • Miller JW, Adamis AP, Shima DT, D’Amore PA, Moulton RS, O’Reilly MS, Folkman J, Dvorak HF, Brown LF, Berse B et al. (1994) Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 145:574–584.

    PubMed  CAS  Google Scholar 

  • Minchenko A, Bauer T, Salceda S, Caro J (1994) Hypoxic stimulation of vascular endothelial growth factor expression in vivo and in vitro. Lab Invest 71:374–379.

    PubMed  CAS  Google Scholar 

  • Monacci WT, Merrill MJ, Oldfield EH (1993) Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264:C995–C1002.

    PubMed  CAS  Google Scholar 

  • Morbidelli L, Chang CH, Douglas JG, Granger HJ, Ledda F, Ziche M (1996) Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 270:H411–H415.

    PubMed  CAS  Google Scholar 

  • Morishita K, Johnson DE, Williams LT (1995) A novel promoter for vascular endothelial growth factor receptor (flt-1) that confers endothelial-specific gene expression. J Biol Chem 270:27948–27953.

    PubMed  CAS  Google Scholar 

  • Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, de Vos AM (1997) Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci USA 94:7192–7197.

    PubMed  CAS  Google Scholar 

  • Nicosia R, Nicosia SV, Smith M (1994) Vascular endothelial growth factor, platelet-derived growth factor and indulin-like growth factor stimulate angiogenesis in vitro. Am J Pathol 145:1023–1029.

    PubMed  CAS  Google Scholar 

  • O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma (see comments). Cell 79:315–328.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Olk RJ, Lee CM (1993) Diabetic retinopathy: practical management. Lippincott, Philadelphia.

    Google Scholar 

  • Olson TA, Mohanraj D, Carson LF, Ramakrishnan S (1994) Vascular permeability factor gene expression in normal and neoplastic human ovaries. Cancer Res 54:276–280.

    PubMed  CAS  Google Scholar 

  • Pajusola K, Aprelikova O, Korhonen J, Kaipainen A, Pertovaara L, Alitalo R, Alitalo K (1992) FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res 52:5738–5743.

    PubMed  CAS  Google Scholar 

  • Park JE, Keller H-A, 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 

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

    PubMed  CAS  Google Scholar 

  • Patterson C, Perrella MA, Hsieh CM, Yoshizumi M, Lee ME, Haber E (1995) Cloning and functional analysis of the promoter for KDR/flk-1, a receptor for vascular endothelial growth factor. J Biol Chem 270:23111–23118.

    PubMed  CAS  Google Scholar 

  • Patterson C, Perrella MA, Endege WO, Yoshizumi M, Lee ME, Haber E (1996) Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor-alpha in cultured human vascular endothelial cells. J Clin Invest 98:490–496.

    PubMed  CAS  Google Scholar 

  • Patz A (1980) Studies on retinal neovascularization. Invest Ophthalmol Vis Sci 19:1133–1138

    PubMed  CAS  Google Scholar 

  • Pearlman JD, Hibberd MG, Chuang ML, Harada K, Lopez JJ, Gladstone SR, Friedman M, Sellke FW, Simons M (1995) Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis. Nat Med 1:1085–1089.

    PubMed  CAS  Google Scholar 

  • Pe’er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E (1996) Upregulated expression of vascular endothelial growth factor in proliferative diabetic retinopathy. Br J Ophthalmol 80:241–245.

    PubMed  Google Scholar 

  • Pekala P, Marlow M, Heuvelman D, Connolly D (1990) Regulation of hexose transport in aortic endothelial cells by vascular permeability factor and tumor necrosis factor-alpha, but not by insulin.J Biol Chem 265:18051–18054

    PubMed  CAS  Google Scholar 

  • Pepper MS, Ferrara N, Orci L, Montesano R (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181:902–906.

    PubMed  CAS  Google Scholar 

  • Pepper MS, Ferrara N, Orci L, Montesano R (1992) Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 189:824–831.

    PubMed  CAS  Google Scholar 

  • Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alitalo K (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 269:6271–6274.

    PubMed  CAS  Google Scholar 

  • Peters KG, De Vries C, Williams LT (1993) Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci USA 90:8915–8919.

    PubMed  CAS  Google Scholar 

  • Phillips HS, Hains J, Leung DW, Ferrara N (1990) Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology 127:965–967.

    PubMed  CAS  Google Scholar 

  • Phillips HS, Armanini M, Stavrou D, Ferrara N, Westphal M (1993) Intense focal expression of vascular endothelial growth factor mRNA in human intracranial neoplasms: Association with regions of necrosis. Int J Oncol 2:913–919.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Plouet J, Moukadiri HJ (1990) Characerization of the receptors for vasculotropin on bovine adrenal cortex-derived capillary endothelial cells. J Biol Chem 265:22071–22075.

    PubMed  CAS  Google Scholar 

  • 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 

  • Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, 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 

  • Qu H, Nagy JA, Senger DR, Dvorak HF, Dvorak AM (1995) Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the albuminal plasma membrane and vesiculovacuolar organelles of tumor microvascular endothelium. J Histochem Cytochem 43:381–389.

    Google Scholar 

  • Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT (1993) Fetal liver kinase 1 is a receptor forvascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci USA 90:7533–7537.

    PubMed  CAS  Google Scholar 

  • Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS (1995) Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55:4575–4580.

    PubMed  CAS  Google Scholar 

  • Ravindranath N, Little-Ihrig L, Phillips HS, Ferrara N, Zeleznik AJ (1992) Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology 131:254–260.

    PubMed  CAS  Google Scholar 

  • Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674.

    PubMed  CAS  Google Scholar 

  • Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108:2369–2379.

    PubMed  CAS  Google Scholar 

  • Roberts WG, Palade GE (1997) Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 57:765–772.

    PubMed  CAS  Google Scholar 

  • Sato K, Yamazaki K, Shizume K, Kanaji Y, Obara T, Ohsumi K, Demura H, Yamaguchi S, Shibuya M (1995) Stimulation by thyroid-stimulating hormone and Grave’s immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and fit mRNA expression in the rat thyroid in vivo. J Clin Invest 96:1295–1302.

    PubMed  CAS  Google Scholar 

  • Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya, M (1995) A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 10:135–147.

    PubMed  CAS  Google Scholar 

  • Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66.

    PubMed  CAS  Google Scholar 

  • Shen H, Clauss M, Ryan J, Schmidt AM, Tijburg P, Borden L, Connolly D, Stern D, Kao J (1993) Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes. Blood 81:2767–2773.

    PubMed  CAS  Google Scholar 

  • Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M (1990) Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase (flt) closely related to the fms family. Oncogene 8:519–527.

    Google Scholar 

  • Shifren JL, Doldi N, Ferrara N, Mesiano S, Jaffe RB (1994) In the human fetus, vascular endothelialgrowth factor is expressed in epithelial cells and myocytes, but not vascular endothelium: implications for mode of action. J Clin Endocrinol Metab 79:316–322.

    PubMed  CAS  Google Scholar 

  • Shifren JL, Tseng JF, Zaloudek CJ, Ryan IP, Meng YG, Ferrara N, Jaffe RB, Taylor RN (1996) Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab 81:3112–3118.

    PubMed  CAS  Google Scholar 

  • Shima DT, Adamis AP, Ferrara N, Yeo KT, Yeo TK, Allende R, Folkman J, D’Amore PA (1995) Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1:182–193.

    PubMed  CAS  Google Scholar 

  • Shima DT, Kuroki M, Deutsch U, Ng YS, Adamis AP, D’Amore PA (1996) The mouse gene for vascular endothelial growth factor. Genomic structure, definition of the transcriptional unit, and characterization of transcriptional and post-transcriptional regulatory sequences. J Biol Chem 271:3877–3883.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Shweiki D, Itin A, Neufeld G, Gitay-Goren H, Keshet E (1993) Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally-mediated angiogenesis. J Clin Invest 91:2235–2243.

    PubMed  CAS  Google Scholar 

  • Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny Baron G, Marme D (1996) Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 56:2299–2301.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180.

    PubMed  CAS  Google Scholar 

  • Suzuki K, Hayashi N, Miyamoto Y, Yamamoto M, Ohkawa K, Ito Y, Sasaki Y, Yamaguchi Y, Nakase H, Noda K, Enomoto N, Arai K, Yamada Y, Yoshihara H, Tujimura T, Kawano K, Yoshikawa K, Kamada T (1996) Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res 56:3004–3009.

    PubMed  CAS  Google Scholar 

  • Takagi H, King GL, Ferrara N, Aiello LP (1996) Hypoxia regulates vascular endothelial growth factor receptor KDR/Flk gene expression through adenosine A2 receptors in retinal capillary endothelial cells. Invest Ophthalmol Vis Sci 37:1311–1321.

    PubMed  CAS  Google Scholar 

  • Takeshita S, Zhung L, Brogi E, Kearney M, Pu L-Q, Bunting S, Ferrara N, Symes JF, Isner JM (1994) Therapeutic angiogenesis: a single intra-arterial bolus of vascular endothelial growth factor augments collateral vessel formation in a rabbit ischemic hind-limb model. J Clin Invest 93:662–670.

    PubMed  CAS  Google Scholar 

  • Takeshita S, Tsurumi Y, Couffinahl T, Asahara T, Bauters C, Symes J, Ferrara N, Isner JM (1996a) Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. Lab Invest 75:487–501.

    PubMed  CAS  Google Scholar 

  • Takeshita S, Weir L, Chen D, Zheng LP, Riessen R, Bauters C, Symes JF, Ferrara N, Isner JM (1996b) Therapeutic angiogenesis following arterial gene transfer of vascular endothelial growth factor in arabbit model of hindlimb ischemia. Biochem Biophys Res Commun 227:628–635.

    PubMed  CAS  Google Scholar 

  • Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB (1991) Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6:1677–1683.

    PubMed  CAS  Google Scholar 

  • Terman BI, Dougher Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Bohlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187:1579–1586.

    PubMed  CAS  Google Scholar 

  • 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  Google Scholar 

  • Toi M, Kondo S, Suzuki H, Yamamoto Y, Inada K, Imazawa T, Taniguchi T, Tominaga T (1996) Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer 77:1101–1106.

    PubMed  CAS  Google Scholar 

  • Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP (1996) Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol 114:964–970.

    PubMed  CAS  Google Scholar 

  • Tuder RM, Flook BE, Voelkel NF (1995) Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Fit in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest 95:1798–1807.

    CAS  Google Scholar 

  • Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153:557–562.

    PubMed  CAS  Google Scholar 

  • Vaisman N, Gospodarowicz D, Neufeld G (1990) Characterization of the receptors for vascular endothelial growth factor. J Biol Chem 265:19461–19466.

    PubMed  CAS  Google Scholar 

  • Viglietto G, Romano A, Maglione D, Rambaldi M, Paoletti I, Lago CT, Califano D, Monaco C, Mineo A, Santelli G, Manzo G, Botti G, Chiappetta G, Persico MG (1996) Neovascularization in human germ cell tumors correlates with a marked increase in the expression of the vascular endothelial growth factor but not the placenta-derived growth factor. Oncogene 13:577–587.

    PubMed  CAS  Google Scholar 

  • Vincenti V, Cassano C, Rocchi M, Persico G (1996) Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93:1493–1495.

    PubMed  CAS  Google Scholar 

  • Volm M, Koomagi R, Mattern J (1997a) Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer. Int J Cancer 74:64–68.

    PubMed  CAS  Google Scholar 

  • Volm M, Koomagi R, Mattern J, Stammler G (1997b) Angiogenic growth factors and their receptors innon-small cell lung carcinomas and their relationships to drug response in vitro. Anticancer Res 17:99–103.

    PubMed  CAS  Google Scholar 

  • Walder CE, Errett CJ, Bunting S, Lindquist P, Ogez JR, Heinsohn HG, Ferrara N, Thomas GR (1996) Vascular endothelial growth factor augments muscle blood flow and function in a rabbit model of chronic hindlimb ischemia. J Cardio vase Pharmacol 27:91–98.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ware JA, Simons M (1997) Angiogenesis in ischemic heart disease. Nat Med 3:158–164.

    PubMed  CAS  Google Scholar 

  • Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N (1995) Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95:1789–1797.

    PubMed  CAS  Google Scholar 

  • Warren RS, Yuan H, Matli MR, Ferrara N, Donner DB (1996) Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma. J Biol Chem 271:29483–29488.

    PubMed  CAS  Google Scholar 

  • Wizigmann Voos S, Breier G, Risau W, Plate KH (1995) Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 55:1358–1364.

    PubMed  CAS  Google Scholar 

  • Yamaguchi TP, Dumont DJ, Conlon RA, Breitman ML, Rossant J (1993) flk-1, an fit-related receptor tyrosine kinase is an early marker for endothelial cell precursors. Development 118:489–898.

    PubMed  CAS  Google Scholar 

  • Yang R, Thomas GR, Bunting S, Ko A, Ferrara N, Keyt B, Ross J, Jin H (1996) Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J Cardiovasc Pharmacol 27:838–844.

    PubMed  CAS  Google Scholar 

  • Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP (1996) Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res 56:2013–2016.

    PubMed  CAS  Google Scholar 

  • Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK (1996) Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 93:14765–14770.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular Research, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA, 94080, USA

    N. Ferrara

Authors
  1. N. Ferrara
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medical Biochemistry and Microbiology Biomedical Center, University of Uppsala, Box 575, Uppsala, S-75123, Sweden

    Lena Claesson-Welsh

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Ferrara, N. (1999). Vascular Endothelial Growth Factor: Molecular and Biological Aspects. In: Claesson-Welsh, L. (eds) Vascular Growth Factors and Angiogenesis. Current Topics in Microbiology and Immunology, vol 237. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59953-8_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-59953-8_1

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64195-4

  • Online ISBN: 978-3-642-59953-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation