Vascular endothelial growth factor (VEGF) and its receptors

FASEB Journal

Volumn 13, Issue 1, 1999, Pages 9-22

  Neufeld, Gera ^a   Cohen, Tzafra ^a   Gengrinovitch, Stela ^a   Poltorak, Zoya ^a  

^a TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

Author keywords

Angiogenesis; Cytokine; Heparan sulfate proteoglycan; Hypoxia; Oncogene

Indexed keywords

VASCULOTROPIN; VASCULOTROPIN RECEPTOR;

ANGIOGENESIS; CELL SURFACE; GROWTH REGULATION; HUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIUM;

EID: 0032907687     PISSN: 08926638     EISSN: None     Source Type: Journal    
DOI: 10.1096/fasebj.13.1.9     Document Type: Review

References (182)

1. Gospodarowicz, D., Abraham, J. A., and Schilling, J. (1989) Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc. Natl. Acad. Sci. USA 86, 7311-7315
2. Ferrara, N., and Henzel, W. J. (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161, 851-858
3. Senger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harvey, V. S., and Dvorak, H. F. (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983-985
4. Keck, P. J., Hauser, S. D., Krivi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, D. T. (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246, 1309-1312
5. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V., and Ferrara, N. (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306-1309
6. Tischer, E., Gospodarowicz, D., Mitchell, R., Silva, M., Schilling, J., Lau, K., Crisp, T., Fiddes, J. C., and Abraham, J. A. (1989) Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem. Biophys. Res. Commun. 165, 1198-1206
7. Vaisman, N., Gospodarowicz, D., and Neufeld, G. (1990) Characterization of the receptors for vascular endothelial growth factor. J. Biol. Chem. 265, 19461-19466
8. Plouet, J., and Moukadiri, H. (1990) Characterization of the receptor to vasculotropin on bovine adrenal cortex-derived capillary endothelial cells. J. Biol. Chem. 265, 22071-22074
9. Devries, C., Escobedo, J. A., Ueno, H., Houck, K., Ferrara, N., and Williams, L. T. (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255, 989-991
10. Terman, B. I., Dougher-Vermazen, M., Carrion, M. E., Dimitrov, D., Armellino, D. C., Gospodarowicz, D., and 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
11. Shweiki, D., Itin, A., Neufeld, G., Gitay-Goren, H., and Keshet, E. (1993) Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally-regulated angiogenesis. J. Clin. Invest. 91, 2235-2243
12. Jakeman, L. B., Armanini, M., Phillips, H. S., and Ferrara, N. (1993) Developmental expression of binding sites and messenger ribonucleic acid for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis. Endocrinology 133, 848-859
13. Kim, K. J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H. S., and Ferrara, N. (1993) Inhibition of vascular endothelial growth factor induced angiogenesis suppresses tumour growth in vivo. Nature (London) 362, 841-844
14. Millauer, B., Shawver, L. K., Plate, K. H., Risau, W., and Ullrich, A. (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature (London) 367, 576-579
15. Shweiki, D., Itin, A., Soffer, D., and Keshet, E. (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature (London) 359, 843-845
16. Plate, K. H., Breier, G., Weich, H. A., and Risau, W. (1992) Vascular endothelial growth factor is a potent tumour angiogenesis factor in human gliomas in vivo. Nature (London) 359, 845-848
17. Aiello, L. P., Avery, R. L., Arrigg, P. G., Keyt, B. A., Jampel, H. D., Shah, S. T., Pasquale, L. R., Thieme, H., Iwamoto, M. A., Park, J. E., Nguyen, H. V., Aiello, L. M., Ferrara, N., and King, G. L. (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331, 1480-1487
18. Adamis, A. P., Miller, J. W., Bernal, M. T., Damico, D. J., Folkman, J., Yeo, T. K., and Yeo, K. T. (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 118, 445-450
19. Brown, L. F., Yeo, K.-T., Berse, B., Yeo, T.-K., Senger, D. R., Dvorak, H. F., and Van de Water, L. (1992) Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J. Exp. Med. 176, 1375-1379
20. Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P., and Persico, M. G. (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl. Acad. Sci. USA 88, 9267-9271
21. Korpelainen, E. I., and Alitalo, K. (1998) Signaling angiogenesis and lymphangiogenesis. Curr. Opin. Cell Biol. 10, 159-164
22. Joukov, V., Kaipainen, A., Jeltsch, M., Pajusola, K., Olofsson, B., Kumar, V., Eriksson, U., and Alitalo, K. (1997) Vascular endothelial growth factors VEGF-B and VEGF-C. J. Cell. Physiol. 173, 211-215
23. Flamme, I., Frolich, T., and Risau, W. (1997) Molecular mechanisms of vasculogenesis and embryonic angiogenesis. J. Cell. Physiol. 173, 206-210
24. Brown, L. F., Detmar, M., Claffey, K., Nagy, J. A., Feng, D., Dvorak, A. M., and Dvorak, H. F. (1997) Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. In: Regulation of Angiogenesis (Goldberd, I. D., and Rosen, E. M., eds) pp. 233-269, Birkhauser Verlag, Basel
25. Risau, W. (1997) Mechanisms of angiogenesis. Nature (London) 386, 671-674
26. Ferrara, N., Carvermoore, K., Chen, H., Dowd, M., Lu, L., Oshea, K. S., Powellbraxton, L., Hillan, K. J., and Moore, M. W. (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature (London) 380, 439-442
27. 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., and Nagy, A. (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature (London) 380, 435-439
28. Shalaby, F., Rossant, J., Yamaguchi, T. P., Gertsenstein, M., Wu, X. F., Breitman, M. L., and Schuh, A. C. (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature (London) 376, 62-66
29. Fong, G. H., Rossant, J., Gertsenstein, M., and Breitman, M. L. (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature (London) 376, 66-70
30. Shalaby, F., Ho, J., Stanford, W. L., Fischer, K. D., Schuh, A. C., Schwartz, L., Bernstein, A., and Rossant, J. (1997) A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 89, 981-990
31. Barleon, B., Sozzani, S., Zhou, D., Weich, H. A., Mantovani, A., and 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
32. Seetharam, L., Gotoh, N., Maru, Y., Neufeld, G., Yamaguchi, S., and Shibuya, M. (1995) A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor (VEGF). Oncogene 10, 135-147
33. Stone, J., Itin, A., Alon, T., Peer, J., Gnessin, H., Chanling, T., and 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
34. Pierce, E. A., Avery, R. L., Foley, E. D., Aiello, L. P., and Smith, L. E. H. (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc. Natl. Acad. Sci. USA 92, 905-909
35. Alon, T., Hemo, I., Itin, A., Peer, J., Stone, J., and Keshet, E. (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Med. 1, 1024-1028
36. Benjamin, L. E., Hemo, I., and Keshet, E. (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the pre-formed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591-1598
37. Pierce, E. A., Foley, E. D., and Smith, L. E. H. (1996) Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch. Ophthalmol. 114, 1219-1228
38. Stone, J., Chanling, T., Peer, J., Itin, A., Gnessin, H., and Keshet, E. (1996) Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest. Ophthalmol. Visual Sci. 37, 290-299
39. Peer, J., Shweiki, D., Itin, A., Hemo, I., Gnessin, H., and Keshet, E. (1995) Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab. Invest. 72, 638-645
40. Aiello, L. P. (1997) Vascular endothelial growth factor and the eye: Biochemical mechanisms of action and implications for novel therapies. Ophthalmic Res. 29, 354-362
41. Okamoto, N., Tobe, T., Hackett, S. F., Ozaki, H., Vinores, M. A., LaRochelle, W., Zack, D. J., and Campochiaro, P. A. (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am. J. Pathol. 151, 281-291
42. Drake, C. J., and Little, C. D. (1995) Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc. Natl. Acad. Sci. USA 92, 7657-7661
43. Ferrara, N., Chen, H., Davis-Smyth, T., Gerber, H. P., Nguyen, T. N., Peers, D., Chisholm, V., Hillan, K. J., and Schwall, R. H. (1998) Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat. Med. 4, 336-340
44. Folkman, J. (1998) Is tissue mass regulated by vascular endothelial cells? Prostate as the first evidence. Endocrinology 139, 441-442
45. Hanahan, D., and Folkman, J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353-364
46. Folkman, J. (1990) What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst. 82, 4-7
47. Esser, S., Wolburg, K., Wolburg, H., Breier, G., Kurzchalia, T., and Risau, W. (1998) Vascular endothelial growth factor induces endothelial fenestrations in vitro. J. Cell Biol. 140, 947-959
48. Roberts, W. G., and Palade, G. E. (1997) Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res. 57, 765-772
49. Dvorak, A. M., Kohn, S., Morgan, E. S., Fox, P., Nagy, J. A., and Dvorak, H. F. (1996) The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J. Leukocyte Biol. 59, 100-115
50. Dvorak, H. F., Nagy, J. A., Berse, B., Brown, L. F., Yeo, K. T., Yeo, T. K., Dvorak, A. M., Vandewater, L., Sioussat, T. M., and Senger, D. R. (1992) Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann. N.Y. Acad. Sci. 667, 110-111
51. Grugel, S., Finkenzeller, G., Weindel, K., Barleon, B., and 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
52. Rak, J., Mitsuhashi, Y., Bayko, L., Filmus, J., Shirasawa, S., Sasazuki, T., and Kerbel, R. S. (1995) Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Res. 55, 4575-4580
53. Kieser, A., Welch, H. A., Brandner, G., Marme, D., and Kolch, W. (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9, 963-969
54. Levy, A. P., Levy, N. S., and Goldberg, M. A. (1996) Hypoxia-inducible protein binding to vascular endothelial growth factor mRNA and its modulation by the von Hippel-Lindau protein. J. Biol. Chem. 271, 25492-25497
55. Schiffenbauer, Y. S., Abramovitch, R., Meir, G., Nevo, N., Holzinger, M., Itin, A., Keshet, E., and Neeman, M. (1997) Loss of ovarian function promotes angiogenesis in human ovarian carcinoma. Proc. Natl. Acad. Sci. USA 94, 13203-13208
56. Shweiki, D., Neeman, M., Itin, A., and Keshet, E. (1995) Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: Implications for tumor angiogenesis. Proc. Natl. Acad. Sci. USA 92, 768-772
57. Albini, A., Soldi, R., Giunciuglio, D., Giraudo, E., Benelli, R., Primo, L., Noonan, D., Salio, M., Camussi, G., Rockl, W., and Bussolino, F. (1996) The angiogenesis induced by HIV-1 Tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nature Med. 2, 1371-1375
58. Ganem, D. (1997) KSHV and Kaposi's sarcoma: the end of the beginning? Cell 91, 157-160
59. Millauer, B., Longhi, M. P., Plate, K. H., Shawver, L. K., Risau, W., Ullrich, A., and Strawn, L. M. (1996) Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res. 56, 1615-1620
60. Skobe, M., Rockwell, P., Goldstein, N., Vosseler, S., and Fusenig, N. E. (1997) Halting angiogenesis suppresses carcinoma cell invasion. Nature Med. 3, 1222-1227
61. Presta, L. G., Chen, H., O'Connor, S. J., Chisholm, V., Meng, Y. G., Krummen, L., Winkler, M., and Ferrara, N. (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593-4599
62. Kendall, R. L., and Thomas, K. A. (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl. Acad. Sci. USA 90, 10705-10709
63. Lin, P. N., Sankar, S., Shan, S. Q., Dewhirst, M. W., Polverini, P. J., Quinn, T. Q., and Peters, K. G. (1998) Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ. 9, 49-58
64. Cheng, S. Y., Huang, H. J. S., Nagane, M., Ji, X. D., Wang, D. G., Shih, C. C. Y., Arap, W., Huang, C. M., and Cavenee, W. K. (1996) Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc. Natl. Acad. Sci. USA 93, 8502-8507
65. Saleh, M., Stacker, S. A., and Wilks, A. F. (1996) Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res. 56, 393-401
66. Ramakrishnan, S., Olson, T. A., Bautch, V. L., and Mohanraj, D. (1996) Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo. Cancer Res. 56, 1324-1330
67. Siemeister, G., Schirner, M., Reusch, P., Barleon, B., Marme, D., and Martiny-Baron, G. (1998) An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells. Proc. Natl. Acad. Sci. USA 95, 4625-4629
68. Rockwell, P., Neufeld, G., Glassman, A., Caron, D., and Goldstein, N. (1995) in vitro neutralization of vascular endothelial growth factor activation of FLK-1 by a monoclonal antibody. Mol. Cell. Diff. 3, 91-109
69. Strawn, L. M., McMahon, G., App, H., Schreck, R., Kuchler, W. R., Longhi, M. P., Hui, T. H., Tang, C., Levitzki, A., Gazit, A., Chen, I., Keri, G., Orfi, L., Risau, W., Flamme, I., Ullrich, A., Hirth, K. P., and Shawver, L. K. (1996) Flk-1 as a target for tumor growth inhibition. Cancer Res. 56, 3540-3545
70. Walder, C. E., Errett, C. J., Bunting, S., Lindquist, P., Ogez, J. R., Heinsohn, H. G., Ferrara, N., and Thomas, G. R. (1996) Vascular endothelial growth factor augments muscle blood flow and function in a rabbit model of chronic hindlimb ischemia. J. Cardiovasc. Pharmacol. 27, 91-98
71. 165 expressed by a replication-deficient recombinant adenovirus vector induces angiogenesis in vivo. Circ. Res. 77, 1077-1086
72. Isner, J. M., Walsh, K., Symes, J., Pieczek, A., Takeshita, S., Lowry, J., Rosenfield, K., Weir, L., Brogi, E., and Jurayj, D. (1996) Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease. Hum. Gene Ther. 7, 959-988
73. Magovern, C. J., Mack, C. A., Zhang, J., Rosengart, T. K., Isom, O. W., and Crystal, R. G. (1997) Regional angiogenesis induced in nonischemic tissue by an adenoviral vector expressing vascular endothelial growth factor. Hum. Gene Ther. 8, 215-227
74. Asahara, T., Bauters, C., Pastore, C., Kearney, M., Rossow, S., Bunting, S., Ferrara, N., Symes, J. F., and Isner, J. M. (1995) Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation 91, 2793-2801
75. Tsurumi, Y., Kearney, M., Chen, D. F., Silver, M., Takeshita, S., Yang, J. H., Symes, J. F., and Isner, J. M. (1997) Treatment of acute limb ischemia by intramuscular injection of vascular endothelial growth factor gene. Circulation 96, 382-388
76. 165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 97, 1114-1123
77. Deroanne, C. F., Hajitou, A., Calberg-Bacq, C. M., Nusgens, B. V., and Lapiere, C. M. (1997) Angiogenesis by fibroblast growth factor 4 is mediated through an autocrine up-regulation of vascular endothelial growth factor expression. Cancer Res. 57, 5590-5597
78. Finkenzeller, G., Sparacio, A., Technau, A., Marme, D., and Siemeister, G. (1997) Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression. Oncogene 15, 669-676
79. Ryuto, M., Ono, M., Izumi, H., Yoshida, S., Weich, H. A., Kohno, K., and Kuwano, M. (1996) Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells - possible roles of SP-1. J. Biol. Chem. 271, 28220-28228
80. Pertovaara, L., Kaipainen, A., Mustonen, T., Orpana, A., Ferrara, N., Saksela, O., and 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
81. Frank, S., Hubner, G., Breier, G., Longaker, M. T., Greenhalgh, D. G., and Werner, S. (1995) Regulation of vascular endothelial growth factor expression in cultured keratinocytes - implications for normal and impaired wound healing. J. Biol. Chem. 270, 12607-12613
82. Goad, D. L., Rubin, J., Wang, H., Tashjian, A. H., and Patterson, C. (1996) Enhanced expression of vascular endothelial growth factor in human SaOS-2 osteoblast-like cells and murine osteoblasts induced by insulin-like growth factor I. Endocrinology 137, 2262-2268
83. Li, J., Perrella, M. A., Tsai, J. C., Yet, S. F., Hsieh, C. M., Yoshizumi, M., Patterson, C., Endege, W. O., Zhou, F., and Lee, M. E. (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
84. Cohen, T., Nahari, D., Cerem-Weiss, L., Neufeld, G., and Levi, B. (1996) Interleukin-6 induces the expression of vascular endothelial growth factor. J. Biol. Chem. 271, 736-741
85. Matsumoto, K., Ohi, H., and Kanmatsuse, K. (1997) Interleukin 10 and interleukin 13 synergize to inhibit vascular permeability factor release by peripheral blood mononuclear cells from patients with lipoid nephrosis. Nephron 77, 212-218
86. Werner, S., Smola, H., Liao, X., Longaker, M. T., Krieg, T., Hofschneider, P. H., and Williams, L. T. (1994) The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science 266, 819-822
87. 121 to one of the three VEGF receptors of vascular endothelial cells. J. Biol. Chem. 271, 5519-5523
88. Brauchle, M., Funk, J. O., Kind, P., and Werner, S. (1996) Ultraviolet B and H2O2 are potent inducers of vascular endothelial growth factor expression in cultured keratinocytes. J. Biol. Chem. 271, 21793-21797
89. Tuder, R. M., Flook, B. E., and Voelkel, N. F. (1995) Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia - modulation of gene expression by nitric oxide. J. Clin. Invest. 95, 1798-1807
90. Chin, K., Kurashima, Y., Ogura, T., Tajiri, H., Yoshida, S., and Esumi, H. (1997) Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells. Oncogene 15, 437-442
91. Murohara, T., Horowitz, J. R., Silver, M., Tsurumi, Y., Chen, D. F., Sullivan, A., and Isner, J. M. (1998) Vascular endothelial growth factor vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 97, 99-107
92. Dembinskakiec, A., Dulak, J., Partyka, L., Huk, I., and Mailnski, T. (1997) VEGF - nitric oxide reciprocal regulation. Nature Med. 3, 1177
93. Hood, J. D., Meininger, C. J., Ziche, M., and Granger, H. J. (1998) VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am. J. Physiol. 274, H1054-H1058
94. Jeltsch, M., Kaipainen, A., Joukov, V., Meng, X. J., Lakso, M., Rauvala, H., Swartz, M., Fukumura, D., Jain, R. K., and Alitalo, K. (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276, 1423-1425
95. Enholm, B., Paavonen, K., Ristimaeki, A., Kumar, V., Gunji, Y., Klefstrom, J., Kivinen, L., Laiho, M., Olofsson, B., Joukov, V., Eriksson, U., and Alitalo, K. (1997) Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14, 2475-2483
96. Goldberg, M. A., and Schneider, T. J. (1994) Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J. Biol. Chem. 269, 4355-4359
97. Levy, A. P., Levy, N. S., Wegner, S., and Goldberg, M. A. (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J. Biol. Chem. 270, 13333-13340
98. Liu, Y. X., Cox, S. R., Morita, T., and Kourembanas, S. (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells - identification of a 5′ enhancer. Circ. Res. 77, 638-643
99. Jiang, B. H., Agani, F., Passaniti, A., and Semenza, G. L. (1997) V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: Involvement of HIF-1 in tumor progression. Cancer Res. 57, 5328-5335
100. Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., and Fujiikuriyama, Y. (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1 alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl. Acad. Sci. USA 94, 4273-4278
101. Flamme, I., Frohlich, T., Vonreutern, M., Kappel, A., Damert, A., and Risau, W. (1997) HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech. Dev. 63, 51-60
102. Stein, I., Neeman, M., Shweiki, D., Itin, A., and Keshet, E. (1995) Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol. Cell Biol. 15, 5363-5368
103. Damert, A., Machein, M., Breier, G., Fujita, M. Q., Hanahan, D., Risau, W., and Plate, K. H. (1997) Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms. Cancer Res._57, 3860-3864
104. Claffey, K. P., Shih, S. C., Mullen, A., Dziennis, S., Cusick, J. L., Abrams, K. R., Lee, S. W., and Detmar, M. (1998) Identification of a human VPF/VEGF 3′ untranslated region mediating hypoxia-induced mRNA stability. Mol. Biol. Cell 9, 469-481
105. Levy, N. S., Chung, S., Furneaux, H., and Levy, A. P. (1998) Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J. Biol. Chem. 273, 6417-6423
106. Stein, I., Itin, A., Einat, P., Skaliter, R., Grossman, Z., and Keshet, E. (1998) Translation of vascular endothelial growth factor mRNA by internal ribosome entry : implications for translation under hypoxia. Mol. Biol. Cell. 18, 3112-3119
107. Akiri, G., Nahari, D., Finkelstein, Y., Le, S., Elroy-Stein, O., and Levi, B. (1998) Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription. Oncogene 12, 227-236.
108. Maher, E. R., and Kaelin, W. G., Jr. (1997) von Hippel-Lindau disease. Medicine (Baltimore) 76, 381-391
109. Siemeister, G., Weindel, K., Mohrs, K., Barleon, B., Martinybaron, G., and 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
110. Stratmann, R., Krieg, M., Haas, R., and Plate, K. H. (1997) Putative control of angiogenesis in hemangioblastomas by the von Hippel-Lindau tumor suppressor gene. J. Neuropathol. Exp. Neurol. 56, 1242-1252
111. Mukhopadhyay, D., Knebelmann, B., Cohen, H. T., Ananth, S., and Sukhatme, V. P. (1997) The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol. Cell Biol. 17, 5629-5639
112. Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin, W. G., Jr., and Goldberg, M. A. (1996) Negative regulation of hypoxia-inducible genes by the von Hippel Lindau protein. Proc. Natl. Acad. Sci. USA 93, 10595-10599
113. Pal, S., Claffey, K. P., Dvorak, H. F., and Mukhopadhyay, D. (1997) The von Hippel-Lindau gene product inhibits vascular permeability factor vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. J. Biol. Chem. 272, 27509-27512
114. Kourembanas, S., Morita, T., Liu, Y., and Christou, H. (1997) Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature. Kidney Int. 51, 438-443
115. Vanmeir, E. G., Polverini, P. J., Chazin, V. R., Huang, H. J. S., Detribolet, N., and Cavenee, W. K. (1994) Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat. Genet. 8, 171-176
116. Mukhopadhyay, D., Tsiokas, L., and Sukhatme, V. P. (1995) Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55, 6161-6165
117. Agani, F., Kirsch, D. G., Friedman, S. L., Kastan, M. B., and Semenza, G. L. (1997) p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene. Cancer Res. 57, 4474-4477
118. Houck, K. A., Ferrara, N., Winer, J., Cachianes, G., Li, B., and Leung, D. W. (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
119. 145: a secreted VEGF form that binds to extracellular matrix. J. Biol. Chem. 272, 7151-7158
120. Tischer, E., Mitchell, R., Hartman, T., Silva, M., Gospodarowicz, D., Fiddes, J. C., and Abraham, J. A. (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266, 11947-11954
121. Park, J. E., Keller, G. A., and Ferrara, N. (1993) Vascular endothelial growth factor (VEGF) isoforms - differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol. Cell 4, 1317-1326
122. 121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells. J. Biol. Chem. 270, 11322-11326
123. Cheng, S. Y., Nagane, M., Huang, H. J. S., and Cavenee, W. K. (1997) Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF(121) and VEGF(165) but not VEGF(189). Proc. Natl. Acad. Sci. USA 94, 12081-12087
124. Plouet, J., Moro, F., Bertagnolli, S., Coldeboeuf, N., Mazarguil, H., Clamens, S., and Bayard, F. (1997) Extracellular cleavage of the vascular endothelial growth factor 189 amino acid form by urokinase is required for its mitogenic effect. J. Biol. Chem. 272, 13390-13396
125. Houck, K. A., Leung, D. W., Rowland, A. M., Winer, J., and Ferrara, N. (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem. 267, 26031-26037
126. Zhang, H. T., Craft, P., Scott, P. A. E., Ziche, M., Weich, H. A., Harris, A. L., and Bicknell, R. (1995) Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J. Natl. Cancer Inst. 87, 213-219
127. Bacic, M., Edwards, N. A., and Merrill, M. J. (1995) Differential expression of vascular endothelial growth factor (vascular permeability factor) forms in rat tissues - Short Communication. Growth Factors 12, 11-15
128. Charnock-Jones, S. D., Sharkey, A. M., Rajput-Williams, J., Burch, D., Schofield, J. P., Fountain, S. A., Boocock, C., and Smith, S. K. (1993) Identification and localization of alternatively spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biol. Reprod. 48, 1120-1128
129. Cheung, C. Y., Singh, M., Ebaugh, M. J., and Brace, R. A. (1995) Vascular endothelial growth factor gene expression in ovine placenta and fetal membranes. Am. J. Obstet. Gynecol. 173, 753-759
130. Jonca, F., Ortega, N., Gleizes, P. E., Bertrand, N., and Plouet, J. (1997) Cell release of bioactive fibroblast growth factor 2 by exon 6′-encoded sequence of vascular endothelial growth factor. J. Biol. Chem. 272, 24203-24209
131. Asahara, T., Bauters, C., Zheng, L. P., Takeshita, S., Bunting, S., Ferrara, N., Symes, J. F., and Isner, J. M. (1995) Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation 92, 365-371
132. Schlessinger, J., Lax, I., and Lemmon, M. (1995) Regulation of growth factor activation by proteoglycans: What is the role of the low affinity receptors? Cell 83, 357-360
133. Gitay-Goren, H., Soker, S., Vlodavsky, I., and Neufeld, G. (1992) The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules. J. Biol. Chem. 267, 6093-6098
134. Weksberg, R., Squire, J. A., and Templeton, D. M. (1996) Glypicans: a growing trend. Nat. Genet. 12, 225-227.
135. Keyt, B. A., Berleau, L. T., Nguyen, H. V., Chen, H., Heinsohn, H., Vandlen, R., and 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
136. Siemeister, G., Schnurr, B., Mohrs, K., Schachtele, C., Marme, D., and Martinybaron, G. (1996) Expression of biologically active isoforms of the tumor angiogenesis factor VEGF in Escherichia coli. Biochem. Biophys. Res. Commun. 222, 249-255
137. Dougher, A. M., Wasserstrom, H., Torley, L., Shridaran, L., Westdock, P., Hileman, R. E., Fromm, J. R., Anderberg, R., Lyman, S., Linhardt, R. J., Kaplan, J., and Terman, B. I. (1997) Identification of a heparin binding peptide on the extracellular domain of the KDR VEGF receptor. Growth Factors 14, 257-268
138. Chiang, M. K., and Flanagan, J. G. (1990) Interactions between the Flk-1 receptor, vascular endothelial growth factor, and cell surface proteoglycan identified with a soluble receptor reagent. Growth Factors 12, 1-10
139. Matthews, W., Jordan, C. T., Weigand, G. W., Pardoll, D., and Lemischka, I. R. (1991) A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell enriched populations. Cell 65, 1143-1152
140. Shibuya, M., Yamaguchi, S., Yamane, A., Ikeda, T., Tojo, A., Matsushime, H., and Sato, M. (1990) Nucleotide sequence and expression of a novel human receptor type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5, 519-524
141. Jussila, L., Valtola, R., Partanen, T. A., Salven, P., Heikkilae, P., Matikainen, M. T., Renkonen, R., Kaipainen, A., Detmar, M., Tschachler, E., Alitalo, R., and Alitalo, K. (1998) Lymphatic endothelium and Kaposi's sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res. 58, 1599-1604
142. Fournier, E., Birnbaum, D., and Borg, J. P. (1997) Receptors for factors of the VEGF family. Bull. Cancer 84, 397-403
143. Charnockjones, D. S., Sharkey, A. M., Boocock, C. A., Ahmed, A., Plevin, R., Ferrara, N., and Smith, S. K. (1994) Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol. Reprod. 51, 524-530
144. Takahashi, T., Shirasawa, T., Miyake, K., Yahagi, Y., Maruyama, N., Kasahara, N., Kawamura, T., Matsumura, O., Mitarai, T., and Sakai, O. (1995) Protein tyrosine kinases expressed in glomeruli and cultured glomerular cells: FLT-1 and VEGF expression in renal mesangial cells. Biochem. Biophys. Res. Commun. 209, 218-226
145. Katoh, O., Tauchi, H., Kawaishi, K., Kimura, A., and 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
146. Yang, X. J., and Cepko, C. L. (1996) Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J. Neurosci. 16, 6089-6099
147. Wen, Y., Edelman, J. L., Kang, T., Zeng, N. X., and Sachs, G. (1998) Two functional forms of vascular endothelial growth factor receptor-2 Flk-1 mRNA are expressed in normal rat retina. J. Biol. Chem. 273, 2090-2097
148. Gitay-Goren, H., Halaban, R., and Neufeld, G. (1993) Human melanoma cells but not normal melanocytes express vascular endothelial growth factor receptors. Biochem. Biophys. Res. Commun. 190, 702-709
149. Terman, B. I., Khandke, L., Doughervermazan, M., Maglione, D., Lassam, N. J., Gospodarowicz, D., Persico, M. G., Bohlen, P., and Eisinger, M. (1994) VEGF receptor subtypes KDR and FLT1 show different sensitivities to heparin and placenta growth factor. Growth Factors 11, 187-195
150. Takahashi, T., and Shibuya, M. (1997) The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene 14, 2079-2089
151. Gerber, H. P., Condorelli, F., Park, J., and Ferrara, N. (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes, flt-1, but not flk-1/kdr, is up-regulated by hypoxia. J. Biol. Chem. 272, 23659-23667
152. Waltenberger, J., Mayr, U., Pentz, S., and Hombach, V. (1996) Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94, 1647-1654
153. Wilting, J., Birkenhager, R., Eichmann, A., Kurz, H., Martinybaron, G., Marme, D., McCarthy, J. E. G., Christ, B., and Weich, H. A. (1996) VEGF (121) induces proliferation of vascular endothelial cells and expression of flk-1 without affecting lymphatic vessels of the chorioallantoic membrane. Dev. Biol. 176, 76-85
154. Barleon, B., Siemeister, G., Martinybaron, G., Weindel, K., Herzog, C., and Marme, D. (1997) Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells. Cancer Res. 57, 5421-5425
155. Keyt, B. A., Nguyen, H. V., Berleau, L. T., Duarte, C. M., Park, J., Chen, H., and Ferrara, N. (1996) 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, 5638-0646
156. Muller, Y. A., Christinger, H. W., Keyt, B. A., and Devos, A. M. (1997) The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 angstrom resolution: multiple copy flexibility and receptor binding. Structure. 5, 1325-1338
157. Wiesmann, C., Fuh, G., Christinger, H. W., Eigenbrot, C., Wells, J. A., and Devos, A. M. (1997) Crystal structure at 1.7 angstrom resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91, 695-704
158. Fuh, G., Li, B., Crowley, C., Cunningham, B., and Wells J. A. (1998) Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor. J. Biol. Chem. 273, 11197-11204
159. Kendall, R. L., Wang, G., and Thomas, K. A. (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
160. Davis-Smyth, T., Chen, H., Park, J., Presta, L. G., and Ferrara, N. (1996) The second immunoglobulin-like domain of the VEGF tyrosine kinase receptor Fit-1 determines ligand binding and may initiate a signal transduction cascade. EMBO J. 15, 4919-4927
161. Davis-Smyth, T., Presta, L. G., and Ferrara, N. (1998) Mapping the charged residues in the second immunoglobulin-like domain of the vascular endothelial growth Factor/Placenta growth factor receptor flt-1 required for binding and structural stability. J. Biol. Chem. 273, 3216-3222
162. Barleon, B., Totzke, F., Herzog, C., Blanke, S., Kremmer, E., Siemeister, G., Marme, D., and Martiny-Baron, G. (1997) Mapping of the sites for ligand binding and receptor dimerization at the extracellular domain of the vascular endothelial growth factor receptor FLT-1. J. Biol. Chem. 272, 10382-10388
163. Blechman, J. M., Lev, S., Barg. J., Eisenstein, M., Vaks, B., Vogel, Z., Givol, D., and Yarden, Y. (1995) The fourth immunoglobulin domain of the stem cell factor receptor couples ligand binding to signal transduction. Cell 80, 103-113
164. Kondo, K., Hiratuska, S., Subbalakshmi, E., Matsushime, H., and Shibuya, M. (1998) Genomic organization of the flt-1 gene encoding for vascular endothelial growth factor (VEGF) receptor-1 suggests an intimate evolutionary relationship between the 7-lg and the 5-lg tyrosine kinase receptors. Gene 208, 297-305
165. Waltenberger, J., Claessonwelsh, L., Siegbahn, A., Shibuya, M., and Heldin, C. H. (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J. Biol. Chem. 269, 26988-26995
166. Yoshida, A., Anand-Apte, B., and Zetter, B. R. (1996) Differential endothelial migration and proliferation to basic fibroblast growth factor and vascular endothelial growth factor. Growth Factors 13, 57-64
167. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G., and 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
168. Kroll, J., and Waltenberger, J. (1997) The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J. Biol. Chem. 272, 32521-32527
169. Unemori, E. N., Ferrara, N., Bauer, E. A., and Amento, E. P. (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J. Cell. Physiol. 153, 557-562
170. Pepper, M. S., Ferrara, N., Orci, L., and Montesano, R. (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhihitor-1 in microvascular endothelial cells. Biochem. Biophys. Res. Commun. 181, 902-906
171. Lamoreaux, W. J., Fitzgerald, M. E. C., Reiner, A., Hasty, K. A., and Charles, S. T. (1998) Vascular endothelial growth factor increases release of gelatinase a and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc. Res. 55, 29-42
172. Friedlander, M., Brooks, P. C., Shaffer, R. W., Kincaid, C. M., Varner, J. A., and Cheresh, D. A. (1995) Definition of two angiogenic pathways by distinct alpha(v) integrins. Science 270, 1500-1502
173. 121. J. Biol. Chem. 271, 5761-5767
174. 165. J. Biol. Chem. 272, 31582-31588
175. He, Z., and Tessier-Lavigne, M. (1997) Neuropilin is a receptor for the axonal chemorepellent semaphorin III. Cell 90, 739-751
176. Kolodkin, A. L., Levengood, D. V., Rowe, E. G., Tai, Y. T., Giger, R. J., and Ginty, D. D. (1997) Neuropilin is a semaphorin III receptor. Cell 90, 753-762
177. Migdal, M., Huppertz, B., Tessler, S., Comforti, A., Shibuya, M., Reich, R., Baumann, H., and Neufeld, G. (1998) Neuropilin-1 is a placenta growth factor-2 receptor. J. Biol. Chem. 273, 22272-22278
178. Kitsukawa, T., Shimizu, M., Sanbo, M., Hirata, T., Taniguchi, M., Bekku, Y., Yagi, T., and Fujisawa, H. (1997) Neuropilinsemaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19, 995-1005
179. Clauss, M., Weich, H., Breier, G., Knies, U., Roeckl, W., Waltenberger, J., and Risau, W. (1996) The vascular endothelial growth factor receptor Flt-1 mediates biological activities - implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J. Biol. Chem. 271, 17629-17634
180. Omura, T., Miyazawa, K., Ostman, A., and Heldin, C. H. (1997) Identification of a 190-kDa vascular endothelial growth factor 165 cell surface binding protein on a human glioma cell line. J. Biol. Chem. 272, 23317-23322
181. Folkman, J. (1997) Angiogenesis and angiogenesis inhibition: an overview. In: Regulation of Angiogenesis (Goldberg, I. D., and Rosen, E. M., eds) pp. 1-8, Birkhauser Verlag, Basel
182. Chen, H., Chedotal, A., He, Z., Goodman, C. S., and Tessier-Lavigne, M. (1997) Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 19, 547-559