Skip to main content
SpringerLink
Log in

Angiogenic Signalling Pathways

  • Protocol
  • First Online:
Angiogenesis Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 467))

Abstract

Hypoxia is widely recognised as a key driving force for tumour angiogenesis by its induction of vascular endothelial growth factor (VEGF) and other direct-acting angiogenic factors. We describe the effect of hypoxia on gene expression and downstream angiogenic signalling; however, the angiogenic process is complex, and many other signalling pathways beyond VEGF are implicated in the formation of new vessels. These include extra-cellular signalling pathways such as the notch/delta, ephrin/Eph receptor, roundabout/slit, and netrin/UNC (uncoordinated) receptor families as well as intracellular proteins such as hedgehog and sprouty. The remarkable diversity in angiogenic signalling pathways provides many opportunities for therapeutic intervention, and anti-angiogenesis is currently a major area of oncology research.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
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 EPUB and 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
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Eskens, F. A. (2004) Angiogenesis inhibitors in clinical development; where are we now and where are we going? Br J Cancer 90, 1–7.

    Article  PubMed  CAS  Google Scholar 

  2. Tonini, T., Rossi, F., Claudio, P. P. (2003) Molecular basis of angiogenesis and cancer. Oncogene 22, 6549–6556.

    Article  PubMed  CAS  Google Scholar 

  3. Bicknell, R., Harris, A. L. (2004) Novel angiogenic signaling pathways and vascular targets. Annu Rev Pharmacol Toxicol 44, 219–238.

    Article  PubMed  CAS  Google Scholar 

  4. Sullivan, D. C., Bicknell, R. (2003) New molecular pathways in angiogenesis. Br J Cancer 89, 228–231.

    Article  PubMed  CAS  Google Scholar 

  5. Carmeliet, P. (2003) Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 4, 710–720.

    Article  PubMed  CAS  Google Scholar 

  6. Martin, P., Lewis, J. (1989) Origins of the neurovascular bundle: interactions between developing nerves and blood vessels in embryonic chick skin. Int J Dev Biol 33, 379–387.

    PubMed  CAS  Google Scholar 

  7. Honma, Y., Araki, T., Gianino, S., (2002) Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35, 267–282.

    Article  PubMed  CAS  Google Scholar 

  8. Kuruvilla, R., Zweifel, L. S., Glebova, N. O., (2004) A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118, 243–255.

    Article  PubMed  CAS  Google Scholar 

  9. Mukouyama, Y. S., Shin, D., Britsch, S., Taniguchi, M., Anderson, D. J. (2002) Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 109, 693–705.

    Article  PubMed  CAS  Google Scholar 

  10. Harris, A. L. (2002) Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2, 38–47.

    Article  PubMed  CAS  Google Scholar 

  11. Wenger, R. H. (2002) Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 16, 1151–1162.

    Article  PubMed  CAS  Google Scholar 

  12. Ivan, M., Kondo, K., Yang, H., (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468.

    Article  PubMed  CAS  Google Scholar 

  13. Leek, R. D., Talks, K. L., Pezzella, F., (2002) Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer. Cancer Res 62, 1326–1329.

    PubMed  CAS  Google Scholar 

  14. Pilch, H., Schlenger, K., Steiner, E., Brockerhoff, P., Knapstein, P., Vaupel, P. (2001) Hypoxia-stimulated expression of angiogenic growth factors in cervical cancer cells and cervical cancer-derived fibroblasts. Int J Gynecol Cancer 11, 137–142.

    Article  PubMed  CAS  Google Scholar 

  15. Ozawa, K., Kondo, T., Hori, O., (2001) Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. J Clin Invest 108, 41–50.

    PubMed  CAS  Google Scholar 

  16. Shimo, T., Kubota, S., Kondo, S., (2001) Connective tissue growth factor as a major angiogenic agent that is induced by hypoxia in a human breast cancer cell line. Cancer Lett 174, 57–64.

    Article  PubMed  CAS  Google Scholar 

  17. Kondo, S., Kubota, S., Shimo, T., (2002) Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis 23, 769–776.

    Article  PubMed  CAS  Google Scholar 

  18. Ambrosini, G., Nath, A. K., Sierra-Honigmann, M. R., Flores-Riveros, J. (2002) Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem 277, 34601–34609.

    Article  PubMed  CAS  Google Scholar 

  19. Hitchon, C., Wong, K., Ma, G., Reed, J., Lyttle, D., El-Gabalawy, H. (2002) Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 46, 2587–2597.

    Article  PubMed  CAS  Google Scholar 

  20. Bacher, M., Schrader, J., Thompson, N., (2003) Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. Am J Pathol 162, 11–17.

    Article  PubMed  CAS  Google Scholar 

  21. Green, C. J., Lichtlen, P., Huynh, N. T., (2001) Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1. Cancer Res 61, 2696–2703.

    PubMed  CAS  Google Scholar 

  22. Murray, B., Wilson, D. J. (2001) A study of metabolites as intermediate effectors in angiogenesis. Angiogenesis 4, 71–77.

    Article  PubMed  CAS  Google Scholar 

  23. Senger, D. R., Connolly, D. T., Van de Water, L., Feder, J., Dvorak, H. F. (1990) Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 50, 1774–1778.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  25. Olsson, A. K., Dimberg, A., Kreuger, J., Claesson-Welsh, L. (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7, 359–371.

    Article  PubMed  CAS  Google Scholar 

  26. Fong, G. H., Rossant, J., Gertsenstein, M., Breitman, M. L. (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70.

    Article  PubMed  CAS  Google Scholar 

  27. Kendall, R. L., Thomas, K. A. (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A 90, 10705–10709.

    Article  PubMed  CAS  Google Scholar 

  28. Goldman, C. K., Kendall, R. L., Cabrera, G., (1998) Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, mortality rate. Proc Natl Acad Sci U S A 95, 8795–8800.

    Article  PubMed  CAS  Google Scholar 

  29. Autiero, M., Waltenberger, J., Communi, D., (2003) Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9, 936–943.

    Article  PubMed  CAS  Google Scholar 

  30. Hiratsuka, S., Maru, Y., Okada, A., Seiki, M., Noda, T., Shibuya, M. (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61, 1207–1213.

    PubMed  CAS  Google Scholar 

  31. Dougher, M., Terman, B. I. (1999) Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization. Oncogene 18, 1619–1627.

    Article  PubMed  CAS  Google Scholar 

  32. Takahashi, T., Yamaguchi, S., Chida, K., Shibuya, M. (2001) A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J 20, 2768–2778.

    Article  PubMed  CAS  Google Scholar 

  33. Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N., Shibuya, M. (2005) Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci U S A 102, 1076–1081.

    Article  PubMed  CAS  Google Scholar 

  34. Matsumoto, T., Bohman, S., Dixelius, J., (2005) VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J 24, 2342–2353.

    Article  PubMed  CAS  Google Scholar 

  35. Zeng, H., Sanyal, S., Mukhopadhyay, D. (2001) Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively. J Biol Chem 276, 32714–32719.

    Article  PubMed  CAS  Google Scholar 

  36. Kaipainen, A., Korhonen, J., Mustonen, T., (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92, 3566–3570.

    Article  PubMed  CAS  Google Scholar 

  37. Jussila, L., Alitalo, K. (2002) Vascular growth factors and lymphangiogenesis. Physiol Rev 82, 673–700.

    PubMed  CAS  Google Scholar 

  38. Dumont, D. J., Jussila, L., Taipale, J., (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282, 946–949.

    Article  PubMed  CAS  Google Scholar 

  39. Valtola, R., Salven, P., Heikkila, P., (1999) VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol 154, 1381–1390.

    Article  PubMed  CAS  Google Scholar 

  40. Partanen, T. A., Alitalo, K., Miettinen, M. (1999) Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer 86, 2406–2412.

    Article  PubMed  CAS  Google Scholar 

  41. Wang, J. F., Zhang, X., Groopman, J. E. (2004) Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. J Biol Chem 279, 27088–27097.

    Article  PubMed  CAS  Google Scholar 

  42. Makinen, T., Veikkola, T., Mustjoki, S., (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20, 4762–4773.

    Article  PubMed  CAS  Google Scholar 

  43. Walter, J. W., North, P. E., Waner, M., (2002) Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer 33, 295–303.

    Article  PubMed  CAS  Google Scholar 

  44. Stevens, A., Soden, J., Brenchley, P. E., Ralph, S., Ray, D. W. (2003) Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res 63, 812–816.

    PubMed  CAS  Google Scholar 

  45. Bajou, K., Masson, V., Gerard, R. D., (2001) The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 152, 777–784.

    Article  PubMed  CAS  Google Scholar 

  46. Luttun, A., Tjwa, M., Moons, L., (2002) Revascularization of ischemic tissues by PlGF treatment, inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8, 831–840.

    PubMed  CAS  Google Scholar 

  47. Pipp, F., Heil, M., Issbrucker, K., (2003) VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte-mediated mechanism. Circ Res 92, 378–385.

    Article  PubMed  CAS  Google Scholar 

  48. Adini, A., Kornaga, T., Firoozbakht, F., Benjamin, L. E. (2002) Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res 62, 2749–2752.

    PubMed  CAS  Google Scholar 

  49. Eriksson, A., Cao, R., Pawliuk, R., (2002) Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell 1, 99–108.

    Article  PubMed  CAS  Google Scholar 

  50. Barbera-Guillem, E., Nyhus, J. K., Wolford, C. C., Friece, C. R., Sampsel, J. W. (2002) Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res 62, 7042–7049.

    PubMed  CAS  Google Scholar 

  51. Pasterkamp, R. J., Kolodkin, A. L. (2003) Semaphorin junction: making tracks toward neural connectivity. Curr Opin Neurobiol 13, 79–89.

    Article  PubMed  CAS  Google Scholar 

  52. Kruger, R. P., Aurandt, J., Guan, K. L. (2005) Semaphorins command cells to move. Nat Rev Mol Cell Biol 6, 789–800.

    Article  PubMed  CAS  Google Scholar 

  53. Guttmann-Raviv, N., Kessler, O., Shraga-Heled, N., Lange, T., Herzog, Y., Neufeld, G. (2006) The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett 231, 1–11.

    Article  PubMed  CAS  Google Scholar 

  54. Bagri, A., Tessier-Lavigne, M. (2002) Neuropilins as Semaphorin receptors: in vivo functions in neuronal cell migration and axon guidance. Adv Exp Med Biol 515, 13–31.

    PubMed  CAS  Google Scholar 

  55. Song, H., Ming, G., He, Z., (1998) Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281, 1515–1518.

    Article  PubMed  CAS  Google Scholar 

  56. de Castro, F., Hu, L., Drabkin, H., Sotelo, C., Chedotal, A. (1999) Chemoattraction and chemorepulsion of olfactory bulb axons by different secreted semaphorins. J Neurosci 19, 4428–4436.

    PubMed  CAS  Google Scholar 

  57. Wong, J. T., Wong, S. T., O’Connor, T. P. (1999) Ectopic semaphorin-1a functions as an attractive guidance cue for developing peripheral neurons. Nat Neurosci 2, 798–803.

    Article  PubMed  CAS  Google Scholar 

  58. Bagnard, D., Lohrum, M., Uziel, D., Puschel, A. W., Bolz, J. (1998) Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. Development 125, 5043–5053.

    PubMed  CAS  Google Scholar 

  59. Miao, H. Q., Soker, S., Feiner, L., Alonso, J. L., Raper, J. A., Klagsbrun, M. (1999) Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol 146, 233–242.

    PubMed  CAS  Google Scholar 

  60. Miao, H. Q., Lee, P., Lin, H., Soker, S., Klagsbrun, M. (2000) Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J 14, 2532–2539.

    Article  PubMed  CAS  Google Scholar 

  61. Tse, C., Xiang, R. H., Bracht, T., Naylor, S. L. (2002) Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line. Cancer Res 62, 542–546.

    PubMed  CAS  Google Scholar 

  62. Xiang, R., Davalos, A. R., Hensel, C. H., Zhou, X. J., Tse, C., Naylor, S. L. (2002) Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice. Cancer Res 62, 2637–2643.

    PubMed  CAS  Google Scholar 

  63. Roche, J., Boldog, F., Robinson, M., (1996) Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin. Oncogene 12, 1289–1297.

    PubMed  CAS  Google Scholar 

  64. Brambilla, E., Constantin, B., Drabkin, H., Roche, J. (2000) Semaphorin SEMA3F localization in malignant human lung and cell lines: a suggested role in cell adhesion and cell migration. Am J Pathol 156, 939–950.

    Article  PubMed  CAS  Google Scholar 

  65. Bielenberg, D. R., Hida, Y., Shimizu, A., (2004) Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 114, 1260–1271.

    PubMed  CAS  Google Scholar 

  66. Neufeld, G., Shraga-Heled, N., Lange, T., Guttmann-Raviv, N., Herzog, Y., Kessler, O. (2005) Semaphorins in cancer. Front Biosci 10, 751–760.

    Article  PubMed  Google Scholar 

  67. Kessler, O., Shraga-Heled, N., Lange, T., (2004) Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res 64, 1008–1015.

    Article  PubMed  CAS  Google Scholar 

  68. Ochi, K., Mori, T., Toyama, Y., Nakamura, Y., Arakawa, H. (2002) Identification of semaphorin3B as a direct target of p53. Neoplasia 4, 82–87.

    Article  PubMed  CAS  Google Scholar 

  69. Xu, X. M., Fisher, D. A., Zhou, L., (2000) The transmembrane protein semaphorin 6A repels embryonic sympathetic axons. J Neurosci 20, 2638–2648.

    PubMed  CAS  Google Scholar 

  70. Dhanabal, M., Wu, F., Alvarez, E., (2005) Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis. Cancer Biol Ther 4, 659–668.

    PubMed  CAS  Google Scholar 

  71. Kolodkin, A. L., Levengood, D. V., Rowe, E. G., Tai, Y. T., Giger, R. J., Ginty, D. D. (1997) Neuropilin is a semaphorin III receptor. Cell 90, 753–762.

    Article  PubMed  CAS  Google Scholar 

  72. Kawasaki, T., Kitsukawa, T., Bekku, Y., (1999) A requirement for neuropilin-1 in embryonic vessel formation. Development 126, 4895–4902.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  74. Rossignol, M., Gagnon, M. L., Klagsbrun, M. (2000) Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics 70, 211–222.

    Article  PubMed  CAS  Google Scholar 

  75. Gagnon, M. L., Bielenberg, D. R., Gechtman, Z., (2000) Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: in vivo expression and antitumor activity. Proc Natl Acad Sci U S A 97, 2573–2578.

    Article  PubMed  CAS  Google Scholar 

  76. Yamada, Y., Takakura, N., Yasue, H., Ogawa, H., Fujisawa, H., Suda, T. (2001) Exogenous clustered neuropilin 1 enhances vasculogenesis and angiogenesis. Blood 97, 1671–1678.

    Article  PubMed  CAS  Google Scholar 

  77. Gluzman-Poltorak, Z., Cohen, T., Herzog, Y., Neufeld, G. (2000) Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. J Biol Chem 275, 18040–18045.

    Article  PubMed  CAS  Google Scholar 

  78. Herzog, Y., Kalcheim, C., Kahane, N., Reshef, R., Neufeld, G. (2001) Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech Dev 109, 115–119.

    Article  PubMed  CAS  Google Scholar 

  79. Yuan, L., Moyon, D., Pardanaud, L., (2002) Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797–4806.

    PubMed  CAS  Google Scholar 

  80. Karkkainen, M. J., Saaristo, A., Jussila, L., (2001) A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 98, 12677–12682.

    Article  PubMed  CAS  Google Scholar 

  81. Takashima, S., Kitakaze, M., Asakura, M., (2002) Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci U S A 99, 3657–3662.

    Article  PubMed  CAS  Google Scholar 

  82. Shen, J., Samul, R., Zimmer, J., (2004) Deficiency of neuropilin 2 suppresses VEGF-induced retinal neovascularization. Mol Med 10, 12–18.

    Article  PubMed  CAS  Google Scholar 

  83. Comoglio, P. M., Trusolino, L. (2002) Invasive growth: from development to metastasis. J Clin Invest 109, 857–862.

    PubMed  CAS  Google Scholar 

  84. Giordano, S., Corso, S., Conrotto, P., (2002) The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 4, 720–724.

    Article  PubMed  CAS  Google Scholar 

  85. Gu, C., Yoshida, Y., Livet, J., (2005) Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307, 265–268.

    Article  PubMed  CAS  Google Scholar 

  86. Toyofuku, T., Zhang, H., Kumanogoh, A., (2004) Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 18, 435–447.

    Article  PubMed  CAS  Google Scholar 

  87. Takahashi, T., Fournier, A., Nakamura, F., (1999) Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99, 59–69.

    Article  PubMed  CAS  Google Scholar 

  88. Tamagnone, L., Artigiani, S., Chen, H., (1999) Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99, 71–80.

    Article  PubMed  CAS  Google Scholar 

  89. Suto, F., Murakami, Y., Nakamura, F., Goshima, Y., Fujisawa, H. (2003) Identification and characterization of a novel mouse plexin, plexin-A4. Mech Dev 120, 385–396.

    Article  PubMed  CAS  Google Scholar 

  90. Takahashi, T., Strittmatter, S. M. (2001) Plexina1 autoinhibition by the plexin sema domain. Neuron 29, 429–439.

    Article  PubMed  CAS  Google Scholar 

  91. Iso, T., Hamamori, Y., Kedes, L. (2003) Notch signaling in vascular development. Arterioscler Thromb Vasc Biol 23, 543–553.

    Article  PubMed  CAS  Google Scholar 

  92. Shawber, C. J., Das, I., Francisco, E., Kitajewski, J. (2003) Notch signaling in primary endothelial cells. Ann N Y Acad Sci 995, 162–170.

    Article  PubMed  CAS  Google Scholar 

  93. Uyttendaele, H., Ho, J., Rossant, J., Kitajewski, J. (2001) Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci U S A 98, 5643–5648.

    Article  PubMed  CAS  Google Scholar 

  94. Mailhos, C., Modlich, U., Lewis, J., Harris, A., Bicknell, R., Ish-Horowicz, D. (2001) Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 69, 135–144.

    Article  PubMed  CAS  Google Scholar 

  95. Shutter, J. R., Scully, S., Fan, W., (2000) Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev 14, 1313–1318.

    PubMed  CAS  Google Scholar 

  96. Villa, N., Walker, L., Lindsell, C. E., (2001) Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 108, 161–164.

    Article  PubMed  CAS  Google Scholar 

  97. Kalaria, R. N., Low, W. C., Oakley, A. E., et al. (2002) CADASIL and genetics of cerebral ischaemia. J Neural Transm Suppl, 75–90.

    Google Scholar 

  98. Xue, Y., Gao, X., Lindsell, C. E., (1999) Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 8, 723–730.

    Article  PubMed  CAS  Google Scholar 

  99. Hrabe de Angelis, M., McIntyre, J., 2nd, Gossler, A. (1997) Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 386, 717–721.

    Article  PubMed  CAS  Google Scholar 

  100. Krebs, L. T., Xue, Y., Norton, C. R., (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14, 1343–1352.

    PubMed  CAS  Google Scholar 

  101. Huppert, S. S., Le, A., Schroeter, E. H., (2000) Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 405, 966–970.

    Article  PubMed  CAS  Google Scholar 

  102. Limbourg, F. P., Takeshita, K., Radtke, F., Bronson, R. T., Chin, M. T., Liao, J. K. (2005) Essential role of endothelial Notch1 in angiogenesis. Circulation 111, 1826–1832.

    Article  PubMed  CAS  Google Scholar 

  103. Fischer, A., Schumacher, N., Maier, M., Sendtner, M., Gessler, M. (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18, 901–911.

    Article  PubMed  CAS  Google Scholar 

  104. Carlson, T. R., Yan, Y., Wu, X., (2005) Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A 102, 9884–9889.

    Article  PubMed  CAS  Google Scholar 

  105. Holder, N., Klein, R. (1999) Eph receptors and ephrins: effectors of morphogenesis. Development 126, 2033–2044.

    PubMed  CAS  Google Scholar 

  106. Adams, R. H., Klein, R. (2000) Eph receptors and ephrin ligands, essential mediators of vascular development. Trends Cardiovasc Med 10, 183–188.

    Article  PubMed  CAS  Google Scholar 

  107. Zhang, J., Hughes, S. (2006) Role of the ephrin and Eph receptor tyrosine kinase families in angiogenesis and development of the cardiovascular system. J Pathol 208, 453–461.

    Article  PubMed  CAS  Google Scholar 

  108. Wilkinson, D. G. (2001) Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci 2, 155–164.

    Article  PubMed  CAS  Google Scholar 

  109. Kullander, K., Klein, R. (2002) Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol 3, 475–486.

    Article  PubMed  CAS  Google Scholar 

  110. Palmer, A., Klein, R. (2003) Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function. Genes Dev 17, 1429–1450.

    Article  PubMed  CAS  Google Scholar 

  111. Gale, N. W., Holland, S. J., Valenzuela, D. M., (1996) Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17, 9–19.

    Article  PubMed  CAS  Google Scholar 

  112. Adams, R. H., Diella, F., Hennig, S., Helmbacher, F., Deutsch, U., Klein, R. (2001) The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 104, 57–69.

    Article  PubMed  CAS  Google Scholar 

  113. Wang, H. U., Chen, Z. F., Anderson, D. J. (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753.

    Article  PubMed  CAS  Google Scholar 

  114. Gerety, S. S., Wang, H. U., Chen, Z. F., Anderson, D. J. (1999) Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4, 403–414.

    Article  PubMed  CAS  Google Scholar 

  115. Adams, R. H., Wilkinson, G. A., Weiss, C., (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, sprouting angiogenesis. Genes Dev 13, 295–306.

    Article  PubMed  CAS  Google Scholar 

  116. Pandey, A., Shao, H., Marks, R. M., Polverini, P. J., Dixit, V. M. (1995) Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science 268, 567–569.

    Article  PubMed  CAS  Google Scholar 

  117. Stein, E., Lane, A. A., Cerretti, D. P., (1998) Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, assembly responses. Genes Dev 12, 667–678.

    Article  PubMed  CAS  Google Scholar 

  118. Ogawa, K., Pasqualini, R., Lindberg, R. A., Kain, R., Freeman, A. L., Pasquale, E. B. (2000) The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19, 6043–6052.

    Article  PubMed  CAS  Google Scholar 

  119. Brantley, D. M., Cheng, N., Thompson, E. J., (2002) Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21, 7011–7026.

    Article  PubMed  CAS  Google Scholar 

  120. Cheng, N., Brantley, D. M., Chen, J. (2002) The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13, 75–85.

    Article  PubMed  CAS  Google Scholar 

  121. Cheng, N., Brantley, D. M., Liu, H., (2002) Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol Cancer Res 1, 2–11.

    Article  PubMed  CAS  Google Scholar 

  122. Wilson, B. D., Ii, M., Park, K. W., (2006) Netrins promote developmental and therapeutic angiogenesis. Science 313, 640–644.

    Article  PubMed  CAS  Google Scholar 

  123. Lu, X., Le Noble, F., Yuan, L., (2004) The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179–186.

    Article  PubMed  CAS  Google Scholar 

  124. Klagsbrun, M., Eichmann, A. (2005) A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev 16, 535–548.

    Article  PubMed  CAS  Google Scholar 

  125. Park, K. W., Crouse, D., Lee, M., (2004) The axonal attractant Netrin-1 is an angiogenic factor. Proc Natl Acad Sci U S A 101, 16210–16215.

    Article  PubMed  CAS  Google Scholar 

  126. Huminiecki, L., Bicknell, R. (2000) In silico cloning of novel endothelial-specific genes. Genome Res 10, 1796–1806.

    Article  PubMed  CAS  Google Scholar 

  127. Suchting, S., Heal, P., Tahtis, K., Stewart, L. M., Bicknell, R. (2005) Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration. FASEB J 19, 121–123.

    PubMed  CAS  Google Scholar 

  128. Wang, B., Xiao, Y., Ding, B. B., (2003) Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell 4, 19–29.

    Article  PubMed  Google Scholar 

  129. Park, K. W., Morrison, C. M., Sorensen, L. K., (2003) Robo4 is a vascular-specific receptor that inhibits endothelial migration. Dev Biol 261, 251–267.

    Article  PubMed  CAS  Google Scholar 

  130. Bedell, V. M., Yeo, S. Y., Park, K. W., (2005) Roundabout4 is essential for angiogenesis in vivo. Proc Natl Acad Sci U S A 102, 6373–6378.

    Article  PubMed  CAS  Google Scholar 

  131. Pola, R., Ling, L. E., Silver, M., (2001) The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 7, 706–711.

    Article  PubMed  CAS  Google Scholar 

  132. Lawson, N. D., Vogel, A. M., Weinstein, B. M. (2002) sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 3, 127–136.

    Article  PubMed  CAS  Google Scholar 

  133. Hacohen, N., Kramer, S., Sutherland, D., Hiromi, Y., Krasnow, M. A. (1998) sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92, 253–263.

    Article  PubMed  CAS  Google Scholar 

  134. Tefft, J. D., Lee, M., Smith, S., (1999) Conserved function of mSpry-2, a murine homolog of Drosophila sprouty, which negatively modulates respiratory organogenesis. Curr Biol 9, 219–222.

    Article  PubMed  CAS  Google Scholar 

  135. de Maximy, A. A., Nakatake, Y., Moncada, S., Itoh, N., Thiery, J. P., Bellusci, S. (1999) Cloning and expression pattern of a mouse homologue of Drosophila sprouty in the mouse embryo. Mech Dev 81, 213–216.

    Article  PubMed  CAS  Google Scholar 

  136. Minowada, G., Jarvis, L. A., Chi, C. L., (1999) Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development 126, 4465–4475.

    PubMed  CAS  Google Scholar 

  137. Sutherland, D., Samakovlis, C., Krasnow, M. A. (1996) branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87, 1091–1101.

    Article  Google Scholar 

  138. Metzger, R. J., Krasnow, M. A. (1999) Genetic control of branching morphogenesis. Science 284, 1635–1639.

    Article  PubMed  CAS  Google Scholar 

  139. Klambt, C., Glazer, L., Shilo, B. Z. (1992) breathless, a Drosophila FGF receptor homolog, is essential for migration of tracheal and specific midline glial cells. Genes Dev 6, 1668–1678.

    Article  PubMed  CAS  Google Scholar 

  140. Lee, T., Hacohen, N., Krasnow, M., Montell, D. J. (1996) Regulated Breathless receptor tyrosine kinase activity required to pattern cell migration and branching in the Drosophila tracheal system. Genes Dev 10, 2912–2921.

    Article  PubMed  CAS  Google Scholar 

  141. Lee, S. H., Schloss, D. J., Jarvis, L., Krasnow, M. A., Swain, J. L. (2001) Inhibition of angiogenesis by a mouse sprouty protein. J Biol Chem 276, 4128–4133.</bh>

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CRUK Molecular Angiogenesis Group, Divisions of Immunity and Infection and Cancer Studies, Institute of Biomedical Research, University of Birmingham, Birmingham, USA

    Zubair Ahmed BSC, PHD & Roy Bicknell BSC, PHD

Authors
  1. Zubair Ahmed BSC, PHD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roy Bicknell BSC, PHD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

    About this protocol

    Cite this protocol

    Ahmed, Z., Bicknell, R. (2009). Angiogenic Signalling Pathways. In: Murray, C., Martin, S. (eds) Angiogenesis Protocols. Methods in Molecular Biology, vol 467. Humana Press. https://doi.org/10.1007/978-1-59745-241-0_1

    Download citation

    • DOI: https://doi.org/10.1007/978-1-59745-241-0_1

    • Published:

    • Publisher Name: Humana Press

    • Print ISBN: 978-1-58829-907-9

    • Online ISBN: 978-1-59745-241-0

    • eBook Packages: Springer Protocols

    Publish with us

    Policies and ethics

    Search

    Navigation