Vascular-specific growth factors and blood vessel formation

Abstract

A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Schematic representation of three families of vascular growth factors and their receptor interactions.
Figure 2: Schematic representation of the roles of VEGF, Ang1, Ang2 and ephrin-B2 during vessel formation.
Figure 3: Models of tumour angiogenesis.

References

  1. 1

    Ferrara, N. Vascular endothelial growth factor: molecular and biological aspects. Curr. Top. Microbiol. Immunol. 237, 1– 30 (1999).

    CAS  PubMed  Google Scholar 

  2. 2

    Dvorak, H. F., Nagy, J. A., Feng, D., Brown, L. F. & Dvorak, A. M. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis . Curr. Top. Microbiol. Immunol. 237, 97 –132 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Eriksson, U. & Alitalo, K. Structure, expression and receptor-binding properties of novel vascular endothelial growth factors. Curr. Top. Microbiol. Immunol. 237, 41–57 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Kenyon, B. M. et al. A model of angiogenesis in the mouse cornea. Invest. Ophthalmol. Vis. Sci. 37, 1625–1632 (1996).

    CAS  PubMed  Google Scholar 

  6. 6

    Ribatti, D., Vacca, A., Roncali, L. & Dammacco, F. The chick embryo chorioallantoic membrane as a model for in vivo research on angiogenesis. Int. J. Dev. Biol. 40, 1189–1197 (1996).

    CAS  PubMed  Google Scholar 

  7. 7

    Gale, N. W. & Yancopoulos, G. D. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 13, 1055–1066 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389–395 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Hellstrom, M., Kaln, M., Lindahl, P., Abramsson, A. & Betsholtz, C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047– 3055 (1999).

    CAS  Google Scholar 

  10. 10

    Hirschi, K. K., Rohovsky, S. A., Beck, L. H., Smith, S. R. & D'Amore, P. A. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Circ. Res. 84, 298–305 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Suri, C. et al. Requisite role of Angiopoietin-1, a ligand for the Tie2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55– 60 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Holash, J., Wiegand, S. J. & Yancopoulos, G. D. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18, 5356–5362 ( 1999).

    CAS  Article  Google Scholar 

  14. 14

    Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999).

    CAS  Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

    Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    ADS  CAS  Article  Google Scholar 

  17. 17

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

    ADS  CAS  Article  Google Scholar 

  18. 18

    Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. & Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. USA 95, 9349–9354 ( 1998).

    ADS  CAS  Article  Google Scholar 

  19. 19

    Taipale, J. et al. Vascular endothelial growth factor receptor-3. Curr. Top. Microbiol. Immunol. 237, 85– 96 (1999).

    CAS  PubMed  Google Scholar 

  20. 20

    Persico, M. G., Vincenti, V. & DiPalma, T. Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr. Top. Microbiol. Immunol. 237, 31–40 ( 1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Olofsson, B., Jeltsch, M., Eriksson, U. & Alitalo, K. Current biology of VEGF-B and VEGF-C. Curr. Opin. Biotechnol. 10, 528–535 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Bellomo, D. et al. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86, E29–E35 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    ADS  CAS  Article  Google Scholar 

  24. 24

    Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439– 442 (1996).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Med. 5, 495– 502 (1999).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  PubMed  Google Scholar 

  27. 27

    Gerber, H. P. et al. VEGF is required for growth and survival in neonatal mice . Development 126, 1149– 1159 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Ferrara, N. et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nature Med. 4, 336– 340 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Gerber, H. P. et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Med. 5, 623–628 ( 1999).

    CAS  Article  Google Scholar 

  30. 30

    Stone, J. et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J. Neurosci. 15, 4738–4747 (1995).

    CAS  Article  Google Scholar 

  31. 31

    Alon, T. et al. 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 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Benjamin, L. E., Hemo, I. & Keshet, E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591 –1598 (1998).

    CAS  Google Scholar 

  33. 33

    Stone, J. et al. Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 37, 290–299 ( 1996).

    CAS  PubMed  Google Scholar 

  34. 34

    Pierce, E. A., Foley, E. D. & Smith, L. E. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch. Ophthalmol . 114, 1219–1228 ( 1996). [Published erratum appears in Arch. Ophthalmol. 115, 427 (1997).]

    CAS  Article  Google Scholar 

  35. 35

    Aiello, L. P. et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331, 1480–1487 ( 1994).

    CAS  Article  Google Scholar 

  36. 36

    Adamis, A. P. et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 118, 445–450 (1994).

    CAS  Article  Google Scholar 

  37. 37

    Springer, M. L., Chen, A. S., Kraft, P. E., Bednarski, M. & Blau, H. M. VEGF gene delivery to muscle: potential role for vasculogenesis in adults. Mol. Cell 2, 549–558 (1998).

    CAS  Article  Google Scholar 

  38. 38

    Detmar, M. et al. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J. Invest. Dermatol. 111, 1–6 (1998 ).

    CAS  Article  Google Scholar 

  39. 39

    Larcher, F., Murillas, R., Bolontrade, M., Conti, C. J. & Jorcano, J. L. VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development. Oncogene 17, 303– 311 (1998).

    CAS  Article  Google Scholar 

  40. 40

    Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511– 2514 (1999).

    CAS  Article  Google Scholar 

  41. 41

    Pettersson, A. et al. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab. Invest. 80, 99– 115 (2000).

    CAS  Article  Google Scholar 

  42. 42

    Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nature Med. 6, 460– 463 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Korhonen, J. et al. Enhanced expression of the tie receptor tyrosine kinase in endothelial cells during neovascularization. Blood 80, 2548–2555 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Maisonpierre, P. C., Goldfarb, M., Yancopoulos, G. D. & Gao, G. Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. Oncogene 8, 1631 –1637. (1993).

    CAS  PubMed  Google Scholar 

  45. 45

    Sato, T. N., Qin, Y., Kozak, C. A. & Audus, K. L. tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc. Natl Acad. Sci. USA 90, 9355–9358 (1993).

    ADS  CAS  Article  Google Scholar 

  46. 46

    Dumont, D. J., Gradwohl, G. J., Fong, G.-H., Auerbach, R. & Breitman, M. L. The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene 8, 1293–1301 ( 1993).

    CAS  Google Scholar 

  47. 47

    Iwama, A. et al. Molecular cloning and characterization of mouse Tie and Tek receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem. Biophys. Res. Commun. 195, 301–309 (1993).

    CAS  Article  Google Scholar 

  48. 48

    Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).

    CAS  Article  Google Scholar 

  49. 49

    Valenzuela, D. et al. Angiopoietins 3 and 4: diverging gene counterparts in mouse and man. Proc. Natl Acad. Sci. USA 96, 1904 –1909 (1999).

    ADS  CAS  Article  Google Scholar 

  50. 50

    Dumont, D. J. et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897– 1909 (1994).

    CAS  Article  Google Scholar 

  51. 51

    Sato, T. N. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).

    ADS  CAS  Article  Google Scholar 

  52. 52

    Suri, C. et al. Angiopoietin-1 promotes increased vascularization in vivo. Science 282, 468–471 ( 1998).

    ADS  CAS  Article  Google Scholar 

  53. 53

    Goede, V., Schmidt, T., Kimmina, S., Kozian, D. & Augustin, H. G. Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis. Lab. Invest. 78, 1385–1394 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Stratmann, A., Risau, W. & Plate, K. H. Cell type-specific expression of Angiopoietin-1 and Angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am. J. Pathol. 153, 1459–1466 (1998).

    CAS  Article  Google Scholar 

  55. 55

    Zagzag, D. et al. In Situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp. Neurol. 159, 391–400 ( 1999).

    CAS  Article  Google Scholar 

  56. 56

    Flanagan, J. G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309–345 (1998).

    CAS  Article  Google Scholar 

  57. 57

    Davis, S. et al. Ligands for the EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266, 816–819 (1994).

    ADS  CAS  Article  Google Scholar 

  58. 58

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

    CAS  Article  Google Scholar 

  59. 59

    Adams, R. H. et al. Roles for ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 13, 295–306 (1999).

    MathSciNet  CAS  Article  Google Scholar 

  60. 60

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

    CAS  Article  Google Scholar 

  61. 61

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

    CAS  Article  Google Scholar 

  62. 62

    Folkman, J. What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Instit. 82, 4–6 (1990).

    CAS  Article  Google Scholar 

  63. 63

    Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    CAS  Article  Google Scholar 

  64. 64

    Wesseling, P., van der Laak, J. A., de Leeuw, H., Ruiter, D. J. & Burger, P. C. Quantitative immunohistological analysis of the microvasculature in untreated human glioblastome multiforme . J Neurosurg. 81, 902– 909 (1994).

    CAS  Article  Google Scholar 

  65. 65

    Holmgren, L., O'Reilly, M. S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1, 149–153 ( 1995).

    CAS  Article  Google Scholar 

  66. 66

    Pezzella, F. et al. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am. J. Pathol. 151, 1417–1423 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844 (1993).

    ADS  CAS  Article  Google Scholar 

  68. 68

    Ferrara, N. & Alitalo, K. Clinical applications of angiogenic growth factors and their inhibitors. Nature Med. 5, 1359–1364 (1999).

    CAS  Article  Google Scholar 

  69. 69

    Henry, T. D. et al. Results of intracoronary recombinant human vascular endothelial growth factor (RhVEGF) administration trial. J. Am. Coll. Cardiol. 31, 65A (1998).

    Article  Google Scholar 

  70. 70

    Chiron Coorporation. Chiron announces preliminary findings from phase II clinical trial of FGF-2. 〈http://www.prnewswire.com/micro/CHIR 〉 Company Press Release 12 March 2000.

  71. 71

    O'Reilly, M. S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis Lung Carcinoma. Cell 79, 315–328 (1994).

    CAS  Article  Google Scholar 

  72. 72

    O'Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).

    CAS  Article  Google Scholar 

  73. 73

    O'Reilly, M. S., Pirie-Shepherd, S., Lane, W. S. & Folkman, J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin . Science 285, 1926–1928 (1999).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yancopoulos, G., Davis, S., Gale, N. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000). https://doi.org/10.1038/35025215

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing