Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis


INEFFICIENT vascular supply and the resultant reduction in tissue oxygen tension often lead to neovascularization in order to satisfy the needs of the tissue1. Examples include the compensatory development of collateral blood vessels in ischaemic tissues that are otherwise quiescent for angiogenesis and angiogenesis associated with the healing of hypoxic wounds2. But the presumptive hypoxia-induced angiogenic factors that mediate this feedback response have not been identified. Here we show that vascular endothelial growth factor (VEGF; also known as vascular permeability factor) probably functions as a hypoxia-inducible angiogenic factor. VEGF messenger RNA levels are dramatically increased within a few hours of exposing different cell cultures to hypoxia and return to background when normal oxygen supply is resumed. In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells.

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  1. 1

    Adair, T. A., Gay, W. J. & Montani, J.-P. Am. J. Physiol. 259, R393–R404 (1990).

    CAS  PubMed  Google Scholar 

  2. 2

    Knighton, D. R. et al. Science 221, 1283–1285 (1983).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Folkman, J. Adv. Cancer Res. 43, 175–202 (1985).

    CAS  Article  Google Scholar 

  4. 4

    Hirano, A. & Matsui, T. Hum. Path. 6, 611–621 (1975).

    CAS  Article  Google Scholar 

  5. 5

    Jellinger, K. Acta neurochirurgica 42, 5–32 (1978).

    CAS  Article  Google Scholar 

  6. 6

    Connolly, D. T. et al. J. clin. Invest. 84, 1470–1478 (1989).

    CAS  Article  Google Scholar 

  7. 7

    Leung, D. W., Cachianes, G., Kuang, W.-J., Goeddel, D. V. & Ferrara, N. Science 246, 1306–1309 (1989).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Gospodarowicz, D., Abraham, J. A. & Schilling, J. Proc. natn. Acad. Sci. U.S.A. 86, 7311–7315 (1989).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Ferrara, N. & Henzel, W. Biochem. biophys. Res. Commun. 161, 851–858 (1989).

    CAS  Article  Google Scholar 

  10. 10

    Conn, J. et al. Proc. natn. Acad. Sci. U.S.A. 87, 1323–1327 (1990).

    ADS  CAS  Article  Google Scholar 

  11. 11

    Burger, P. C., Vogel, F. S., Green, S. B. & Strike, T. A. Cancer 56, 1106–1111 (1985).

    CAS  Article  Google Scholar 

  12. 12

    Dvorak, H. F. et al. J. exp. Med. 174, 1275–1278 (1991).

    CAS  Article  Google Scholar 

  13. 13

    Tischler, E. et al. J. biol. Chem. 266, 11947–11954 (1991).

    Google Scholar 

  14. 14

    Ferrara, N., Houck, K. A., Jakeman, L. B., Winer, J. & Leung, D. W. J. cell Biochem. 47, 211–218 (1991).

    CAS  Article  Google Scholar 

  15. 15

    Jakeman, L. B., Winer, J., Bennett, G. L., Altar, A. & Ferrara, N. J. clin. Invest. 89, 244–253 (1992).

    CAS  Article  Google Scholar 

  16. 16

    D'Amore, P. A. & Thompson, R. W. A. Rev. Physiol. 49, 453–464 (1987).

    CAS  Article  Google Scholar 

  17. 17

    Vlodavsky, I. et al. Proc. natn. Acad. Sci. U.S.A. 84, 2292–2296 (1987).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Kourembanas, S., Hannan, R. I. & Faller, D. V. J. clin. Invest. 86, 670–674 (1990).

    CAS  Article  Google Scholar 

  19. 19

    Rondon, I. J. et al. J. biol. Chem. 266, 16594–16598 (1991).

    CAS  PubMed  Google Scholar 

  20. 20

    Knighton, D., Schumerth, S. & Fiegel, V. in Current Communications in Molecular Biology (eds Rifkin, D. B. & Klagsbrun, M.) 150–154 (Cold Spring Harbor Laboratory Press, New York, 1987).

    Google Scholar 

  21. 21

    Senger, D. R. et al. Science 219, 983–985 (1983).

    ADS  CAS  Article  Google Scholar 

  22. 22

    Keck, P. J. et al. Science 246, 1309–1312 (1989).

    ADS  CAS  Article  Google Scholar 

  23. 23

    Kinasewitz, G., Groome, L., Marshall, R., Leslie, W. & Diana, H. J. appl. Physiol. 61, 554–560 (1986).

    CAS  Article  Google Scholar 

  24. 24

    Olsen, S. P. Brain Res. 368, 24–29 (1986).

    Article  Google Scholar 

  25. 25

    Motro, B., Itin, A., Sachs, L. & Keshet, E. Proc. natn. Acad. Sci. U.S.A. 87, 3092–3096 (1990).

    ADS  CAS  Article  Google Scholar 

  26. 26

    Bonthron, D. et al. Nucleic Acids Res. 14, 7125–7127 (1986).

    CAS  Article  Google Scholar 

  27. 27

    Benda, P., Lightbody, J., Sato, G., Levine, L. & Sweet, W. Science 161, 370–371 (1968).

    ADS  CAS  Article  Google Scholar 

  28. 28

    Yaffe, D. & Saxel, O. Differentiation 7, 159–166 (1977).

    CAS  Article  Google Scholar 

  29. 29

    Chrigwin, J. M. Przbyla, A. E., McDonald, R. T. & Rutter, W. J. Biochemistry 18, 5294–5299 (1979).

    Article  Google Scholar 

  30. 30

    Minty, A. J. et al. J. biol. Chem. 256, 1008–1014 (1981).

    CAS  PubMed  Google Scholar 

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

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