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Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

Abstract

ANGIOGENESIS is required for a wide variety of physiological and pathological processes1. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF)2,3 is a major mediator of pathological angiogenesis4–6. Also, the expression of VEGF and its two receptors, Flt-1 and Flk-1/KDR, is related to the formation of blood vessels in mouse and rat embryos7–10. Mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5 (refs 11,12). However, ligand(s) other than VEGF might activate such receptors13,14. To assess the role of VEGF directly, we disrupted the VEGF gene in embryonic stem cells. Here we report the unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12. Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. Furthermore, VEGF-null embryonic stem cells exhibit a dramatically reduced ability to form tumours in nude mice.

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References

  1. Folkman, J. & Shing, Y. J. biol. Chem. 267, 10931–10934 (1992).

    CAS  Google Scholar 

  2. Ferrara, N., Houck, K., Jakeman, L. & Leung, D. W. Endocr. Rev. 13, 18–32 (1992).

    Article  CAS  Google Scholar 

  3. Dvorak, H. F., Brown, L. F., Detmar, M. & Dvorak, A. M. Am. J. Path. 146, 1029–1039 (1995).

    CAS  PubMed  Google Scholar 

  4. Kim, K. J. et al. Nature 362, 841–844 (1993).

    Article  ADS  CAS  Google Scholar 

  5. Adamis, A. P. et al. Am. J. Ophthalmol. 118, 445–450 (1994).

    Article  CAS  Google Scholar 

  6. Aiello, L. P. et al. New Engl. J. Med. 331, 1480–1487 (1994).

    Article  CAS  Google Scholar 

  7. Breier, G., Albrecht, U., Sterrer, S. & Risau, W. Development 114, 521–532 (1992).

    CAS  Google Scholar 

  8. Jakeman, L. B., Armanini, M., Phillips, H. S. & Ferrara, N. Endocrinology 133, 848–859 (1993).

    Article  CAS  Google Scholar 

  9. Quinn, T., Peters, K. G., deVries, C., Ferrara, N. & Williams, L. T. Proc. natn. Acad. Sci. U.S.A. 90, 7533–7537 (1993).

    Article  ADS  CAS  Google Scholar 

  10. Peters, K. G., deVries, C. & Williams, L. T. Proc. natn. Acad. Sci. U.S.A. 90, 8915–8919 (1993).

    Article  ADS  CAS  Google Scholar 

  11. Fong, G.-H., Rossant, J., Gertenstein, M. & Breitman, M. Nature 376, 66–70 (1995).

    Article  ADS  CAS  Google Scholar 

  12. Shalabi, F. et al. Nature 376, 62–66 (1995).

    Article  ADS  Google Scholar 

  13. Park, J. E., Chen, H., Winer, J., Houck, K. A. & Ferrara, N. J. biol. Chem. 269, 25646–25654 (1994).

    CAS  Google Scholar 

  14. Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P. & Persico, M. G. Proc. natn. Acad. Sci. U.S.A. 88, 9267–9271 (1991).

    Article  ADS  CAS  Google Scholar 

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

    Google Scholar 

  16. Tybulewicz, V. L. J., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Cell 65, 1153–1163 (1991).

    Article  CAS  Google Scholar 

  17. Vigon, I. M. et al. Proc. natn. Acad. Sci. U.S.A. 89, 5640–5644 (1992).

    Article  ADS  CAS  Google Scholar 

  18. Risau, W. et al. Development 102, 471–478 (1988).

    CAS  Google Scholar 

  19. Hilberg, F. & Wagner, E. F. Oncogene 7, 2371–2380 (1992).

    CAS  Google Scholar 

  20. Pugh, R. B. C. Pathology of the Testis (Blackwell, Oxford, 1976).

    Google Scholar 

  21. Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo 2nd edn (Cold Spring Harbor Laboratory Press, NY, 1994).

    Google Scholar 

  22. Bradley, A. in Teratocarcinoma and Embryonic Stem Cells: A Practical Approach (ed. Robertson, E. G.) 113–152 (ERL, Oxford, 1987).

    Google Scholar 

  23. Theiler, K. The House Mouse. Atlas of Embryonic Development (Springer, New York, 1989).

    Book  Google Scholar 

  24. Brandon, E. P., Idzerda, R. L. & McKnight, G. S. Curr. Biol. 5, 625–634 (1995).

    Article  CAS  Google Scholar 

  25. McBride, W. G. Lancet ii, 1358–1364 (1987).

    Google Scholar 

  26. D'Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. Proc. natn. Acad. Sci. U.S.A. 91, 4082–4085 (1994).

    Article  ADS  CAS  Google Scholar 

  27. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning, a Laboratory Manual 2nd edn (Cold Spring Harbor Laboratory Press, NY, 1989).

    Google Scholar 

  28. Mansour, S. L., Thomas, K. R. & Capecchi, M. R. Nature 336, 348–352 (1988).

    Article  ADS  CAS  Google Scholar 

  29. Mortensen, R. M., Conner, D. A., Chao, S., Geisterfer-Lowrance, A. A. & Seldman, J. G. Molec. cell. Biol. 12, 2391–2395 (1992).

    Article  CAS  Google Scholar 

  30. Lu, L. H. & Gillett, N. Cell Vision 1, 169–176 (1994).

    CAS  Google Scholar 

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Ferrara, N., Carver-Moore, K., Chen, H. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996). https://doi.org/10.1038/380439a0

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