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Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

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Abstract

THE endothelial cell-specific vascular endothelial growth factor (VEGF)1–5 and its cellular receptors Flt-1 (refs 6,7) and Flk-1 (refs 8,9) have been implicated in the formation of the embryonic vasculature. This is suggested by their colocalized expression during embryogenesis10,11 and the impaired vessel formation in Flk-1 (ref. 12) and Flt-1 (ref. 13) deficient embryos. However, because Flt-1 also binds placental growth factor14,15, a VEGF homologue, the precise role of VEGF was unknown. Here we report that formation of blood vessels was abnormal, but not abolished, in heterozygous VEGF-deficient (VEGF+/-) embryos, generated by aggregation of embryonic stem (ES) cells with tetraploid embryos (T-ES)16,17, and even more impaired in homozygous VEGF-deficient (VEGF-/-) T-ES embryos, resulting in death at mid-gestation. Similar phenotypes were observed in F1-VEGF-/- embryos, generated by germline transmission. We believe that this heterozygous lethal phenotype, which differs from the homozygous lethality in VEGF-receptor-deficient embryos, is unprecedented for a targeted autosomal gene inacti-vation, and is indicative of a tight dose-dependent regulation of embryonic vessel development by VEGF.

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Authors and Affiliations

  1. Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, B-3000, Leuven, Belgium

    Peter Carmeliet, Valérie Ferreira, Saskia Pollefeyt, Lena Kieckens, Ann Vandenhoeck, Cathérine Declercq, Lieve Moons & Désiré Collen

  2. Abteilung Molekulare Zellbiologie, Max-Planck-Institute für physiologische und Klinische Forschung, W. G. Kerckhoff-lnstitut, Bad Nauheim, Germany

    Georg Breier, Michaela Fahrig, Carmen Eberhardt & Werner Risau

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Marina Gertsenstein, Kendraprasad Harpal, Judy Pawling & Andras Nagy

  4. Department of Medical Genetics, University of Toronto, Ontario, Canada

    Andras Nagy

Authors
  1. Peter Carmeliet
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  2. Valérie Ferreira
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  3. Georg Breier
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  4. Saskia Pollefeyt
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  5. Lena Kieckens
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  6. Marina Gertsenstein
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  7. Michaela Fahrig
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  8. Ann Vandenhoeck
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  10. Carmen Eberhardt
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  11. Cathérine Declercq
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  12. Judy Pawling
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  13. Lieve Moons
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  14. Désiré Collen
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  15. Werner Risau
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  16. Andras Nagy
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Carmeliet, P., Ferreira, V., Breier, G. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996). https://doi.org/10.1038/380435a0

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  • DOI: https://doi.org/10.1038/380435a0

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