Heterozygous Embryonic Lethality Induced by Targeted Inactivation of the VEGF Gene

Nature. 1996 Apr 4;380(6573):439-42. doi: 10.1038/380439a0.

Abstract

Angiogenesis is required for a wide variety of physiological and pathological processes. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF) is a major mediator of pathological angiogenesis. 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 embryos. Mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5. However, ligand(s) other than VEGF might activate such receptors. 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.

MeSH terms

  • Alleles
  • Animals
  • Chimera
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / blood supply
  • Embryonic and Fetal Development / genetics
  • Embryonic and Fetal Development / physiology
  • Endothelial Growth Factors / genetics*
  • Endothelial Growth Factors / physiology*
  • Female
  • Fetal Death / genetics*
  • Gene Deletion
  • Gene Targeting
  • Heterozygote*
  • Lymphokines / genetics*
  • Lymphokines / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Neovascularization, Physiologic / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Stem Cells
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Lymphokines
  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1