Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

N Ferrara; K Carver-Moore; H Chen; M Dowd; L Lu; K S O'Shea; L Powell-Braxton; K J Hillan; M W Moore

doi:10.1038/380439a0

Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

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

Authors

N Ferrara¹, K Carver-Moore, H Chen, M Dowd, L Lu, K S O'Shea, L Powell-Braxton, K J Hillan, M W Moore

Affiliation

¹ Department of Cardiovascular Research, Genentech Inc., South San Francisco, California 94080, USA.

PMID: 8602242
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