title: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.
abstract: The endothelial cell-specific vascular endothelial growth factor (VEGF) and its cellular receptors Flt-1 and Flk-1 have been implicated in the formation of the embryonic vasculature. This is suggested by their colocalized expression during embryogenesis and the impaired vessel formation in Flk-1 and Flt-1 deficient embryos. However, because Flt-1 also binds placental growth factor, 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) 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 inactivation, and is indicative of a tight dose-dependent regulation of embryonic vessel development by VEGF.
authors.affiliation: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
authors.forename: V
authors.initials: V
authors.lastname: Ferreira
authors.forename: G
authors.initials: G
authors.lastname: Breier
authors.forename: S
authors.initials: S
authors.lastname: Pollefeyt
authors.forename: L
authors.initials: L
authors.lastname: Kieckens
authors.forename: M
authors.initials: M
authors.lastname: Gertsenstein
authors.forename: M
authors.initials: M
authors.lastname: Fahrig
authors.forename: A
authors.initials: A
authors.lastname: Vandenhoeck
authors.forename: K
authors.initials: K
authors.lastname: Harpal
authors.forename: C
authors.initials: C
authors.lastname: Eberhardt
authors.forename: C
authors.initials: C
authors.lastname: Declercq
authors.forename: J
authors.initials: J
authors.lastname: Pawling
authors.forename: L
authors.initials: L
authors.lastname: Moons
authors.forename: D
authors.initials: D
authors.lastname: Collen
authors.forename: W
authors.initials: W
authors.lastname: Risau
authors.forename: A
authors.initials: A
authors.lastname: Nagy
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000002:abnormalities* / Q000196:embryology; D002460:Cell Line; D046508:Culture Techniques; D017931:DNA Primers; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000098:blood supply; D004625:Embryo, Nonmammalian; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D016228:Endothelial Growth Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D005313:Fetal Death / Q000235:genetics; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D008222:Lymphokines / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D008969:Molecular Sequence Data; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors