Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.
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.
Carmeliet
P
P
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Ferreira
V
V
Breier
G
G
Pollefeyt
S
S
Kieckens
L
L
Gertsenstein
M
M
Fahrig
M
M
Vandenhoeck
A
A
Harpal
K
K
Eberhardt
C
C
Declercq
C
C
Pawling
J
J
Moons
L
L
Collen
D
D
Risau
W
W
Nagy
A
A
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
D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors