301. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.
- Author
-
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, and Nagy A
- Subjects
- Alleles, Animals, Base Sequence, Blood Vessels embryology, Cell Line, Culture Techniques, DNA Primers, Embryo, Mammalian blood supply, Embryonic and Fetal Development genetics, Embryonic and Fetal Development physiology, Endothelial Growth Factors deficiency, Fetal Death genetics, Gene Deletion, Heterozygote, Homozygote, Lymphokines deficiency, Molecular Sequence Data, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Blood Vessels abnormalities, Embryo, Mammalian abnormalities, Embryo, Nonmammalian, Endothelial Growth Factors genetics, Endothelial Growth Factors physiology, Lymphokines genetics, Lymphokines physiology
- 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.
- Published
- 1996
- Full Text
- View/download PDF