Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

Peter Carmeliet, Valérie Ferreira, Georg Breier, Saskla Pollefeyt, Lena Kieckens, Marina Gertsenstein, Michaela Fahrig, Ann Vandenhoeck, Kendraprasad Harpal, Carmen Eberhardt, Cathérine Declercq, Judy Pawling, Lieve Moons, Désiré Collen, Werner Risaut, Andras Nagy

Research output: Contribution to journalArticleResearchpeer-review

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-defrcient (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.

Original languageEnglish
Pages (from-to)435-439
Number of pages5
JournalNature
Volume380
Issue number6573
DOIs
Publication statusPublished - 4 Apr 1996
Externally publishedYes

Cite this

Carmeliet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kieckens, L., Gertsenstein, M., ... Nagy, A. (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature, 380(6573), 435-439. https://doi.org/10.1038/380435a0
Carmeliet, Peter ; Ferreira, Valérie ; Breier, Georg ; Pollefeyt, Saskla ; Kieckens, Lena ; Gertsenstein, Marina ; Fahrig, Michaela ; Vandenhoeck, Ann ; Harpal, Kendraprasad ; Eberhardt, Carmen ; Declercq, Cathérine ; Pawling, Judy ; Moons, Lieve ; Collen, Désiré ; Risaut, Werner ; Nagy, Andras. / Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. In: Nature. 1996 ; Vol. 380, No. 6573. pp. 435-439.
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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-defrcient (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.",
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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, Risaut, W & Nagy, A 1996, 'Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele' Nature, vol. 380, no. 6573, pp. 435-439. https://doi.org/10.1038/380435a0

Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. / Carmeliet, Peter; Ferreira, Valérie; Breier, Georg; Pollefeyt, Saskla; Kieckens, Lena; Gertsenstein, Marina; Fahrig, Michaela; Vandenhoeck, Ann; Harpal, Kendraprasad; Eberhardt, Carmen; Declercq, Cathérine; Pawling, Judy; Moons, Lieve; Collen, Désiré; Risaut, Werner; Nagy, Andras.

In: Nature, Vol. 380, No. 6573, 04.04.1996, p. 435-439.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Carmeliet, Peter

AU - Ferreira, Valérie

AU - Breier, Georg

AU - Pollefeyt, Saskla

AU - Kieckens, Lena

AU - Gertsenstein, Marina

AU - Fahrig, Michaela

AU - Vandenhoeck, Ann

AU - Harpal, Kendraprasad

AU - Eberhardt, Carmen

AU - Declercq, Cathérine

AU - Pawling, Judy

AU - Moons, Lieve

AU - Collen, Désiré

AU - Risaut, Werner

AU - Nagy, Andras

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N2 - 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-defrcient (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.

AB - 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-defrcient (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.

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JO - Nature

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Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996 Apr 4;380(6573):435-439. https://doi.org/10.1038/380435a0