Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system

Peter Carmeliet, Lieve Moons, M. Dewerchin, Nigel Mackman, Thomas Luther, Georg Breier, V. Ploplis, M. Müller, A. Nagy, E. Plow, R. Gerard, Thomas Edgington, W. Risau, Désiré Collen

Research output: Contribution to journalArticle

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Abstract

VEGF has been proposed to participate in normal and pathological vessel formation. Surprisingly, lack of only a single VEGF allele resulted in embryonic lethality due to abnormal formation of intra- and extra-embryonic vessels. Homozygous VEGF-deficient embryos, generated by tetraploid aggregation, revealed an even more severe defect in vessel formation. These results (1) suggest a tight regulation of early vessel development by VEGF and, indirectly, the presence of other VEGF-like molecules; (2) reveal an unprecedented lethal phenotype associated with heterozygous deficiency of an autosomal gene, and (3) demonstrate that tetraploid aggregation was a valid and the only method to study the phenotype of the homozyogous VEGF-deficient embryos. The dominant and strict dose-dependent role of VEGF in vivo renders this molecule a desirable therapeutic target for promoting or preventing angiogenesis. Tissue factor (TF) is the principal cellular initiator of coagulation and its deregulated expression has been related to thrombogenesis in sepsis, cancer, and inflammation. However, TF appears to be also involved in a variety of non-hemostatic functions including inflammation, cancer, brain function, immune response, and tumor-associated angiogenesis. Surprisingly, TF deficiency resulted in embryonic lethality due to abnormal extra-embryonic vessel development and defective vitello-embryonic circulation. The abnormal yolk sac vasculature is reminiscent of that observed in embryos lacking VEGF, possibly suggesting that both gene functions are interconnected. These targeting studies extend the recently documented role of TF in tumor-associated angiogenesis and warrant further study of its role in angiogenesis during other pathological disorders. The plasminogen system, via its triggers, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), has been implicated in thrombosis, arterial neointima formation, and atherosclerosis. Studies in mice with targeted gene inactivation of t-PA, u-PA, PAI-1, the urokinase receptor (u-PAR), and plasminogen (Plg) revealed (1) that deficiency of t-PA or u-PA increase the susceptibility to thrombosis associated with inflammation and that combined deficiency of t-PA:u-PA or deficiency of Plg induces severe spontaneous thrombosis; (2) that vascular injury-induced neointima formation is reduced in mice lacking u-PA-mediated plasmin proteolysis, unaltered in t-PA- or u-PAR-deficient mice and accelerated in PAI-1-deficient mice, but that it can be reverted by adenoviral PAI-1 gene transfer; and (3) that atherosclerosis in mice doubly deficient in apolipoprotein E (apoE) and PAI-1 is reduced after 10 weeks of cholesterol-rich diet. Thus, the plasminogen system significantly affects thrombosis, restenosis, and atherosclerosis.

Original languageEnglish (US)
Pages (from-to)191-206
Number of pages16
JournalAnnals of the New York Academy of Sciences
Volume811
DOIs
StatePublished - 1997

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Plasminogen
Thromboplastin
Urokinase-Type Plasminogen Activator
Vascular Endothelial Growth Factor A
Blood Vessels
Plasminogen Activator Inhibitor 1
Plasminogen Activators
Thrombosis
Neointima
Atherosclerosis
Tetraploidy
Embryonic Structures
Genes
Inflammation
Tumors
Agglomeration
Proteolysis
Gene transfer
Phenotype
Plasminogen Inactivators

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. / Carmeliet, Peter; Moons, Lieve; Dewerchin, M.; Mackman, Nigel; Luther, Thomas; Breier, Georg; Ploplis, V.; Müller, M.; Nagy, A.; Plow, E.; Gerard, R.; Edgington, Thomas; Risau, W.; Collen, Désiré.

In: Annals of the New York Academy of Sciences, Vol. 811, 1997, p. 191-206.

Research output: Contribution to journalArticle

Carmeliet, P, Moons, L, Dewerchin, M, Mackman, N, Luther, T, Breier, G, Ploplis, V, Müller, M, Nagy, A, Plow, E, Gerard, R, Edgington, T, Risau, W & Collen, D 1997, 'Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system', Annals of the New York Academy of Sciences, vol. 811, pp. 191-206. https://doi.org/10.1111/j.1749-6632.1997.tb52002.x
Carmeliet, Peter ; Moons, Lieve ; Dewerchin, M. ; Mackman, Nigel ; Luther, Thomas ; Breier, Georg ; Ploplis, V. ; Müller, M. ; Nagy, A. ; Plow, E. ; Gerard, R. ; Edgington, Thomas ; Risau, W. ; Collen, Désiré. / Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. In: Annals of the New York Academy of Sciences. 1997 ; Vol. 811. pp. 191-206.
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T1 - Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system

AU - Carmeliet, Peter

AU - Moons, Lieve

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AU - Mackman, Nigel

AU - Luther, Thomas

AU - Breier, Georg

AU - Ploplis, V.

AU - Müller, M.

AU - Nagy, A.

AU - Plow, E.

AU - Gerard, R.

AU - Edgington, Thomas

AU - Risau, W.

AU - Collen, Désiré

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