Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/flk-1 and flt-1

William Leenders, Nicolette Lubsen, Margarethe Van Altena, Matthias Clauss, Martine Deckers, Clemens Löwik, Georg Breier, Dirk Ruiter, Robert De Waal

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Because of its central role in pathological angiogenesis, vascular endothelial growth factor (VEGF) has become a major target for anti-angiogenic therapies. We report here the construction of a heterodimeric antagonistic VEGF variant (HD-VEGF). In this antagonist, binding domains for the VEGF-receptors KDR/Flk-1 and Flt-1 are present at one pole of the dimer, whereas the other pole carries domain swap mutations, which prevent binding to either receptor. As HD-VEGF can only bind to monomeric receptors, it does not lead to signal transduction. Moreover, it antagonizes VEGF and possibly other members of the VEGF family, which are KDR/Flk-1 and Flt-1 ligands. We show here that HD-VEGF is a potent inhibitor of VEGF-mediated proliferation and tissue factor induction in endothelial cell cultures, requiring only a 20-fold and a 4-fold excess, respectively, to block the activity of wtVEGF completely. A 4-fold excess of HD-VEGF over wtVEGF was also sufficient to abrogate vascular permeability as determined in the Miles assay in vivo. Furthermore, HD-VEGF inhibited fetal bone angiogenesis in an ex vivo assay. Thus, HD-VEGF blocks KDR- and Flt-1-mediated VEGF activities that are crucial in the angiogenic process and is therefore a promising, multipotent compound in the treatment of angiogenesis-related diseases.

Original languageEnglish (US)
Pages (from-to)473-481
Number of pages9
JournalLaboratory Investigation
Volume82
Issue number4
StatePublished - 2002
Externally publishedYes

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Vascular Endothelial Growth Factor A
Pathologic Neovascularization
Vascular Endothelial Growth Factor Receptor
Capillary Permeability
Thromboplastin
Signal Transduction
Endothelial Cells
Cell Culture Techniques
Ligands
Bone and Bones
Mutation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Leenders, W., Lubsen, N., Van Altena, M., Clauss, M., Deckers, M., Löwik, C., ... De Waal, R. (2002). Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/flk-1 and flt-1. Laboratory Investigation, 82(4), 473-481.

Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/flk-1 and flt-1. / Leenders, William; Lubsen, Nicolette; Van Altena, Margarethe; Clauss, Matthias; Deckers, Martine; Löwik, Clemens; Breier, Georg; Ruiter, Dirk; De Waal, Robert.

In: Laboratory Investigation, Vol. 82, No. 4, 2002, p. 473-481.

Research output: Contribution to journalArticle

Leenders, W, Lubsen, N, Van Altena, M, Clauss, M, Deckers, M, Löwik, C, Breier, G, Ruiter, D & De Waal, R 2002, 'Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/flk-1 and flt-1', Laboratory Investigation, vol. 82, no. 4, pp. 473-481.
Leenders, William ; Lubsen, Nicolette ; Van Altena, Margarethe ; Clauss, Matthias ; Deckers, Martine ; Löwik, Clemens ; Breier, Georg ; Ruiter, Dirk ; De Waal, Robert. / Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/flk-1 and flt-1. In: Laboratory Investigation. 2002 ; Vol. 82, No. 4. pp. 473-481.
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