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 Scopus citations


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
Issue number4
StatePublished - Apr 2002
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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