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

Lab Invest. 2002 Apr;82(4):473-81. doi: 10.1038/labinvest.3780440.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Division / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Embryonic and Fetal Development
  • Endothelial Growth Factors / pharmacology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Extracellular Matrix Proteins / antagonists & inhibitors*
  • Extracellular Matrix Proteins / metabolism
  • Guinea Pigs
  • Metatarsal Bones / blood supply
  • Metatarsal Bones / drug effects
  • Metatarsal Bones / embryology
  • Mice
  • Molecular Sequence Data
  • Myosin Heavy Chains
  • Neovascularization, Physiologic / drug effects
  • Nonmuscle Myosin Type IIB
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Growth Factor / antagonists & inhibitors*
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1


  • Endothelial Growth Factors
  • Extracellular Matrix Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Flt1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1
  • Nonmuscle Myosin Type IIB
  • nonmuscle myosin type IIB heavy chain
  • Myosin Heavy Chains