Blocking VEGFR-3 Suppresses Angiogenic Sprouting and Vascular Network Formation

Nature. 2008 Jul 31;454(7204):656-60. doi: 10.1038/nature07083. Epub 2008 Jun 25.

Abstract

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Cell Line, Tumor
  • Dipeptides / pharmacology
  • Down-Regulation
  • Endothelial Cells / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neoplasms / blood supply*
  • Neoplasms / drug therapy
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Dipeptides
  • Ligands
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Receptors, Notch
  • Vascular Endothelial Growth Factor Receptor-3