Functional interaction of VEGF-C and VEGF-D with neuropilin receptors

FASEB J. 2006 Jul;20(9):1462-72. doi: 10.1096/fj.05-5646com.


Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Cloning, Molecular
  • DNA Primers
  • Drosophila
  • Endothelium, Vascular / physiology
  • Heparin / physiology
  • Humans
  • Kidney
  • Lymphatic System / physiology
  • Molecular Sequence Data
  • Neovascularization, Physiologic*
  • Neuropilin-2 / metabolism*
  • Polymerase Chain Reaction
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Swine
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vascular Endothelial Growth Factor D / genetics
  • Vascular Endothelial Growth Factor D / metabolism*


  • DNA Primers
  • Neuropilin-2
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D
  • Heparin