Involvement of αvβ3 integrin in gremlin-induced angiogenesis

Angiogenesis. 2013 Jan;16(1):235-43. doi: 10.1007/s10456-012-9309-6. Epub 2012 Sep 30.


α(v)β(3) integrin modulates pro-angiogenic endothelial cell (EC) responses following vascular endothelial growth factor receptor-2 (VEGFR2) engagement. The bone morphogenic protein antagonist gremlin is a novel non-canonical VEGFR2 ligand that promotes the acquisition of a pro-angiogenic phenotype in ECs. Here we investigated the role of α(v)β(3) and extracellular matrix components on EC activation induced by gremlin. Gremlin triggers VEGFR2 phosphorylation and cell motility in ECs adherent to the α(v)β(3) ligand fibrinogen but not in ECs adherent to type-I collagen or fibronectin. Also, gremlin and VEGF-A stimulate the formation of VEGFR2/α(v)β(3) integrin complexes as shown by co-immunoprecipitation experiments and fluorescence resonance energy transfer analysis of β(3)-ECFP/VEGFR2-EYFP co-transfected ECs. Accordingly, anti-β(3) antibodies block the angiogenic activity exerted by gremlin or VEGF-A in vitro, ex vivo and in vivo. The results demonstrate a non-redundant role for α(v)β(3) in gremlin-induced angiogenesis and emphasize its contribution to the formation of functional multi-molecular VEGFR2 complexes responsible for the neovascularization events triggered by canonical and non-canonical pro-angiogenic VEGFR2 ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chickens
  • Cytokines
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • In Vitro Techniques
  • Integrin alphaVbeta3 / metabolism*
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • MCF-7 Cells
  • Mice
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic / drug effects*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Cktsf1b1 protein, mouse
  • Cytokines
  • Integrin alphaVbeta3
  • Intercellular Signaling Peptides and Proteins
  • Vascular Endothelial Growth Factor Receptor-2