Premium
Vascular endothelial‐cadherin stimulates syndecan‐1‐coupled insulin‐like growth factor‐1 receptor and cross‐talk between α V β3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis
Author(s) -
Rapraeger Alan C.,
Ell Brian J.,
Roy Madhuchhanda,
Li Xuehui,
Morrison Orrianne R.,
Thomas Grant M.,
Beauvais DeannaLee M.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12134
Subject(s) - angiogenesis , kinase insert domain receptor , microbiology and biotechnology , integrin , s1pr1 , vascular endothelial growth factor , vascular endothelial growth factor b , vascular endothelial growth factor a , biology , insulin like growth factor 1 receptor , vascular endothelial growth inhibitor , endothelial stem cell , receptor , chemistry , growth factor , cancer research , biochemistry , vegf receptors , in vitro
Vascular endothelial growth factor ( VEGF )‐stimulated angiogenesis depends on a cross‐talk mechanism involving VEGF receptor 2 ( VEGFR 2), vascular endothelial ( VE )‐cadherin and the αVβ3 integrin. Because we have shown that αVβ3 integrin activation is dependent on its incorporation, along with the insulin‐like growth factor‐1 receptor ( IGF 1R) kinase, into a ternary receptor complex organized by the matrix receptor syndecan‐1 ( S dc1), we questioned the role of this core complex in VEGF ‐stimulated angiogenesis. We find that the S dc1‐coupled ternary receptor complex is required for VEGF signalling and for stimulation of vascular endothelial cell migration by vascular endothelial cadherin ( VE ‐cadherin) engagement. VE ‐cadherin binding to Fc/ VE ‐cadherin extracellular domain chimera activates Sdc1‐coupled IGF 1R and αvβ3 integrin; this depends on VEGFR 2 and c‐Src activated by the cadherin. Blocking homotypic VE ‐cadherin engagement disrupts VEGF ‐stimulated cell migration, which is restored by clustering the cadherin in the absence of cell–cell adhesion. This cadherin‐dependent stimulation requires VEGFR 2 and IGF 1R and is blocked by synstatin ( SSTN ) 92–119 , a peptide that competitively disrupts the Sdc1‐coupled ternary complex and prevents the αVβ3 integrin activation required for VEGFR 2 activation. VEGFR 2‐stimulated angiogenesis in the mouse aortic ring explant assay is disrupted by SSTN , although only early in the process, suggesting that IGF 1R coupling to Sdc1 and αVβ3 integrin comprises a core activation mechanism activated by VE ‐cadherin that is necessary for VEGFR 2 and integrin activation in the initial stages of endothelial cell dissemination during angiogenesis.