Vascular endothelial-cadherin stimulates syndecan-1-coupled insulin-like growth factor-1 receptor and cross-talk between αVß3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis.
FEBS J
; 280(10): 2194-206, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-23331867
ABSTRACT
Vascular endothelial growth factor (VEGF)-stimulated angiogenesis depends on a cross-talk mechanism involving VEGF receptor 2 (VEGFR2), vascular endothelial (VE)-cadherin and the αVß3 integrin. Because we have shown that αVß3 integrin activation is dependent on its incorporation, along with the insulin-like growth factor-1 receptor (IGF1R) kinase, into a ternary receptor complex organized by the matrix receptor syndecan-1 (Sdc1), we questioned the role of this core complex in VEGF-stimulated angiogenesis. We find that the Sdc1-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 IGF1R and αvß3 integrin; this depends on VEGFR2 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 VEGFR2 and IGF1R and is blocked by synstatin (SSTN)(92-119), a peptide that competitively disrupts the Sdc1-coupled ternary complex and prevents the αVß3 integrin activation required for VEGFR2 activation. VEGFR2-stimulated angiogenesis in the mouse aortic ring explant assay is disrupted by SSTN, although only early in the process, suggesting that IGF1R coupling to Sdc1 and αVß3 integrin comprises a core activation mechanism activated by VE-cadherin that is necessary for VEGFR2 and integrin activation in the initial stages of endothelial cell dissemination during angiogenesis.
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Base de dados:
MEDLINE
Assunto principal:
Antígenos CD
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Caderinas
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Receptores de Somatomedina
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Receptor 2 de Fatores de Crescimento do Endotélio Vascular
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Integrina alfaVbeta3
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Células Endoteliais
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Sindecana-1
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article