title: Vascular endothelial-cadherin stimulates syndecan-1-coupled insulin-like growth factor-1 receptor and cross-talk between αVβ3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis.
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 αVβ3 integrin. Because we have shown that αVβ3 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 αvβ3 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 αVβ3 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 αVβ3 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.
authors: Department of Human Oncology, University of Wisconsin-Madison, WI 53705, USA. rapraeger@humonc.wisc.edu
authors: Alan C
authors: AC
authors: Rapraeger
authors: Brian J
authors: BJ
authors: Ell
authors: Madhuchhanda
authors: M
authors: Roy
authors: Xuehui
authors: X
authors: Li
authors: Orrianne R
authors: OR
authors: Morrison
authors: Grant M
authors: GM
authors: Thomas
authors: DeannaLee M
authors: DM
authors: Beauvais
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020239:Receptor Cross-Talk; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053668:Syndecan-1 / Q000378:metabolism*; D050801:Ternary Complex Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D015820:Cadherins; D003094:Collagen; D039302:Integrin alphaVbeta3; D010455:Peptides; D017451:Receptors, Somatomedin; D053668:Syndecan-1; D050801:Ternary Complex Factors; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C508241:SDC1 protein, human