Vascular endothelial cadherin is an endostatin receptor

Angiogenesis is involved in tumor growth and metastasis. Endostatin inhibits angiogenesis, but its precise mechanism is not fully understood. To clarify signal transduction involved in endostatin-induced angiogenesis inhibition (endothelial cell growth inhibition), it is important to identify an endostatin receptor, which is the aim of the present study. We hypothesized that vascular endothelial cadherin (VE-cadherin) is an endostatin receptor and found that endostatin induced apoptosis in cultured calf pulmonary artery endothelium (CPAE) cells. Immunoprecipitation and western blots revealed that endostatin specifically bound to VE-cadherin in a Ca2+-dependent manner. Binding of endostatin to VE-cadherin induced tyrosine phosphorylation of VE-cadherin, β-catenin recruitment, and endothelial cell death. Antisense oligonucleotides against VE-cadherin rescued endostatin-induced endothelial cell death. Inhibition of tyrosine phosphorylation of VE-cadherin inhibited endostatin-induced β-catenin recruitment and CPAE cell death. Taken together, we conclude that VE-cadherin is an endostatin receptor.