Vessel sprouting from pre-existing vasculature is a key step for the formation of a functional vasculature. The low level of vascular endothelial growth factor (VEGF) induces normal and stable angiogenesis, whereas high level of VEGF causes irregular and over sprouted vasculature. Intermedin (IMD) is a novel member of calcitonin family, and was found to be able to restrict the excessive vessel sprouting. However, the underlying mechanism had not been elucidated. In this study, using in vitro and in vivo angiogenic models, we found that the loosening of endothelial junction could significantly increase the ability of low-dose VEGF to induce vessel sprouting. IMD inhibited the junction dissociation-induced vessel sprouting by re-establishing the complex of vascular endothelial cadherin on the cell cell contact. Our findings suggested a novel mechanism through which IMD could restrict the excessive vessel sprouting by preventing the endothelial junction from dissociation, and provide new insight into the understanding of the regulation of sprouting angiogenesis. (C) 2015 Elsevier Inc. All rights reserved.