The vasostatin-1 fragment of chromogranin A preserves a quiescent phenotype in hypoxia-driven endothelial cells and regulates tumor neovascularization

The angiogenic switch is a fundamental process for many diseases and for tumor growth. The main proangiogenic stimulus is hypoxia, through activation of the hypoxia-inducible factor (HIF)-1 alpha pathway in endothelial cells (ECs). We have previously shown that the vasostatin-1 (VS-1) fragment of chromogranin A inhibits TNF-alpha-induced vessel permeability and VEGF-induced EC proliferation, together with migration and matrix invasion, which are all critical steps in angiogenesis. The present study was undertaken to investigate the effect of VS-1 on tumor angiogenesis. We found mouse mammary adenocarcinomas (TS/A), genetically engineered to secrete VS-1 (TS/A 1B8), to be characterized by reduced vascular density and more regular vessels, compared with nontransfected tumors [TS/A wild type (WT)]. Supernatants from TS/A WT cells, but not those from TS/A 1B8, generated tip cells and promoted the permeability of primary human umbilical vein ECs, via VE-cadherin redistribution and cytoskeletal disorganization. These effects were abrogated by mAb 5A8, a VS-1-blocking antibody. Furthermore, VS-1 inhibited hypoxia-driven EC morphological changes, VE-cadherin redistribution, intercellular gap formation, tube morphogenesis, and HIF-1 alpha nuclear translocation in vitro. Our findings highlight a previously undescribed function of VS-1 as a regulator of tumor vascularization.-Veschini, L., Crippa, L., Dondossola, E., Doglioni, C., Corti, A., Ferrero, E. The vasostatin-1 fragment of chromogranin a preserves a quiescent phenotype in hypoxia-driven endothelial cells and regulates tumor neovascularization. FASEB J. 25, 3906-3914 (2011). www.fasebj.org