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)‐1α pathway in endothelial cells (ECs). We have previously shown that the vasostatin‐1 (VS‐1) fragment of chromogranin A inhibits TNF‐α‐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‐1α 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