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The vasostatin-I fragment of chromogranin A inhibits VEGF-induced endothelial cell proliferation and migration

Daniela Belloni^*,1, Silvia Scabini^*,1, Chiara Foglieni, Lorenzo Veschini^*, Alessio Giazzon, Barbara Colombo^*, Alessandro Fulgenzi, Karen B. Helle, Maria Elena Ferrero, Angelo Corti^* and Elisabetta Ferrero^*

^* Department of Oncology and IIT Network Research Unit of Molecular Neurosciences, and

Cardiovascular Department, DIBIT, San Raffaele H Scientific Institute, Milan, Italy;

Department of Biomedicine, University of Bergen, Bergen, Norway; and

Institute of General Pathology and Center for Studies on Cellular Pathology of the CNR, Milan, Italy

²Correspondence: DIBIT, San Raffaele H Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. E-mail: elisabetta.ferrero{at}hsr.it

A growing body of evidence suggests that chromogranin A (CgA), a secretory protein released by many neuroendocrine cells and frequently used as a diagnostic and prognostic serum marker for a range of neuroendocrine tumors, is a precursor of several bioactive fragments. This work was undertaken to assess whether the N-terminal fragment CgA_1–76 (called vasostatin I) can inhibit the proangiogenic activity of vascular endothelial growth factor (VEGF), a factor involved in tumor growth. The effect of recombinant human vasostatin I (VS-1) on VEGF-induced human umbilical endothelial cells (HUVEC) signaling, proliferation, migration, and organization has been investigated. We have found that VS-1 (3 µg/ml; 330 nM) can inhibit VEGF-induced ERK phosphorylation, as well as cell migration, proliferation, morphogenesis, and invasion of collagen gels in various in vitro assays. In addition, VS-1 could inhibit the formation of capillary-like structures in Matrigel plugs in a rat model. VS-1 could also inhibit basal ERK phosphorylation and motility of HUVEC, leading to a more quiescent state in the absence of VEGF, without inducing apoptotic or necrotic effects. Conclusion: These findings suggest that vasostatin I may play a novel role as a regulator of endothelial cell function and homeostasis. —Belloni, D., Scabini, S., Foglieni, C., Veschini, L., Giazzon, A., Colombo, B., Fulgenzi, A., Helle, K. B., Ferrero, M. E., Corti, A., Ferrero, E. The vasostatin-I fragment of chromogranin A inhibits VEGF-induced endothelial cell proliferation and migration.

Key Words: ERK/MAPK • capillary-like structures