Chromogranin A protects vessels against tumor necrosis factor alpha-induced vascular leakage.

Elisabetta Ferrero, Silvia Scabini, Elena Magni, Chiara Foglieni, Daniela Belloni, Barbara Colombo, Flavio Curnis, Antonello Villa, Maria Elena Ferrero, Angelo Corti

Research output: Contribution to journalArticle

Abstract

Elevated levels of circulating chromogranin A (CgA), a protein stored in the secretory granules of many neuroendocrine cells and neurons, have been detected in the blood of patients with neuroendocrine tumors or heart failure. The pathophysiological role of increased secretion of CgA is unknown. Using mice bearing subcutaneous tumors genetically engineered to secrete CgA in circulation, we have found that increased blood levels of this protein prevent vascular leakage induced by tumor necrosis factor-alpha (TNF) in the liver venous system. Structure-activity studies, carried out with CgA fragments administered to normal mice, showed that an active site is located within residues 7-57 of CgA. Accordingly, an anti-CgA antibody directed to residues 53-57 inhibited the effect of circulating CgA, either endogenously produced or exogenously administered, on liver vessels. Studies of the mechanism of action showed that CgA inhibits TNF-induced VE-cadherin down-regulation and barrier alteration of cultured endothelial cells, in an indirect manner. Other effectors, such as thrombin and vascular endothelial growth factor were partially inhibited by CgA N-terminal fragments in in vitro permeability assays. These findings suggest that circulating CgA could help regulate the endothelial barrier function and to protect vessels against TNF-induced plasma leakage in pathological conditions characterized by increased production of TNF and CgA, such as cancer or heart failure.

Original languageEnglish
Pages (from-to)554-556
Number of pages3
JournalFASEB Journal
Volume18
Issue number3
Publication statusPublished - 2004

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  • Cite this

    Ferrero, E., Scabini, S., Magni, E., Foglieni, C., Belloni, D., Colombo, B., Curnis, F., Villa, A., Ferrero, M. E., & Corti, A. (2004). Chromogranin A protects vessels against tumor necrosis factor alpha-induced vascular leakage. FASEB Journal, 18(3), 554-556.