Chromogranin A protects vessels against tumor necrosis factor alpha-induced vascular leakage.
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.
Ferrero
Elisabetta
E
Department Biological and Technological Research (DIBIT), San Raffaele H Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. elisabetta.ferrero@hsr.it
Scabini
Silvia
S
Magni
Elena
E
Foglieni
Chiara
C
Belloni
Daniela
D
Colombo
Barbara
B
Curnis
Flavio
F
Villa
Antonello
A
Ferrero
Maria Elena
ME
Corti
Angelo
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D001665:Binding Sites; D015820:Cadherins / Q000502:physiology; D019559:Capillary Leak Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects; D053379:Chromogranin A; D002864:Chromogranins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000517:prevention & control; D005260:Female; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D008102:Liver Circulation / Q000187:drug effects; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013917:Thrombin / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D000099152:Cadherin 5
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015820:Cadherins; D053379:Chromogranin A; D002864:Chromogranins; D010446:Peptide Fragments; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D013917:Thrombin; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C506150:CHGA protein, human; C506155:chromogranin A, mouse