title: A new chromogranin A-dependent angiogenic switch activated by thrombin.
abstract: Angiogenesis, the formation of blood vessels from pre-existing vasculature, is regulated by a complex interplay of anti and proangiogenic factors. We found that physiologic levels of circulating chromogranin A (CgA), a protein secreted by the neuroendocrine system, can inhibit angiogenesis in various in vitro and in vivo experimental models. Structure-activity studies showed that a functional anti-angiogenic site is located in the C-terminal region, whereas a latent anti-angiogenic site, activated by cleavage of Q76-K77 bond, is present in the N-terminal domain. Cleavage of CgA by thrombin abrogated its anti-angiogenic activity and generated fragments (lacking the C-terminal region) endowed of potent proangiogenic activity. Hematologic studies showed that biologically relevant levels of forms of full-length CgA and CgA1-76 (anti-angiogenic) and lower levels of fragments lacking the C-terminal region (proangiogenic) are present in circulation in healthy subjects. Blood coagulation caused, in a thrombin-dependent manner, almost complete conversion of CgA into fragments lacking the C-terminal region. These results suggest that the CgA-related circulating polypeptides form a balance of anti and proangiogenic factors tightly regulated by proteolysis. Thrombin-induced alteration of this balance could provide a novel mechanism for triggering angiogenesis in pathophysiologic conditions characterized by prothrombin activation.
authors.affiliation: Tumor Biology and Vascular Targeting Unit, Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Crippa
authors.forename: Mimma
authors.initials: M
authors.lastname: Bianco
authors.forename: Barbara
authors.initials: B
authors.lastname: Colombo
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gasparri
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferrero
authors.forename: Y Peng
authors.initials: YP
authors.lastname: Loh
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
mesh_terms: D000818:Animals; D002642:Chick Embryo; D053379:Chromogranin A / Q000737:chemistry* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D053379:Chromogranin A; D010446:Peptide Fragments