A new chromogranin A–dependent angiogenic switch activated by thrombin

• Published in: Blood Vol. 121; no. 2; pp. 392 - 402
• Main Authors: Crippa, Luca, Bianco, Mimma, Colombo, Barbara, Gasparri, Anna M., Ferrero, Elisabetta, Loh, Y. Peng, Curnis, Flavio, Corti, Angelo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.01.2013; American Society of Hematology
• Subjects: Animals; Chick Embryo; Chromogranin A - chemistry; Chromogranin A - metabolism; Enzyme-Linked Immunosorbent Assay; Humans; Mice; Neovascularization, Pathologic - metabolism; Neovascularization, Physiologic - physiology; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Rats; Structure-Activity Relationship; Vascular Biology
• DOI: 10.1182/blood-2012-05-430314
• ISSN: 0006-4971; 1528-0020

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 tightlyregulated byproteolysis. Thrombin-induced alteration of this balance could provide a novel mechanism for triggering angiogenesis in pathophysiologic conditions characterized by prothrombin activation. •Circulating chromogranin A and its fragments form a balance of anti- and pro-angiogenic factors regulated by thrombin-dependent cleavage.•The alteration of this balance could provide a new mechanism for triggering angiogenesis in cancer and other pathophysiologic conditions.