Chromogranin A: a paradoxical player in angiogenesis and vascular biology

Abstract

Half a century after the discovery of chromogranin A as a secreted product of the catecholamine storage granules in the bovine adrenal medulla, the physiological role for the circulating pool of this protein has been recently coined, namely as an important player in vascular homeostasis. While the circulating chromogranin A since 1984 has proved to be a significant and useful marker of a wide range of pathophysiological and pathological conditions involving the diffuse neuroendocrine system, this protein has now been assigned a physiological "raison d'etre" as a regulator in vascular homeostasis. Moreover, chromogranin A processing in response to tissue damage and blood coagulation provides the first indication of a difference in time frame of the regulation of angiogenesis evoked by the intact chromogranin A and its two major peptide products, vasostatin-1 and catestatin. The impact of these discoveries on vascular homeostasis, angiogenesis, cancer, tissue repair and cardio-regulation will be discussed.

Fig. 1

Schematic representation of three different ELISAs with different specificity for full-length CgA and fragments. a. Schematic representation of full-length human CgA_1–439. The regions corresponding to vasostatin-1 (CgA_1–76, N-terminal region), catestatin (CgA_352–372), and C-terminal region 410–439 are also represented with box and circles. b–d Schematic representation of three CgA-ELISAs with different specificity [13]. These assays are based on the use of the same capture antibody (a monoclonal antibody against an epitope present in the N-terminal region of CgA and vasostatin-1) and of three different detection antibodies against epitopes located in the central region of CgA (non-selective ELISA for intact and processed CgA) (b), or against the six C-terminal residues of full-length CgA (selective ELISA for intact CgA) (c), or the six C-terminal residues of vasostatin-1 (selective ELISA for vasostatin-1) (d)

Fig. 2

Schematic representation of the CgA-dependent angiogenic switch activated by thrombin. a Anti-angiogenic sites. The full-length CgA is an anti-angiogenic molecule with the active site in the C-terminal region 410–439. A latent or less active site in the N-terminal region corresponds to vasostatin-1. Proteolytic cleavage at Q76 liberates vasostatin-1, exerting anti-angiogenic activity at physiological concentrations [13]. Both full-length CgA and vasostatin-1 can inhibit bFGF and VEGF, two potent pro-angiogenic factors. Pro-angiogenic sites: full-length CgA contains also a latent pro-angiogenic site within residues 352–372 (corresponding to the catestatin region). Cleavage of CgA at residue R373 by thrombin generates the fragment CgA_1–373 that, like catestatin, can promote angiogenesis by inducing the release of bFGF from endothelial cells [13, 15]. b The angiogenic switch. Schematic representation of the thrombin-activated angiogenic switch in CgA. According to this model, systemically circulating CgA and vasostatin-1 maintain endothelial cell quiescence by their anti-angiogenic potencies. Local activation of thrombin, e.g. in damaged tissues, increases CgA_1-373 at the expense of full-length CgA, shifting the local balance toward a pro-angiogenic state [13]