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.

Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame

“…It has been reported that three different ELISA assays display different specificities for full-length CgA and its fragments, due to the use of the same capture antibody against CgA or VST I N-terminal regions coupled with three different detection antibodies against epitopes located in the central region of CgA, or against the six C-terminal residues of full-length CgA, or the six C-terminal residues of VST I. Indeed, these assays could detect intact and processed CgA, only intact CgA or only VST I, respectively (Helle & Corti 2015). Therefore, the detection of intact/cleaved CgA depends on the employed antibody.…”

“…Besides being stored into secretory vesicles, the members of the granin family have many common properties, such as a similar acidic isoelectric point, the capacity to bind calcium ions and the ability to form aggregates. Furthermore, their structure typically includes multiple dibasic cleavage sites, which allow the processing into smaller peptides, each displaying a differential function (O'Connor & Frigon 1984, Gerdes et al 1988, Borges et al 2010, Mahata et al 2010, SanchezMargalet et al 2010, Helle & Corti 2015. Human CgA is encoded by the CHGA gene, located on chromosome 14q32.12.…”

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…Figure 6 shows the effects of IGF-1 deficiency and hypertension on the hippocampal expression of the angiogenesis inhibitors Serpinf1 (PEDF), f i b u l i n -5 ( F b l n 5 ) ( S u l l i v a n e t a l . 2 0 0 7 ) , thromhospondin-1 (Thbs1) (Lawler 2002), Thbs2 (Volpert et al 1995), the potent anti-angiogenic chemokine platelet factor 4 (Pf4) (Bikfalvi 2004); vasohibin-1 (Vash1), which is a newly recognized (Takano et al 2014), Adamts1 ("a disintegrin and metalloproteinase with thrombospondin motifs 1"), which inhibits angiogenesis (Lee et al 2006) by suppressing endothelial cell proliferation; Col18a1, whose expression level impacts endostatin signaling and endothelial angiogenic capacity (Li and Olsen 2004) (endostatin, a potent inhibitor of angiogenesis, is a 20-kDa C-terminal fragment derived from type XVIII collagen); semaphorin-3F (Sema3f) (Ungvari et al 2011b;Frisbee et al 2007); tenomodulin (Tnmd) (Oshima et al 2003); brainspecific angiogenesis inhibitor 1 (Bai1; also known as adhesion G protein-coupled receptor B1 [ADGRB1]) (Nishimori et al 1997); chromogranin A (Chga), which encodes the precursor to several angiogenesis inhibitor peptides including vasostatin-1 and vasostatin-2 (Helle and Corti 2015) and maspin ("mammary serine protease inhibitor"; encoded by the Serpinb5 gene (Qin and Zhang 2010). Figure 7 shows the expression of Tnfa, whose overproduction has been causally linked to microvascular rarefaction (Frisbee et al 2014); Tgfb1, which regulates multiple aspects of the angiogenic process and contributes to hypertension-induced microvascular rarefaction in the heart (Koitabashi et al 2011); Tgfa; angiogenin (Ang, also known as ribonuclease 5), which is a potent stimulator of angiogenesis and an inhibitor of endothelial apoptosis; Edil3 (EGF-like repeats and discoidin Ilike domains 3), which encodes a glycoprotein secreted by endothelial cells that regulates apoptosis, cell migration (Zhong et al 2003) and induces cerebral angiogenesis in mice (Fan et al 2008); midkine (Mdk, also known as neurite growth-promoting factor 2 or NEGF2), which is a pleiotropic growth factor regulating cell proliferation, cell migration and promoting angiogenesis (Mashour et al 2001 [HB-GAM]), which is a pro-angiogenic growth factor that is structurally related to midkine and whose expression in the adult brain is induced by ischemia; Tymp (thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor [ECGF1], which stimulates endothelial cell proliferation and induces angiogenesis in the brain …”

Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients

“…Among the wide range of angiogenesis regulators so far discovered, recent studies have shown that chromogranin A (CgA) may have an important role in the regulation of angiogenesis (15,16). CgA is a glycosylated, sulfated, and phosphorylated protein, 439 residue-long, stored in the secretory vesicles of many neuroendocrine cells and neurons (17), and exocytotically released in circulation together with the costored hormones, to reach 0.5 to 1 nmol/L levels in normal conditions (18).…”