**1. Introduction**

Human chromogranin A (CgA), a member of the "*granin*" protein family, is a 439-residues long protein present in the secretory vesicles of various normal and neoplastic neuroendocrine tissues and neurons, and exocytotically released into the blood stream upon cell stimulation [1,2].

Abnormal levels of CgA, detected by immunoassay, are present in the blood of patients with neuroendocrine tumors or with other diseases, such as cardiovascular, gastrointestinal, renal, and inflammatory diseases [3].

CgA undergoes various post-translational modifications in different cells and tissues, including phosphorylation, sulphation, glycosylation, and proteolytic cleavage [2,4]. Intra-granular and/or extra-cellular proteolytic enzymes, such as furin, cathepsin L, prohormone convertase 1 and 2, thrombin and plasmin, can cleave the full-length CgA precursor (CgA1-439) at different sites to generate various biologically active fragments involved in the regulation of the innate immunity [5–8], cardiovascular system [9–12], metabolism [13–15], angiogenesis [16–18], tissue repair [19] and tumor growth [14,20,21]. These fragments include N-terminal large polypeptide fragments (e.g., CgA1-373) [17], as well as shorter fragments, such as CgA1-76 (vasostatin-1) [9], CgA79-113 (vasoconstrictive-inhibitory factor) [22],

**Citation:** Corti, A.; Anderluzzi, G.; Curnis, F. Neuropilin-1 and Integrins as Receptors for Chromogranin A-Derived Peptides. *Pharmaceutics* **2022**, *14*, 2555. https://doi.org/ 10.3390/pharmaceutics14122555

Academic Editor: Tatiana B. Tennikova

Received: 14 October 2022 Accepted: 18 November 2022 Published: 22 November 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

CgA1-113 (vasostatin-2) [23], CgA250-301 (pancreastatin) [13], CgA352-372 (catestatin) [24], CgA411-436 (serpinin) [25,26], and others [3,14]. The in vitro and in vivo assays used to investigate the biological effects of all these fragments and their mechanisms are reviewed in detail elsewhere [2,6,10,12,14,18,26].

Marie Hélène Metz-Boutigue and coll. were the first to demonstrate that vasostatin-1 and catestatin, two of the most investigated fragments, are endowed of antibacterial and antifungal activities [2,6,27,28]. However, several studies have shown that these peptides can also affect the physiology of mammalian cells and exert several regulatory functions under physiological and pathological conditions. For example, catestatin and vasostatin-1 induce vasodilation [2,9,29]. In addition, catestatin inhibits nicotinic-cholinergic-stimulated catecholamine secretion [24], promotes the release of histamine from rat mast cells and stimulates monocyte chemotaxis [30]. Furthermore, vasostatin-1, catestatin, and fulllength CgA1-439 reduce myocardial contractility and relaxation [31–33], counteract the β-adrenergic-stimulated positive inotropism, and regulate the coronary tone [12]. Additionally, CgA and vasostatin-1 can affect, in an opposite manner, the adhesion of cardiomyocytes, keratinocytes, fibroblasts, and smooth muscle cells to proteins of the extracellular matrix [2,34]. CgA and vasostatin-1 can also prevent the disassembly of vascular endothelial cadherin-dependent adherens junctions [35], inhibit vascular leakage induced by tumor necrosis factor-α [35], and exert angiogenic effects [17], whereas catestatin and CgA1-373 promote angiogenesis [16,17]. In human microvascular endothelial cells, vasostatin-1 inhibits the expression of tumor necrosis factor-α–induced intercellular adhesion molecule-1, the release of monocyte chemoattractant protein-1, and the relocation of high mobility group box-1 [36]. Physiological concentrations of full-length CgA1-439, and vasostatin-1 may also have a regulatory role in wound healing [19] and tumor growth [21,37,38], and exert several other biological effects in the regulation of metabolism and cardiovascular system [14].

Despite the numerous activities reported for CgA, vasostatin-1, and catestatin, limited information is available on the underlying receptors. Biochemical studies have shown that vasostatin-1 can interact with phosphatidylserine and other membrane-relevant phospholipids [39]. Furthermore, a mechanism involving the binding of vasostatin-1 to heparan sulfate proteoglycans and phosphoinositide 3-kinase-dependent eNOS phosphorylation has been observed in bovine aortic endothelial cells [40]. Other studies have shown that the nicotinic acetylcholine receptor mediates the inhibitory effect of catestatin on the secretion of catecholamines from chromaffin cells [14,24]. Catestatin can also act on the β2-adrenergic receptor, as suggested by the results of a combination of experimental and computational studies [41]. Interestingly, recent studies have shown that integrins and neuropilin-1 may also act as important receptors for CgA, vasostatin-1, CgA1-373, and other fragments, in endothelial cell biology, cardiovascular function, angiogenesis, wound healing, and tumor growth. Here, we review the structural requirements for the interactions of CgA and CgA-fragments with neuropilin-1 and integrins, their biological effects, their mechanisms, and the potential use of compounds targeting these ligand-receptor interactions for cancer diagnosis and therapy.
