Secretoneurin: A New Player in Angiogenesis and Chemotaxis Linking Nerves, Blood Vessels and the Immune System

Abstract

Secretoneurin (SN) represents a 33 amino acid neuropeptide, which is highly conserved between mammals, reptiles, birds, amphibians and fish. It is specifically expressed in endocrine, neuroendocrine and neuronal tissues. In brain, the pattern of SN expression is widespread and unique, partially overlapping with established neurotransmitters. ProSN, the precursor protein, also named secretogranin II, belongs to a class of proteins collectively called chromogranins. Changes in ProSN mRNA, which is significantly regulated by cell depolarisation, represent a useful marker for both rapid and long-lasting changes (positive and negative) of neuronal activity. Under pathophysiological conditions, especially following cellular hypoxia, SN expression can be induced in non-endocrine tissues like muscle cells, pneumocytes or tumor epithelial cells. Several biological effects were attributed to SN. SN releases dopamine from rat striatal slices in a dose dependent manner and influences neurite outgrowth in the developing cerebellum. It potently and specifically attracts monocytes, eosinophils and endothelial cells towards a concentration gradient and acts as an angiogenic cytokine comparable in potency to VEGF. Thus, SN contributes to neurogenic inflammation and might play a role in the (hypoxia-driven) induction of neo-vascularisation in ischemic diseases like peripheral or coronary artery disease, diabetic retinopathia, cerebral ischemia or in solid tumors. The signalling pathways of various biological effects have not been identified in detail, but most data point to a G-protein coupled receptor structure with respective associated intracellular events.

Ceacam1L Modulates STAT3 Signaling to Control the Proliferation of Glioblastoma-Initiating Cells

“…We showed that Ceacam1L-overexpressing hGICs formed larger colonies in soft agar and tumors with massive hemorrhaging in the brains of immunodeficient mice, whereas the knockdown of Ceacam1 blocked GIC proliferation. In addition to previous findings in which Ceacam1 acted as a major effector of VEGFinduced angiogenesis (19,31), we revealed that Ceacam1L regulated the expression of Angpt1, IL18, and secretogranin II, all of which play an important role in vascular development and angiogenesis in GICs (32)(33)(34). Because neovascularization is not only a common characteristic of GBM, but has also been correlated with poor outcomes, these findings indicate that Ceacam1L is an indispensable therapeutic target for GBM.…”

Secretoneurin facilitates endothelium-dependent relaxations in porcine coronary arteries

“…When infused into the brain, secretoneurin stimulates dopamine release from striatal neurons and the basal ganglia, suggesting a role in the neuroendocrine system (35). The protein is constitutively expressed in the adrenal medulla, spinal cord, brain, and ileum (5). The expression of secretoneurin is increased under pathological conditions such as tumoral growth and hypoxia (5,31), and it has been used clinically as a marker for the presence of tumors since its plasma concentration in patients with cancer ranges from 58.3 Ϯ 8.1 to 410 Ϯ 113.9 compared with the 22.1 Ϯ 1.1 fmol/ml levels in healthy subjects (10,28).…”

“…It was abolished when the preparations were incubated with L-NAME in combination with the cyclooxygenase inhibitor indomethacin. The relaxation was not affected by the combination of 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) and 6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-etheno-7H-dibenzo[b,m] [1,5,12,16]tetraazacyclotricosine-5,13-diiumditrifluoroacetate hydrate (UCL 1684), which abrogates endothelium-dependent hyperpolarizations. These results indicate that secretoneurin acutely induces relaxation through the activation of endothelial nitric oxide synthase (eNOS) and cyclooxygenase, with nitric oxide playing the dominant role.…”

“…This gene encodes several peptides including secretogranin, EM66, LF19, manserin, and AM5 (5). Of those, secretoneurin [a 33 amino acid-long, acidic, amphipathic, and heat-stable peptide (5) with high homology in birds, reptiles, fishes, as well as in mammals (18,22)] has been intensively studied in relation to endothelial function.…”

Differential expression and processing of secretogranin II in relation to the status of pheochromocytoma: implications for the production of the tumoral marker EM66

“…In particular, the sequence of human secretogranin II (SgII or SCG2 as given in the HUGO database) contains nine pairs of basic amino acids that represent potential cleavage sites by PCs. Indeed, proteolytic processing of SgII leads to the production of several peptides, such as secretoneurin (SN; SgII 152-184 ) which regulates neurotransmission, inflammatory responses, and gonadotrope activity (Fischer-Colbrie et al 2005, Shyu et al 2008, Zhao et al 2010; EM66 (SgII ) which may participate in the control of feeding behavior in rodents (Boutahricht et al 2005(Boutahricht et al , 2007; and manserin ) whose putative role remains to be established (Yajima et al 2004, Tano et al 2010. The ubiquitous distribution of granins and their derived peptides in nervous, endocrine, and neuroendocrine tissues makes these entities useful markers of secretion from neuroendocrine cells and neoplasms (Rosa & Gerdes 1994).…”