The Neuropeptide Catestatin Acts As a Novel Angiogenic Cytokine via a Basic Fibroblast Growth Factor–Dependent Mechanism

Abstract

Rationale:The neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone.Objective: Catestatin shares several functions with angiogenic factors. We therefore reasoned that catestatin induces growth of new blood vessels. Methods and Results:Catestatin induced migration, proliferation, and antiapoptosis in endothelial cells and exerted capillary tube formation in vitro in a Matrigel assay, and such effects were mediated via G protein, mitogen-activated protein kinase, and Akt. Catestatin-induced endothelial cell functions are further mediated by basic fibroblast growth factor, as shown by blockade of effects by a neutralizing fibroblast growth factor antibody. Furthermore, catestatin released basic fibroblast growth factor from endothelial cells and stimulated fibroblast growth factor signaling. In addition to its function on endothelial cells, catestatin also exerted effects on endothelial progenitor cells and vascular smooth muscle cells. In vivo, catestatin induced angiogenesis in the mouse cornea neovascularization assay and increased blood perfusion and number of capillaries in the hindlimb ischemia model. In addition to angiogenesis, catestatin increased density of arterioles/arteries and incorporation of endothelial progenitor cells in the hindlimb ischemia model, indicating induction of arteriogenesis and postnatal vasculogenesis. Conclusion:We conclude that catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. (Circ Res. 2010;107:1326-1335.) Key Words: angiogenesis Ⅲ blood vessels Ⅲ endothelium Ⅲ endothelial progenitor cells C hromogranin (Cg)A, the index member of the chromogranin/secretogranin protein family, is the major soluble protein of catecholamine storage vesicles of sympathetic nerve terminals and the adrenal medulla. 1,2 CgA is a proprotein giving rise to biological active peptides like the dysglycemic hormone pancreastatin, 3 the vasodilator vasostatin, 4 and catestatin 5 (CST) ), which inhibits catecholamine release by acting as a nicotinic cholinergic antagonist, resulting in a negative-feedback mechanism. Although plasma CgA is high in human essential (hereditary) hypertension, the plasma concentration of CST is lower in both established cases and in normotensive subjects with a family history of the disease, 6 suggesting a mechanism whereby diminished CST might increase the risk for later development of hypertension. Consistent with the human findings, high blood pressure has been reported in mice after targeted ablation of the Chga gene (Chga knockout), and such high blood pressure can be "rescued" either by replacement with CST or introduction of the human ortholog in the Chga knockout background. 7 Angiogenesis, the growth of new vessels from the preexisting vasculature, is an important process in many physiological conditions including embryonic development and wound healing. However, defects in the regula- Original received February 25, 2010; revision received September 27, 2010;...

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“…[ 53 ] In addition, CGA, the protein from which CAT is derived, was shown to be upregulated by hypoxia in neuronal cells after transient hypoxia, [ 54 ] a typical characteristic of angiogenic factors like vascular endothelial growth factor (VEGF). In order to investigate both biocompatibility and the angiogenic potential of the fi lms, HUVECs were seeded on the (PAR/HA) 24 +CAT and compared with control surfaces, tissue culture poly(styrene (TCPS), and (PAR/HA) 24 .…”

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“…It functions in many diferent processes within the body including secretion of histamine from mast cells, defense against microbes, vasodilation, and atraction of monocytes. It has also been observed that catestatin acts in a proangiogenic capacity, involved in inducing proliferation and migration of endothelial cells Physiologic and Pathologic Angiogenesis -Signaling Mechanisms and Targeted Therapyas well as formation of capillary tubes [49,50]. This is accomplished through stimulating release of bFGF, which in turn will activate MAPK via binding to FGFR-1 as previously discussed [49,50].…”

“…This is accomplished through stimulating release of bFGF, which in turn will activate MAPK via binding to FGFR-1 as previously discussed [49,50]. It has also been shown that catestatin activates other signal cascades such as PI3K/Akt, serving an anti-apoptotic role to promote cell survival [50].…”

“…as well as formation of capillary tubes [49,50]. This is accomplished through stimulating release of bFGF, which in turn will activate MAPK via binding to FGFR-1 as previously discussed [49,50].…”

Nanoprecipitated catestatin released from pharmacologically active microcarriers (PAMs) exerts pro-survival effects on MSC

“…Moreover a positive effect of CST on monocyte migration in-vitro and the induction of angiogenesis, arteriogenesis and vasculogenesis in the unilateral mouse hind limb ischemia model by a basic fibroblast growth factor (bFGF)-dependent mechanism has been demonstrated (Egger et al, 2008;Theurl et al, 2010). Based on the above-mentioned 70 findings, it is clear that CST exerts a protective and proangiogenetic role via the activation of survival kinases.…”