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;...

Background Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is up-regulated by hypoxia and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells. Methods and Results In-vivo secretoneurin improved left ventricular function, inhibited remodeling and reduced scar formation. In the infarct border zone secretoneurin induced coronary angiogenesis as shown by increased density of capillaries and arteries. In-vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis and activated Akt and ERK in coronary endothelial cells. Effects were abrogated by a VEGF-antibody and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells and binding was blocked by heparinase indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its co-receptor neuropilin 1. In endothelial cells secretoneurin also stimulated FGF receptor-3 and IGF-1 receptor and in coronary vascular smooth muscle cells we observed stimulation of VEGF receptor-1 and FGF receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin m-RNA and protein. Conclusions Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low affinity binding sites and neuropilin 1 and stimulates further growth factor receptors like FGF receptor-3. Our in-vivo findings indicate that secretoneurin might be a promising therapeutic tool in ischemic heart disease.