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;...
Key Words: angiogenesis Ⅲ endothelium Ⅲ gene therapy Ⅲ hypoxia Ⅲ peripheral vascular disease C ardiovascular diseases represent the leading cause of death worldwide. 1 In the case of peripheral arterial disease, a substantial number of patients who develop critical limb ischemia are not eligible for surgical or interventional revascularization and, despite optimal medical therapy, have reduced quality of life and life expectancy. 2,3 This group of patients would require new therapeutic methods to increase collateral blood flow to areas of decreased tissue perfusion distal to arterial occlusion.Angiogenesis, the growth of new blood vessels from the preexisting vasculature, plays an important role in wound healing, tumor growth, diabetic retinopathy, tissue ischemia, and inflammatory diseases. 4 Cytokines mediating this process include vascular endothelial growth factor (VEGF) 5 and basic fibroblast growth factor (b-FGF). 6 For stability of newly formed vessels, recruitment of pericytes and smooth muscle cells (SMCs) is important; such recruitment is known as arteriogenesis, which is mediated by cytokines such as monocyte chemoattractant protein-1 and platelet-derived growth factor (PDGF)-BB. 7,8 Postnatal vasculogenesis, which is the mobilization and incorporation of bone marrow-derived endothelial progenitor cells (EPCs), also plays an important role in the growth of new vessels. 9 Recently, application of endothelial cytokines as proteins or genes has been of scientific and clinical interest to treat limb or myocardial ischemia, a procedure called therapeutic angiogenesis. 10 -14 We recently demonstrated that the neuropeptide secretoneurin (SN) induces angiogenesis and postnatal vasculogen- MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Construction of the Human SN Expression PlasmidSynthetic oligonucleotides encoding SN and a signal peptide were cloned into the expression vector pAAV-MCS (Stratagene). The plasmid vector is described in the Online Data Supplement. Animals, Mouse Hindlimb Ischemia Model, SN Gene Therapy, and Bone Marrow Transplantation ModelMice at ages between 12 and 18 months were subjected to unilateral hindlimb surgery and injected with plasmid DNA expressing SN or green fluorescent protein (GFP) into thigh and calf muscles immediately after surgery.Bone marrow transplantation was performed as described. 19 After hindlimb ischemia, injection of SN plasmid or saline was performed. Blood Flow Measurement and In Vivo Assessment of Limb Function and Ischemic DamageBlood flow measurements were performed using a laser-Doppler perfusion imaging (LDPI) analyzer. Blood perfusion is expressed as LDPI index representing the ratio of left (ie, operated, ischemic leg) versus right (ie, unoperated, not-ischemic leg) limb blood flow. Movement score and analysis of necrosis are described in the Online Data Supplement. Immunofluorescence and Fluorescence-Activated Cell Sorting AnalysisECs were stained for CD31, and arteries/arteriole...
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