The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells.
The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells.
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DOI：
10.1161/circulationaha.111.076950
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发表时间：
2012-11-20
期刊：
影响因子：
37.8
通讯作者：
Kirchmair R
中科院分区：
文献类型：
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作者：
Albrecht-Schgoer K;Schgoer W;Holfeld J;Theurl M;Wiedemann D;Steger C;Gupta R;Semsroth S;Fischer-Colbrie R;Beer AG;Stanzl U;Huber E;Misener S;Dejaco D;Kishore R;Pachinger O;Grimm M;Bonaros N;Kirchmair R
分泌神经磷酸酶是一种位于沿着血管的神经纤维中的神经肽，在缺氧时上调并诱导血管生成。我们检验了分泌神经磷酸酶基因治疗在心肌梗死大鼠模型中发挥有益作用的假设，并评估了对冠状动脉内皮细胞的作用机制。体内分泌神经素改善左心室功能，抑制重塑，减少瘢痕形成。在梗死边缘区，分泌神经素诱导的冠状动脉血管生成，表现为毛细血管和动脉密度增加。分泌神经磷酸酶在体外可诱导冠状动脉内皮细胞形成毛细血管，刺激其增殖，抑制其凋亡，并激活Akt和ERK。通过VEGF抗体和分泌神经磷酸酶刺激这些细胞中的VEGF受体来消除效果。此外，分泌神经磷酸酶增加VEGF与内皮细胞的结合，并且结合被肝素酶阻断，表明分泌神经磷酸酶刺激VEGF与硫酸乙酰肝素蛋白聚糖结合位点的结合。此外，分泌神经磷酸酶增加VEGF与其共受体神经纤毛蛋白1的结合。在内皮细胞中，分泌神经素也刺激FGF受体-3和IGF-1受体，在冠状动脉血管平滑肌细胞中，我们观察到VEGF受体-1和FGF受体-3的刺激。心肌梗死后心肌细胞暴露于缺氧和缺血心脏显示分泌神经磷酸酶mRNA和蛋白质增加。我们的数据表明，分泌神经磷酸酶作为一种内源性刺激血管内皮细胞的VEGF信号通过增强结合的VEGF低亲和力结合位点和神经纤毛蛋白1，并刺激进一步的生长因子受体，如FGF受体-3。我们的体内研究结果表明，分泌神经磷酸酶可能是一个有前途的治疗工具，在缺血性心脏病。
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. 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. 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.