Systemic administration of thrombin peptide TP508 enhances VEGF-stimulated angiogenesis and attenuates effects of chronic hypoxia.
Systemic administration of thrombin peptide TP508 enhances VEGF-stimulated angiogenesis and attenuates effects of chronic hypoxia.
复制标题
全身给予凝血酶肽 TP508 可增强 VEGF 刺激的血管生成并减弱慢性缺氧的影响。
DOI：
10.1159/000348250
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发表时间：
2013
影响因子：
1.7
通讯作者：
Carney,DarrellH
中科院分区：
文献类型：
--
作者：
Olszewska-Pazdrak,Barbara;Carney,DarrellH
由于内皮功能障碍和血管生成因子不能刺激血管生成，慢性伤口和缺血组织的血管重建被削弱。我们最近发现TP508，一种非蛋白水解凝血酶肽，在慢性缺血心脏中增加灌注和NO依赖性血管舒张，并刺激内皮细胞产生NO。在这项研究中，我们研究了TP508对体外常氧和缺氧条件下vegf刺激的血管生成的全身体内影响。小鼠注射生理盐水或TP508, 24 h后切除主动脉，培养定量内皮发芽。注射TP508可增加内皮细胞发芽，增强体外对VEGF的反应。对照外植体暴露于缺氧条件下，基底和vegf刺激的内皮细胞发芽受到抑制。注射TP508可明显阻止这种缺氧作用。因此，全身给药TP508增加了主动脉内皮细胞对VEGF的反应性，减少了慢性缺氧对内皮细胞发芽的影响。对培养的人内皮细胞的研究表明，TP508在缺氧时的保护作用可能涉及刺激内皮细胞NO的产生。这些数据表明，将全身TP508和局部VEGF联合用于缺血性组织血运重建的潜在临床益处。
Revascularization of chronic wounds and ischemic tissue is attenuated by endothelial dysfunction and the inability of angiogenic factors to stimulate angiogenesis. We recently showed that TP508, a nonproteolytic thrombin peptide, increases perfusion and NO-dependent vasodilation in hearts with chronic ischemia and stimulates NO production by endothelial cells. In this study, we investigated systemic in vivo effects of TP508 on VEGF-stimulated angiogenesis in vitro using aortic explants in normoxic and hypoxic conditions. Mice were injected with saline or TP508 and 24 h later aortas were removed and cultured to quantify endothelial sprouting. TP508 injection increased endothelial sprouting and potentiated the in vitro response to VEGF. Exposure of control explants to hypoxia inhibited basal and VEGF-stimulated endothelial cell sprouting. This effect of hypoxia was significantly prevented by TP508 injection. Thus, TP508 systemic administration increases responsiveness of aortic endothelial cells to VEGF and diminishes the effect of chronic hypoxia on endothelial cell sprouting. Studies using human endothelial cells in culture suggest that protective effects of TP508 during hypoxia may involve stimulation of endothelial cell NO production. These data suggest potential clinical benefit of using a combination of systemic TP508 and local VEGF as a therapy for revascularization of ischemic tissue.