Angiogenic effects of adrenomedullin in ischemia and tumor growth
Angiogenic effects of adrenomedullin in ischemia and tumor growth
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DOI：
10.1161/01.res.0000138018.61065.d1
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发表时间：
2004-08-20
影响因子：
20.1
通讯作者：
Nagai, R
中科院分区：
文献类型：
--
作者：
Iimuro, S;Shindo, T;Nagai, R
肾上腺髓质素（AM）是一种新型的血管舒张肽，参与调节循环稳态，并与心血管疾病的病理生理有关。我们测试了AM也具有血管生成特性的假设。利用激光多普勒灌注成像，我们发现AM刺激小鼠后肢缺血模型中患肢的血流恢复。AM通过促进缺血肢体血管内皮生长因子（VEGF）的表达发挥了这种作用，CD 31免疫染色显示血流增强反映了侧支毛细血管密度增加。AM通过促进肿瘤血管生成，促进皮下移植肉瘤180肿瘤细胞的生长。然而，杂合子AM基因敲除小鼠（AM（+/-））表现出显着较少的血流恢复与较少的侧支毛细血管的发展和VEGF表达比野生型同窝仔。类似地，用AM的竞争性抑制剂AM 22 -52处理的小鼠显示毛细血管发育减少，并且肉瘤180肿瘤的生长在AM（+/-）和AM 22 -52处理的小鼠中被抑制。值得注意的是，VEGF或AM的施用挽救了AM（+/-）和AM 22 -52处理的小鼠中的血流恢复和毛细血管形成。在内皮细胞和成纤维细胞的共培养物中，AM增强VEGF诱导的毛细血管形成，而在内皮细胞的培养物中，AM增强VEGF诱导的Akt激活。这些结果表明，AM具有新的血管生成特性介导的能力，增强VEGF的表达和Akt的活性。这可能使AM成为缓解缺血的有用治疗工具;相反，AM抑制剂可能有助于肿瘤生长的临床管理。
Adrenomedullin (AM) is a novel vasodilating peptide involved in the regulation of circulatory homeostasis and implicated in the pathophysiology of cardiovascular disease. We tested the hypothesis that AM also possesses angiogenic properties. Using laser Doppler perfusion imaging, we found that AM stimulated recovery of blood flow to the affected limb in the mouse hind-limb ischemia model. AM exerted this effect in part by promoting expression of vascular endothelial growth factor (VEGF) in the ischemic limb, and immunostaining for CD31 showed the enhanced flow to reflect increased collateral capillary density. By enhancing tumor angiogenesis, AM also promoted the growth of subcutaneously transplanted sarcoma 180 tumor cells. However, heterozygotic AM knockout mice (AM(+/-)) showed significantly less blood flow recovery with less collateral capillary development and VEGF expression than their wild-type littermates. Similarly, mice treated with AM22-52, a competitive inhibitor of AM, showed reduced capillary development, and growth of sarcoma 180 tumors was inhibited in AM(+/-) and AM22-52-treated mice. Notably, administration of VEGF or AM rescued blood flow recovery and capillary formation in AM(+/-) and AM22-52-treated mice. In cocultures of endothelial cells and fibroblasts, AM enhanced VEGF-induced capillary formation, whereas in cultures of endothelial cells AM enhanced VEGF-induced Akt activation. These results show that AM possesses novel angiogenic properties mediated by its ability to enhance VEGF expression and Akt activity. This may make AM a useful therapeutic tool for relieving ischemia; conversely, inhibitors of AM could be useful for clinical management of tumor growth.