Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis
Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis
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DOI：
10.1038/sj.ki.5002112
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发表时间：
2007-04-01
影响因子：
19.6
通讯作者：
Guba, M.
中科院分区：
文献类型：
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作者：
Huber, S.;Bruns, C. J.;Guba, M.
淋巴系统并发症是肾移植中基于哺乳动物雷帕霉素靶蛋白（mTOR）的免疫抑制剂的常见副作用。因此，我们研究了mTOR抑制剂雷帕霉素，除了其已知的抗血管生成作用，是否也阻碍再生淋巴管生成。在小鼠皮瓣模型中，雷帕霉素损害了手术切口淋巴流的恢复，导致这些动物的伤口水肿延长。重要的是，雷帕霉素的抗淋巴管生成作用与伤口愈合的一般抑制无关，如体内Matrigel TM淋巴管生成测定和淋巴管瘤模型所示。低至1 ng/ml的雷帕霉素浓度在体外分别有效抑制血管内皮生长因子（VEGF）-C驱动的分离的人淋巴管内皮细胞（LEC）的增殖和迁移。在机制上，mTOR抑制损害VEGF-A以及VEGF-C经由mTOR到LEC中的p70 S6激酶的下游信号传导。总之，我们提供了广泛的实验证据，mTOR抑制剂的抗淋巴管生成活性，这表明应避免在组织损伤后早期使用mTOR抑制剂。相反，雷帕霉素及其衍生物的抗淋巴管生成特性可能分别为恶性肿瘤的预防和治疗提供治疗价值。
Lymphatic complications are common side effects of mammalian target of rapamycin ( mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigel TM lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.