Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: Pleiotropic and dose-dependent effect on tumor vascular stabilization
Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: Pleiotropic and dose-dependent effect on tumor vascular stabilization
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DOI：
10.3892/ijo.2013.1833
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发表时间：
2013-04-01
影响因子：
5.2
通讯作者：
Wu, Gang
中科院分区：
文献类型：
--
作者：
Chen, Yeshan;Zhang, Sheng;Wu, Gang
他汀类药物已被证实对糖尿病视网膜病变中的微血管具有保护作用，涉及降低血管通透性、维持内皮连接完整性和改善血液灌注，这些是血管“正常化”的替代标志物，但目前没有关于他汀类药物对肿瘤内皮功能的疗效的数据。由于他汀类药物对微血管的生物学行为表现出双相剂量相关反应，我们试图确定双极浓度的他汀类药物是否可以改善血管功能障碍，然后增加刘易斯肺癌和B16 F10黑色素瘤模型中化疗药物的效率。我们的体外研究表明，辛伐他汀以浓度依赖性方式减少缺氧诱导的人脐静脉内皮细胞（HUVEC）的内皮渗漏。在荷瘤小鼠中，低剂量辛伐他汀（0.2 mg/kg）诱导内皮型一氧化氮合酶（eNOS）的上调，使血管偏向周细胞包被和稳定的模式，而高剂量辛伐他汀（10 mg/kg）显着降低活性氧（ROS）诱导的缺氧诱导因子（HIF-1 α）和血管内皮生长因子（VEGF）的表达，减弱VEGF驱动的肿瘤血管高通透性。这些变化最终改善了肿瘤内灌注并减少了肿瘤缺氧。给予辛伐他汀治疗的小鼠顺铂和环磷酰胺导致肿瘤生长较慢。总的来说，辛伐他汀可以促进肿瘤血管正常化，并与化疗药物联合使用时显示出临床获益。
Statins have been confirmed with protective effect to microvessels in diabetic retinopathy, implicated as reducing vascular permeability, maintaining endothelial junction integrity and improving blood perfusion, which are surrogate markers of vascular 'normalization', but no data are currently available on efficacy of statins on tumor endothelial functions. Since statins have been shown to exhibit a biphasic dose-related response on biological behaviour of microvessels, we sought to determine whether statins with bipolar concentrations can ameliorate vessel dysfunction and then increase efficiency of chemotherapeutics in Lewis lung carcinoma and B16F10 melanoma models. Our in vitro study showed that simvastatin reduces hypoxia-induced endothelium leakage in human umbilical vein endothelial cells (HUVEC) in a concentration-dependent manner. In tumor-bearing mice, low-dose simvastatin (0.2 mg/kg) induced upregulation of endothelial NO synthase (eNOS) skewed vessels to a pericyte-coated and stable pattern, while high-dose simvastatin (10 mg/kg) remarkably deceased reactive oxygen species (ROS)-induced hypoxia-inducible factor (HIF-1 alpha) and vascular endothelial growth factor (VEGF) expression, attenuating VEGF-drived tumor vessel hyperpermeability. These changes ultimately improved intratumoral perfusion and decreased tumor hypoxia. Administration of cisplatin and cyclophosphamide to the simvastatin-treated mice resulted in slower tumor growth. Collectively, simvastatin may promote tumor vessel normalization and show clinical benefit when used in combination with chemotherapeutics.