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

  • Authors:
    • Yeshan Chen
    • Sheng Zhang
    • Gang Peng
    • Jing Yu
    • Tao Liu
    • Rui Meng
    • Zhenyu Li
    • Yanxia Zhao
    • Gang Wu
  • View Affiliations

  • Published online on: February 19, 2013     https://doi.org/10.3892/ijo.2013.1833
  • Pages: 1325-1336
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Abstract

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-1α) 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.
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April 2013
Volume 42 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Chen, Y., Zhang, S., Peng, G., Yu, J., Liu, T., Meng, R. ... Wu, G. (2013). 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. International Journal of Oncology, 42, 1325-1336. https://doi.org/10.3892/ijo.2013.1833
MLA
Chen, Y., Zhang, S., Peng, G., Yu, J., Liu, T., Meng, R., Li, Z., Zhao, Y., Wu, G."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". International Journal of Oncology 42.4 (2013): 1325-1336.
Chicago
Chen, Y., Zhang, S., Peng, G., Yu, J., Liu, T., Meng, R., Li, Z., Zhao, Y., Wu, G."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". International Journal of Oncology 42, no. 4 (2013): 1325-1336. https://doi.org/10.3892/ijo.2013.1833