Simvastatin enhances bone marrow stromal cell differentiation into endothelial cells via Notch signaling pathway

  • Xu J
  • Liu X
  • Chen J
 et al. 
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Bone marrow stromal cells (BMSCs), are capable of differentiating into multiple cell lineages including endothelial cells. Simvastatin, a HMG-CoA reductase inhibitor that is used as a cholesterol-lowering agent, promotes endothelial differentiation from epithelial progenitor cells (EPC). The Notch signaling pathway, which plays a key role in multiple cell functions such as differentiation, proliferation and apoptosis, can be regulated by simvastatin. Therefore, we examined the effect of simvastatin on BMSC differentiation into endothelial cells and the underlying mechanisms. We observed that simvastatin stimulation of rat BMSCs resulted in a significantly increased expression of endothelial-specific genes and proteins, including von Willebrand factor (vWF), CD31, vascular endothelial-cadherin (VE-cadherin), vascular endothelial growth factor receptor-2 (VEGFR2, Flk-1) and VEGF receptor 1 (VEGFR-1, Flt-1). Simvastatin also significantly increased capillary tube-like formation of the BMSCs The intracellular cleavage of Notch (NICD) was markedly facilitated by simvastatin in BMSCs. Incubation of BMSCs with a gamma-secretase inhibitor or Notch1 siRNA, which significantly inhibited the formation of NICD, blocked the expression of endothelial-specific markers in BMSCs and their differentiation into functional endothelial cells. These data suggest that simvastatin induces rat BMSCs differentiation into endothelial cells via a Notch signaling pathway. Key words: BMSCs, Endothelial cell differentiation, Simvastatin, Notch signaling.

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  • J Xu

  • X Liu

  • J Chen

  • A Zacharek

  • X Cui

  • S Savant-Bhonsale

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