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Am J Physiol Cell Physiol 296: C535-C543, 2009. First published December 24, 2008; doi:10.1152/ajpcell.00310.2008
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

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

Jian Xu,1,2,3,* Xinfeng Liu,1,* Jieli Chen,3 Alex Zacharek,3 Xu Cui,3 Smita Savant-Bhonsale,4 Zhenguo Liu,2 and Michael Chopp3,5

1Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; 2Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio; 3Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan; 4Neurobiology, Theradigm, Baltimore, Maryland; 5Department of Physics, Oakland University, Rochester, Michigan

Submitted 11 June 2008 ; accepted in final form 19 December 2008

Bone marrow stromal cells (BMSCs) are capable of differentiating into multiple cell lineages including endothelial cells. Simvastatin, an 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 involved in this process. We observed that simvastatin stimulation of rat BMSCs resulted in 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 tubelike formation of the BMSCs. In addition, the intracellular cleavage of Notch (NICD) was markedly enhanced by simvastatin in BMSCs. Incubation of BMSCs with a {gamma}-secretase inhibitor, or Notch1 small interfering RNA (siRNA) that 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.

endothelial-specific gene and protein expression; intracellular cleavage of Notch; tube formation


Address for reprint requests and other correspondence: J. Chen, Henry Ford Hospital, Neurology Research, Education & Research Bldg, Rm. 3091, Detroit, MI, 48202 (E-mail: jieli{at}neuro.hfh.edu) or Z. Liu, Davis Heart & Lung Research Institute, The Ohio State Univ. Medical Center, Rm. 260 DHLRI; 473 West 12th Ave., Columbus, OH 43210 (E-mail: zhenguo.liu{at}osumc.edu)






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