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mTOR regulates vascular smooth muscle cell differentiation from human bone marrow-derived mesenchymal progenitors

Authors

  • B. Hegner
  • M. Lange
  • A. Kusch
  • K. Essin
  • O. Sezer
  • E. Schulze-Lohoff
  • F.C. Luft
  • M. Gollasch
  • D. Dragun

Journal

  • Arteriosclerosis Thrombosis and Vascular Biology

Citation

  • Arterioscler Thromb Vasc Biol 29 (2): 232-238

Abstract

  • OBJECTIVE: Vascular smooth muscle cells (VSMCs) and circulating mesenchymal progenitor cells (MSCs) with a VSMC phenotype contribute to neointima formation and lumen loss after angioplasty and during allograft arteriosclerosis. We hypothesized that phosphoinositol-Akt-mammalian target of rapamycin-p70S6 kinase (PI3K/Akt/mTOR/p70S6K) pathway activation regulates VSMC differentiation from MSCs. METHODS AND RESULTS: We studied effects of PI3K/Akt/mTOR signaling on phenotypic modulation of MSC and VSMC marker expression, including L-type Ca(2+) channels. Phosphorylation of Akt and p70S6K featured downregulation of VSMC markers in dedifferentiated MSCs. mTOR inhibition with rapamycin at below pharmacological concentrations blocked p70S6K phosphorylation and induced a differentiated contractile phenotype with smooth muscle (sm)-calponin, sm-alpha-actin, and SM protein 22-alpha (SM22alpha) expression. The PI3K inhibitor Ly294002 abolished Akt and p70S6K phosphorylation and reversed the dedifferentiated phenotype via induction of sm-calponin, sm-alpha-actin, SM22alpha, and myosin light chain kinase. Rapamycin acted antiproliferative without impairing MSC viability. In VSMCs, rapamycin increased a homing chemokine for MSCs, stromal cell-derived factor-1-alpha, at mRNA and protein levels. The CXCR4-mediated MSC migration toward conditioned medium of rapamycin-treated VSMCs was enhanced. CONCLUSIONS: We describe novel pleiotropic effects of rapamycin at very low concentrations that stabilized differentiated contractile VSMCs from MSCs in addition to exerting antiproliferative and enhanced homing effects.


DOI

doi:10.1161/ATVBAHA.108.179457