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

Item Type:Article
Title:mTOR regulates vascular smooth muscle cell differentiation from human bone marrow-derived mesenchymal progenitors
Creators Name:Hegner, B. and Lange, M. and Kusch, A. and Essin, K. and Sezer, O. and Schulze-Lohoff, E. and Luft, F.C. and Gollasch, M. and Dragun, D.
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.
Keywords:1-Phosphatidylinositol 3-Kinase, Bone Marrow Cells, L-Type Calcium Channels, Cell Differentiation, Cell Survival, Cultured Cells, Chemokine CXCL12, Chemotaxis, Chromones, Drug Dose-Response Relationship, Mesenchymal Stem Cells, Morpholines, Muscle Proteins, Vascular Smooth Muscle, Smooth Muscle Myocytes, Phenotype, Protein Kinase Inhibitors, Protein Kinases, Proto-Oncogene Proteins c-akt, 70-kDa Ribosomal Protein S6 Kinases, Signal Transduction, Sirolimus, Time Factors
Source:Arteriosclerosis Thrombosis and Vascular Biology
Publisher:American Heart Association
Page Range:232-238
Date:February 2009
Official Publication:https://doi.org/10.1161/ATVBAHA.108.179457
PubMed:View item in PubMed

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