Beschreibung:
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<jats:italic>Objective—</jats:italic>
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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.
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<jats:italic>Methods and Results—</jats:italic>
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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-α-actin, and SM protein 22-alpha (SM22α) expression. The PI3K inhibitor Ly294002 abolished Akt and p70S6K phosphorylation and reversed the dedifferentiated phenotype via induction of sm-calponin, sm-α-actin, SM22α, 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.
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<jats:italic>Conclusions—</jats:italic>
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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.
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