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1 Department of Surgery, Dartmouth Medical School, Lebanon, NH, USA; Department of Pharmacology and Toxicology, Dartmouth Medical School, Lebanon, NH, USA
2 Department of Surgery, Dartmouth Medical School, Lebanon, NH, USA
3 Department of Cell Biology, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: Kathleen.A.Martin{at}Dartmouth.edu.
Vascular smooth muscle cells (VSMC) in mature, normal blood vessels exhibit a differentiated, quiescent, contractile morphology, but injury induces a phenotypic modulation toward a proliferative, de-differentiated, migratory phenotype with upregulated extracellular matrix protein synthesis (synthetic phenotype) which contributes to intimal hyperplasia. The mTOR pathway inhibitor rapamycin inhibits intimal hyperplasia in animal models and in human clinical trials. We report that rapamycin treatment induces differentiation in cultured synthetic phenotype VSMC from multiple species. VSMC treated with rapamycin assumed a contractile morphology, quantitatively reflected by a 67% decrease in cell area. Total protein and collagen synthesis were also inhibited by rapamycin. Rapamycin induced expression of the VSMC differentiation marker contractile proteins SM 
-actin, calponin, and SM myosin heavy chain (SM-MHC), as observed by immunoblotting and immunohistochemistry. Notably, we detected a striking rapamycin induction of calponin and SM-MHC mRNA, suggesting a role for mTOR in transcriptional control of VSMC gene expression. Rapamycin also induced expression of the cyclin dependent kinase inhibitors p21cip and p27kip, consistent with cell cycle withdrawal. Rapamycin inhibits mTOR, a signaling protein that regulates protein synthesis effectors, including p70 S6K1. Overexpression of p70 S6K1 inhibited rapamycin-induced contractile protein and p21cip expression, suggesting that this kinase opposes VSMC differentiation. In conclusion, we report that regulation of VSMC differentiation is a novel function of the rapamycin-sensitive mTOR signaling pathway.
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