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dc.contributor.authorBalcells-Camps, Mercedes
dc.contributor.authorMartorell Lopez, Jordi
dc.contributor.authorOlive, Carla
dc.contributor.authorSantacana, Marina
dc.contributor.authorChitalia, Vipul C.
dc.contributor.authorCardoso, Angelo A.
dc.contributor.authorEdelman, Elazer R.
dc.date.accessioned2012-12-13T21:33:01Z
dc.date.available2012-12-13T21:33:01Z
dc.date.issued2010-05
dc.identifier.issn0009-7322
dc.identifier.issn1524-4539
dc.identifier.urihttp://hdl.handle.net/1721.1/75728
dc.descriptionavailable in PMC 2011 May 25en_US
dc.description.abstractBackground— Local modulation of vascular mammalian target of rapamycin (mTOR) signaling reduces smooth muscle cell (SMC) proliferation after endovascular interventions but may be associated with endothelial cell (EC) toxicity. The trilaminate vascular architecture juxtaposes ECs and SMCs to enable complex paracrine coregulation but shields SMCs from flow. We hypothesized that flow differentially affects mTOR signaling in ECs and SMCs and that SMCs regulate mTOR in ECs. Methods and Results— SMCs and/or ECs were exposed to coronary artery flow in a perfusion bioreactor. We demonstrated by flow cytometry, immunofluorescence, and immunoblotting that EC expression of phospho-S6 ribosomal protein (p-S6RP), a downstream target of mTOR, was doubled by flow. Conversely, S6RP in SMCs was growth factor but not flow responsive, and SMCs eliminated the flow sensitivity of ECs. Temsirolimus, a sirolimus analog, eliminated the effect of growth factor on SMCs and of flow on ECs, reducing p-S6RP below basal levels and inhibiting endothelial recovery. EC p-S6RP expression in stented porcine arteries confirmed our in vitro findings: Phosphorylation was greatest in ECs farthest from intact SMCs in metal stented arteries and altogether absent after sirolimus stent elution. Conclusions— The mTOR pathway is activated in ECs in response to luminal flow. SMCs inhibit this flow-induced stimulation of endothelial mTOR pathway. Thus, we now define a novel external stimulus regulating phosphorylation of S6RP and another level of EC-SMC crosstalk. These interactions may explain the impact of local antiproliferative delivery that targets SMC proliferation and suggest that future stents integrate design influences on flow and drug effects on their molecular targets.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH/NIGMS RO1/GM049039)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH-NIDDK (1K08DK080946))en_US
dc.description.sponsorshipFundación Empresas IQSen_US
dc.description.sponsorshipBarcelona Chamber of Commerceen_US
dc.language.isoen_US
dc.publisherAmerican Heart Associationen_US
dc.relation.isversionofhttp://dx.doi.org/10.1161/CIRCULATIONAHA.109.877282en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alike 3.0en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/en_US
dc.sourcePMCen_US
dc.titleSmooth muscle cells orchestrate the endothelial cell response to flow and injuryen_US
dc.typeArticleen_US
dc.identifier.citationBalcells, M. et al. “Smooth Muscle Cells Orchestrate the Endothelial Cell Response to Flow and Injury.” Circulation 121.20 (2010): 2192–2199. Web.en_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technologyen_US
dc.contributor.mitauthorBalcells-Camps, Mercedes
dc.contributor.mitauthorMartorell Lopez, Jordi
dc.contributor.mitauthorOlive, Carla
dc.contributor.mitauthorSantacana, Marina
dc.contributor.mitauthorChitalia, Vipul C.
dc.contributor.mitauthorEdelman, Elazer R.
dc.relation.journalMolecular Cardiologyen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsBalcells, M.; Martorell, J.; Olive, C.; Santacana, M.; Chitalia, V.; Cardoso, A. A.; Edelman, E. R.en
dc.identifier.orcidhttps://orcid.org/0000-0002-7832-7156
mit.licenseOPEN_ACCESS_POLICYen_US
mit.metadata.statusComplete


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