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dc.contributorUniversitat Ramon Llull. IQS
dc.contributor.authorBalcells Camps, Mercedes
dc.contributor.authorGils, Janine M. van
dc.contributor.authorRamkhelawon, Bhama
dc.contributor.authorFernandes, Luciana
dc.contributor.authorStewart, Merran C.
dc.contributor.authorGuo, Liang
dc.contributor.authorSeibert, Tara
dc.contributor.authorMenezes, Gustavo B.
dc.contributor.authorCara, Denise C.
dc.contributor.authorChow, Camille
dc.contributor.authorKinane, T. Bernard
dc.contributor.authorFisher, Edward A.
dc.contributor.authorAlvarez-Leite, Jacqueline
dc.contributor.authorLacy-Hulbert, Adam
dc.contributor.authorMoore, Kathryn J.
dc.date.accessioned2021-01-19T13:46:12Z
dc.date.accessioned2023-07-13T05:46:46Z
dc.date.available2021-01-19T13:46:12Z
dc.date.available2023-07-13T05:46:46Z
dc.date.issued2013-05
dc.identifier.urihttp://hdl.handle.net/20.500.14342/1151
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.eng
dc.format.extent9 p.cat
dc.language.isoengcat
dc.publisherAmerican Heart Associationcat
dc.relation.ispartofCirculation. Vol.3, n.5 (2013), p.911–919cat
dc.rights© American Heart Association, Inc. Tots els drets reservats
dc.sourceRECERCAT (Dipòsit de la Recerca de Catalunya)
dc.subject.otherAterosclerosicat
dc.subject.otherEndotelicat
dc.subject.otherLeucòcitscat
dc.subject.otherAxonscat
dc.subject.otherAtherosclerosiscat
dc.subject.otherAxonal guidancecat
dc.subject.otherEndothelial–leukocyte interactioncat
dc.subject.otherMigrationcat
dc.titleEndothelial expression of guidance cues in vessel wall homeostasis: dysregulation under proatherosclerotic conditionscat
dc.typeinfo:eu-repo/semantics/articlecat
dc.typeinfo:eu-repo/semantics/publishedVersioncat
dc.rights.accessLevelinfo:eu-repo/semantics/openAccess
dc.embargo.termscapcat
dc.subject.udc616.1
dc.identifier.doihttps://doi.org/10.1161/ATVBAHA.112.301155cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI/PN I+D/BFU2009-09804cat


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