2026-04-14T03:22:56Zhttps://recercat.cat/oai/request

oai:recercat.cat:20.500.14342/11512025-05-27T14:36:25Zcom_2072_482405com_2072_183628col_2072_482414

00925njm 22002777a 4500 dc Balcells, Mercedes author Gils, Janine M. van author Ramkhelawon, Bhama author Fernandes, Luciana author Stewart, Merran C. author Guo, Liang author Seibert, Tara author Menezes, Gustavo B. author Cara, Denise C. author Chow, Camille author Kinane, T. Bernard author Fisher, Edward A. author Alvarez-Leite, Jacqueline author Lacy-Hulbert, Adam author Moore, Kathryn J. author 2013-05 Background— 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. http://hdl.handle.net/20.500.14342/1151 https://doi.org/10.1161/ATVBAHA.112.301155 Aterosclerosi Endoteli Leucòcits Axons Atherosclerosis Axonal guidance Endothelial–leukocyte interaction Migration Endothelial expression of guidance cues in vessel wall homeostasis: dysregulation under proatherosclerotic conditions