Smooth Muscle Cells Orchestrate the Endothelial Cell Response to Flow and Injury

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 parac...

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Bibliographic Details
Published in:	Circulation (New York, N.Y.) Vol. 121; no. 20; pp. 2192 - 2199
Main Authors:	BALCELLS, Mercedes, MARTORELL, Jordi, OLIVE, Carla, SANTACANA, Marina, CHITALIA, Vipul, CARDOSO, Angelo A, EDELMAN, Elazer R
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 25-05-2010
Subjects:	Animals Aorta - physiology Arteries - physiology Arteries - physiopathology Biological and medical sciences Blood and lymphatic vessels Blood vessels and receptors Cardiology. Vascular system Cell Communication - physiology Cells, Cultured Coronary Vessels - physiology Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Endothelial Cells - metabolism Endothelium, Vascular - injuries Endothelium, Vascular - pathology Endothelium, Vascular - physiopathology Fundamental and applied biological sciences. Psychology Humans In Vitro Techniques Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism Medical sciences Muscle, Smooth, Vascular - pathology Muscle, Smooth, Vascular - physiopathology Myocytes, Smooth Muscle - metabolism Phosphorylation Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Regional Blood Flow - drug effects Regional Blood Flow - physiology Ribosomal Protein S6 - metabolism Signal Transduction Sirolimus - analogs & derivatives Sirolimus - pharmacology Stents - adverse effects Swine Swine, Miniature TOR Serine-Threonine Kinases Transcription Factors - metabolism Vertebrates: cardiovascular system Antineoplastic agent Endothelial cell Sirolimus muscle, smooth stents mammalian target of rapamycin (mTOR) Lactone Smooth muscle Cardiovascular disease Macrolide Stent Macrocycle Blood flow Endothelium Signal transduction Antibiotic Hemodynamics Protein synthesis inhibitor Immunosuppressive agent Molecular biology
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Summary:	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. 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. 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.
ISSN:	0009-7322 1524-4539
DOI:	10.1161/CIRCULATIONAHA.109.877282