title: Shear stress induces synthetic-to-contractile phenotypic modulation in smooth muscle cells via peroxisome proliferator-activated receptor alpha/delta activations by prostacyclin released by sheared endothelial cells.
abstract: BACKGROUND
  Phenotypic modulation of smooth muscle cells (SMCs), which are located in close proximity to endothelial cells (ECs), is critical in regulating vascular function. The role of flow-induced shear stress in the modulation of SMC phenotype has not been well defined.
  
  
  OBJECTIVE
  The objective was to elucidate the role of shear stress on ECs in modulating SMC phenotype and its underlying mechanism.
  
  
  RESULTS
  Application of shear stress (12 dyn/cm2) to ECs cocultured with SMCs modulated SMC phenotype from synthetic to contractile state, with upregulation of contractile markers, downregulation of proinflammatory genes, and decreased percentage of cells in the synthetic phase. Treating SMCs with media from sheared ECs induced peroxisome proliferator-activated receptor (PPAR)-alpha, -delta, and -gamma ligand binding activities; transfecting SMCs with specific small interfering (si)RNAs of PPAR-alpha and -delta, but not -gamma, inhibited shear induction of contractile markers. ECs exposed to shear stress released prostacyclin (PGI2). Transfecting ECs with PGI2 synthase-specific siRNA inhibited shear-induced activation of PPAR-alpha/delta, upregulation of contractile markers, downregulation of proinflammatory genes, and decrease in percentage of SMCs in synthetic phase. Mice with PPAR-alpha deficiency (compared with control littermates) showed altered SMC phenotype toward a synthetic state, with increased arterial contractility in response to angiotensin II.
  
  
  CONCLUSIONS
  These results indicate that laminar shear stress induces synthetic-to-contractile phenotypic modulation in SMCs through the activation of PPAR-alpha/delta by the EC-released PGI2. Our findings provide insights into the mechanisms underlying the EC-SMC interplays and the protective homeostatic function of laminar shear stress in modulating SMC phenotype.
authors.affiliation: Division of Medical Engineering Research, National Health Research Institutes, Miaoli 350, Taiwan.
authors.forename: Min-Chien
authors.initials: MC
authors.lastname: Tsai
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Tang
authors.forename: Tzu-Fang
authors.initials: TF
authors.lastname: Hsu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu-Tsung
authors.initials: YT
authors.lastname: Shih
authors.forename: Hsin-Hsin
authors.initials: HH
authors.lastname: Peng
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Jeng-Jiann
authors.initials: JJ
authors.lastname: Chiu
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D010641:Phenotype; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D014158:Transcription, Genetic; D014162:Transfection; D014661:Vasoconstriction
chemical_list: D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D008024:Ligands; D008840:Microfilament Proteins; D009124:Muscle Proteins; D047493:PPAR alpha; D047494:PPAR delta; D026362:Serum Response Factor; C051615:transgelin; D000804:Angiotensin II; D011464:Epoprostenol