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.
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.
Tsai
Min-Chien
MC
Division of Medical Engineering Research, National Health Research Institutes, Miaoli 350, Taiwan.
Chen
Lihong
L
Zhou
Jing
J
Tang
Zhihui
Z
Hsu
Tzu-Fang
TF
Wang
Ying
Y
Shih
Yu-Tsung
YT
Peng
Hsin-Hsin
HH
Wang
Nanping
N
Guan
Youfei
Y
Chien
Shu
S
Chiu
Jeng-Jiann
JJ
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
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