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(Circulation Research. 2009;105:471.)
© 2009 American Heart Association, Inc.

Cellular Biology

Shear Stress Induces Synthetic-to-Contractile Phenotypic Modulation in Smooth Muscle Cells via Peroxisome Proliferator-Activated Receptor / Activations by Prostacyclin Released by Sheared Endothelial Cells

Min-Chien Tsai, Lihong Chen, Jing Zhou, Zhihui Tang, Tzu-Fang Hsu, Ying Wang, Yu-Tsung Shih, Hsin-Hsin Peng, Nanping Wang, Youfei Guan, Shu Chien, Jeng-Jiann Chiu

From the Graduate Institute of Life Sciences (M.-C.T., Y.-T.S., J.-J.C.), National Defense Medical Center, Taiwan; Division of Medical Engineering Research (M.-C.T., J.Z., T.-F.H., Y.-T.S., H.H.P., J.-J.C.), National Health Research Institutes, Miaoli, Taiwan; Department of Physiology and Pathophysiology (L.C., Y.G.) and Institute of Cardiovascular Science (Z.T., Y.W., N.W.), Peking University Health Science Center, Beijing, China; Departments of Bioengineering and Medicine and Institute of Engineering in Medicine (S.C.), University of California, San Diego, La Jolla.

Correspondence to Jeng-Jiann Chiu, PhD, Division of Medical Engineering Research, National Health Research Institutes, Miaoli 350, Taiwan. E-mail jjchiu{at}nhri.org.tw

Rationale: 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.

Methods and 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)-, -, and - ligand binding activities; transfecting SMCs with specific small interfering (si)RNAs of PPAR- and -, but not -, 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-/, upregulation of contractile markers, downregulation of proinflammatory genes, and decrease in percentage of SMCs in synthetic phase. Mice with PPAR- 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-/ 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.

Key Words: endothelial cell • peroxisome proliferator-activated receptor • prostacyclin • shear stress • smooth muscle cell