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.
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.
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DOI：
10.1161/circresaha.109.193656
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发表时间：
2009-08-28
影响因子：
20.1
通讯作者：
Chiu JJ
中科院分区：
文献类型：
--
作者：
Tsai MC;Chen L;Zhou J;Tang Z;Hsu TF;Wang Y;Shih YT;Peng HH;Wang N;Guan Y;Chien S;Chiu JJ
平滑肌细胞（SMCs）紧邻内皮细胞（ECs），其表型调节对血管功能的调节至关重要。血流诱导的剪应力在平滑肌细胞表型调节中的作用尚未明确界定。
本研究目的是阐明剪应力对内皮细胞在调节平滑肌细胞表型中的作用及其潜在机制。
对与平滑肌细胞共培养的内皮细胞施加剪应力（12达因/平方厘米）可将平滑肌细胞表型从合成型调节为收缩型，表现为收缩标志物上调、促炎基因下调以及合成期细胞百分比降低。用来自受剪应力作用的内皮细胞的培养基处理平滑肌细胞可诱导过氧化物酶体增殖物激活受体（PPAR）-α、-δ和-γ配体结合活性；用PPAR -α和-δ（而非-γ）的特异性小干扰RNA（siRNAs）转染平滑肌细胞可抑制收缩标志物的剪应力诱导作用。暴露于剪应力的内皮细胞释放前列环素（PGI₂）。用PGI₂合酶特异性siRNA转染内皮细胞可抑制剪应力诱导的PPAR -α/δ激活、收缩标志物上调、促炎基因下调以及合成期平滑肌细胞百分比降低。PPAR -α缺陷小鼠（与同窝对照小鼠相比）的平滑肌细胞表型向合成型改变，对血管紧张素II的动脉收缩反应增强。
这些结果表明，层流剪应力通过内皮细胞释放的PGI₂激活PPAR -α/δ，诱导平滑肌细胞从合成型向收缩型表型调节。我们的研究结果为内皮细胞 - 平滑肌细胞相互作用的潜在机制以及层流剪应力在调节平滑肌细胞表型中的稳态保护功能提供了见解。
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. The objective was to elucidate the role of shear stress on ECs in modulating SMC phenotype and its underlying mechanism. Application of shear stress (12 dynes/cm2) to ECs co-cultured with SMCs modulated SMC phenotype from synthetic to contractile state, with up-regulation of contractile markers, down-regulation of pro-inflammatory genes, and decreased percentage of cells in the synthetic phase. Treating SMCs with media from sheared ECs induced peroxisome proliferator-activated receptor (PPAR)-α, -δ, and -γ ligand binding activities; transfecting SMCs with specific small interfering RNAs (siRNAs) of PPAR-α and -δ, but not -γ, 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-α/δ, up-regulation of contractile markers, down-regulation of pro-inflammatory genes, and decrease in percentage of SMCs in synthetic phase. Mice with PPAR-α deficiency (compared with control littermates) showed altered SMC phenotype toward a synthetic state, with increased arterial contractility in response to angiotensin II. These results indicate that laminar shear stress induces synthetic-to-contractile phenotypic modulation in SMCs through the activation of PPAR-α/δ 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.