Stretch of the vascular wall induces smooth muscle differentiation by promoting actin polymerization
Stretch of the vascular wall induces smooth muscle differentiation by promoting actin polymerization
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DOI：
10.1074/jbc.m403370200
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发表时间：
2004-08-13
影响因子：
4.8
通讯作者：
Hellstrand, P
中科院分区：
文献类型：
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作者：
Albinsson, S;Nordström, I;Hellstrand, P
由腔内血压引起的血管壁拉伸刺激蛋白质合成，有助于平滑肌收缩表型的维持。大多数平滑肌特异性基因的表达受到血清反应因子的调节，并受到肌动蛋白聚合增加的刺激。因此，我们假设拉伸诱导的分化是由肌动蛋白聚合促进的。完整的小鼠门静脉在纵向应力下培养，并与未拉伸的对照组进行比较。在未拉伸的静脉中，与收缩/细胞骨架系统相关的几种蛋白质（α -肌动蛋白、钙钙蛋白、sm22 α、原肌球蛋白和desmin）的合成速率显著低于拉伸静脉，而其他蛋白质（β -肌动蛋白和热休克蛋白）的合成速率相似。细胞骨架蛋白-肌动蛋白和波形蛋白对拉伸敏感性较弱。与不施加机械应力相比，Y-27632培养拉伸静脉对rho相关激酶的抑制效果相似，但效果较弱。茉莉烯内酯诱导肌动蛋白聚合使未拉伸静脉的sm22 α合成增加到拉伸静脉的水平。拉伸刺激Rho活性和肌动蛋白切断蛋白cofilin-2的磷酸化，尽管这两种作用的起效都较慢（Rho- gtp, > 15分钟；cofilin-P, > 1小时）。Y-27632抑制拉伸静脉Cofilin-2磷酸化。通过超离心和phalloidin/DNase I标记的共聚焦成像显示，拉伸静脉培养24 h后的F/G-actin比值明显大于未拉伸静脉。结果表明，血管壁的拉伸刺激肌动蛋白聚合，激活平滑肌特异性蛋白质的合成。Rho下游的Rho相关激酶和cofilin部分介导了这种作用，但可能不是完全介导。
Stretch of the vascular wall by the intraluminal blood pressure stimulates protein synthesis and contributes to the maintenance of the smooth muscle contractile phenotype. The expression of most smooth muscle specific genes has been shown to be regulated by serum response factor and stimulated by increased actin polymerization. Hence we hypothesized that stretch-induced differentiation is promoted by actin polymerization. Intact mouse portal veins were cultured under longitudinal stress and compared with unstretched controls. In unstretched veins the rates of synthesis of several proteins associated with the contractile/cytoskeletal system (alpha-actin, calponin, SM22alpha, tropomyosin, and desmin) were dramatically lower than in stretched veins, whereas other proteins (beta-actin and heat shock proteins) were synthesized at similar rates. The cytoskeletal proteins beta-actin and vimentin were weakly stretch-sensitive. Inhibition of Rho-associated kinase by culture of stretched veins with Y-27632 produced similar but weaker effects compared with the absence of mechanical stress. Induction of actin polymerization by jasplakinolide increased SM22alpha synthesis in unstretched veins to the level in stretched veins. Stretch stimulated Rho activity and phosphorylation of the actin-severing protein cofilin-2, although both effects were slow in onset (Rho-GTP, > 15 min; cofilin-P, > 1 h). Cofilin-2 phosphorylation of stretched veins was inhibited by Y-27632. The F/G-actin ratio after 24 h of culture was significantly greater in stretched than in unstretched veins, as shown by both ultracentrifugation and confocal imaging with phalloidin/DNase I labeling. The results show that stretch of the vascular wall stimulates increased actin polymerization, activating synthesis of smooth muscle-specific proteins. The effect is partially, but probably not completely, mediated via Rho-associated kinase and cofilin downstream of Rho.