Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and intact actin filaments.
Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and intact actin filaments.
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DOI：
10.1161/01.res.85.1.5
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发表时间：
1999-07
影响因子：
20.1
通讯作者：
K. Numaguchi;Satoru Eguchi;Tadashi Yamakawa;E. Motley;Tadashi Inagami
中科院分区：
文献类型：
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作者：
K. Numaguchi;Satoru Eguchi;Tadashi Yamakawa;E. Motley;Tadashi Inagami
机械应力对血管平滑肌细胞（VSMCs）的促生长作用与高血压血管病变的进展有关。细胞外信号调节激酶（ERK）参与了机械牵张诱导的细胞反应，如血管重塑。然而，机械拉伸如何激活ERK仍有待确定。细胞骨架似乎是最有可能将力传递到细胞内部的候选者。因此，我们研究了（1）细胞骨架是否涉及机械牵张诱导的信号传导，（2）Rho是否被牵张激活，以及（3）Rho是否介导大鼠培养的VSMC中牵张诱导的信号传导。机械拉伸激活ERK，在20分钟时观察到峰值响应，随后DNA合成显著增加。用ERK激酶-1抑制剂PD 98059处理，抑制牵张诱导的DNA合成增加。细胞松弛素D，选择性地破坏肌动蛋白丝的网络，显着抑制拉伸诱导的ERK激活。在对照状态下，RhoA主要在胞质组分中观察到，但它部分地被易位到响应于机械拉伸的颗粒组分中。肉毒杆菌C3外切酶，它灭活Rho p21（已知参与肌动蛋白细胞骨架的重组），衰减拉伸诱导的ERK激活。Rho激酶（p160 ROCK）的抑制也抑制牵张诱导的ERK激活，呈剂量依赖性。我们的研究结果表明，在VSMCs的mechanotransduction是依赖于完整的肌动蛋白丝，Rho被激活的拉伸，和Rho/p160 ROCK介导的拉伸诱导的ERK激活和血管增生。
The growth-promoting effect of mechanical stress on vascular smooth muscle cells (VSMCs) has been implicated in the progress of vascular disease in hypertension. Extracellular signal-regulated kinases (ERKs) have been implicated in cellular responses, such as vascular remodeling, induced by mechanical stretch. However, it remains to be determined how mechanical stretch activates ERKs. The cytoskeleton seems the most likely candidate for force transmission into the interior of the cell. Therefore, we examined (1) whether the cytoskeleton involves mechanical stretch-induced signaling, (2) whether Rho is activated by stretch, and (3) whether Rho mediates the stretch-induced signaling in rat cultured VSMCs. Mechanical stretch activated ERKs, with a peak response observed at 20 minutes, followed by a significant increase in DNA synthesis. Treatment with the ERK kinase-1 inhibitor, PD98059, inhibited the stretch-induced increase in DNA synthesis. Cytochalasin D, which selectively disrupts the network of actin filaments, markedly inhibited stretch-induced ERK activation. In the control state, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to mechanical stretch. Botulinum C3 exoenzyme, which inactivates Rho p21 (known to participate in the reorganization of the actin cytoskeleton), attenuated stretch-induced ERK activation. Inhibition of Rho kinase (p160ROCK) also suppressed stretch-induced ERK activation dose dependently. Our results suggest that mechanotransduction in VSMCs is dependent on intact actin filaments, that Rho is activated by stretch, and that Rho/p160ROCK mediates stretch-induced ERK activation and vascular hyperplasia.