ROCK controls matrix synthesis in vascular smooth muscle cells - Coupling vasoconstriction to vascular remodeling
ROCK controls matrix synthesis in vascular smooth muscle cells - Coupling vasoconstriction to vascular remodeling
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DOI：
10.1161/01.res.0000246172.77441.f1
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发表时间：
2006-10-13
影响因子：
20.1
通讯作者：
Jones, Peter Lloyd
中科院分区：
文献类型：
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作者：
Chapados, Rene;Abe, Khotaro;Jones, Peter Lloyd
腱生蛋白-C（TN-C）是在重塑体动脉和肺动脉（PA）内表达的细胞外基质（ECM）蛋白，在其中它支持血管平滑肌细胞（SMC）增殖。以前，我们发现，A10 SMC上培养的天然I型胶原蛋白具有纺锤形的形态，不表达TN-C，而那些变性胶原蛋白具有明确的F-肌动蛋白应力纤维网络，蔓延形态，他们表达TN-C。为了确定细胞骨架结构的变化是否控制TN-C，用细胞松弛素D处理变性胶原上的SMC，细胞松弛素D降低SMC的扩散和细胞外信号调节激酶1/2（ERK 1/2）的活化，细胞外信号调节激酶1/2是TN-C转录所需的信号效应物。接下来，为了确定由F-肌动蛋白细胞骨架决定的细胞形状是否调节TN-C，在变性胶原蛋白上设计了不同几何形状的SMC（从铺展到圆形）：随着SMC逐渐变圆，ERK 1/2活性和TN-C转录下降。由于RhoA和Rho激酶（ROCK）通过控制细胞骨架结构来调节细胞形态，我们推断这些因子也可能调节TN-C。事实上，在变性胶原上的SMC具有比在天然胶原上的那些更高水平的RhoA活性，并且阻断RhoA或ROCK活性减弱了SMC在变性胶原上的铺展、ERK 1/2活性和SMC中的TN-C表达。因此，ROCK以允许ERK 1/2依赖性TN-C产生的方式控制F-肌动蛋白细胞骨架和SMC形状的构型。最后，我们发现ROCK活性的抑制抑制SMC TN-C的表达和疾病的进展，在高血压大鼠PA。因此，除了其在调节血管收缩中的作用外，ROCK还控制基质的产生。
Tenascin-C (TN-C) is an extracellular matrix (ECM) protein expressed within remodeling systemic and pulmonary arteries (PAs), where it supports vascular smooth muscle cell (SMC) proliferation. Previously, we showed that A10 SMCs cultivated on native type I collagen possess a spindle-shaped morphology and do not express TN-C, whereas those on denatured collagen possess a well-defined F-actin stress fiber network, a spread morphology, and they do express TN-C. To determine whether changes in cytoskeletal architecture control TN-C, SMCs on denatured collagen were treated with cytochalasin D, which decreased SMC spreading and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling effectors required for TN-C transcription. Next, to determine whether cell shape, dictated by the F-actin cytoskeleton, regulates TN-C, different geometries of SMCs (ranging from spread to round) were engineered on denatured collagen: as SMCs progressively rounded, ERK1/2 activity and TN-C transcription declined. Because RhoA and Rho kinase (ROCK) regulate cell morphology by controlling cytoskeletal architecture, we reasoned that these factors might also regulate TN-C. Indeed, SMCs on denatured collagen possessed higher levels of RhoA activity than those on native collagen, and blocking RhoA or ROCK activities attenuated SMC spreading, ERK1/2 activity, and TN-C expression in SMCs on denatured collagen. Thus, ROCK controls the configuration of the F-actin cytoskeleton and SMC shape in a manner that is permissive for ERK1/2-dependent production of TN-C. Finally, we showed that inhibition of ROCK activity suppresses SMC TN-C expression and disease progression in hypertensive rat PAs. Thus, in addition to its role in regulating vasoconstriction, ROCK also controls matrix production.