Fibronectin matrix polymerization regulates smooth muscle cell phenotype through a Rac1 dependent mechanism.
Fibronectin matrix polymerization regulates smooth muscle cell phenotype through a Rac1 dependent mechanism.
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DOI：
10.1371/journal.pone.0094988
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sottile J
中科院分区：
文献类型：
--
作者：
Shi F;Long X;Hendershot A;Miano JM;Sottile J
血管壁中的平滑肌细胞保持分化状态，但在损伤后可被调节为合成表型。平滑肌表型改变在血管闭塞性疾病的病理过程中起着重要作用。表型调节的平滑肌细胞表现出更强的增殖和迁移特性，伴随着平滑肌细胞标记蛋白的下调。细胞外基质蛋白，包括纤维连接蛋白，当用作黏附底物时，可以调节平滑肌的表型。然而，细胞产生和组织一种三维纤维状细胞外基质，它可以以不同于用作粘连底物的原构体二维基质蛋白的方式影响细胞行为。我们之前已经证明，纤维连接蛋白在细胞外基质中的沉积/聚合可以在体外调节其他细胞外基质分子的沉积和组织。此外，我们发表的数据显示，纤维连接蛋白聚合抑制剂的存在导致体内血管细胞分化蛋白表达增加，并抑制血管重塑。在这篇手稿中，我们使用体外细胞培养系统来确定纤维连接蛋白聚合影响平滑肌表型改变的机制。我们的数据表明，纤维连接蛋白聚合降低了多种平滑肌分化基因的基因水平，并通过依赖于α的机制下调了平滑肌肌动蛋白和钙蛋白的水平。平滑肌基因的表达受纤维连接蛋白聚合的转录调控，在纤维连接蛋白聚合抑制剂存在的情况下，荧光素酶报告结构的活性增加就是证据。纤维连接蛋白聚合还促进平滑肌细胞的生长，并减少肌动蛋白应激纤维的水平。这些数据确定了一条依赖于rac1的途径，在该途径中，纤维连接蛋白聚合通过调节平滑肌细胞分化蛋白的表达来促进SMC合成表型。
Smooth muscle cells are maintained in a differentiated state in the vessel wall, but can be modulated to a synthetic phenotype following injury. Smooth muscle phenotypic modulation is thought to play an important role in the pathology of vascular occlusive diseases. Phenotypically modulated smooth muscle cells exhibit increased proliferative and migratory properties that accompany the downregulation of smooth muscle cell marker proteins. Extracellular matrix proteins, including fibronectin, can regulate the smooth muscle phenotype when used as adhesive substrates. However, cells produce and organize a 3-dimensional fibrillar extracellular matrix, which can affect cell behavior in distinct ways from the protomeric 2-dimensional matrix proteins that are used as adhesive substrates. We previously showed that the deposition/polymerization of fibronectin into the extracellular matrix can regulate the deposition and organization of other extracellular matrix molecules in vitro. Further, our published data show that the presence of a fibronectin polymerization inhibitor results in increased expression of smooth muscle cell differentiation proteins and inhibits vascular remodeling in vivo. In this manuscript, we used an in vitro cell culture system to determine the mechanism by which fibronectin polymerization affects smooth muscle phenotypic modulation. Our data show that fibronectin polymerization decreases the mRNA levels of multiple smooth muscle differentiation genes, and downregulates the levels of smooth muscle α-actin and calponin proteins by a Rac1-dependent mechanism. The expression of smooth muscle genes is transcriptionally regulated by fibronectin polymerization, as evidenced by the increased activity of luciferase reporter constructs in the presence of a fibronectin polymerization inhibitor. Fibronectin polymerization also promotes smooth muscle cell growth, and decreases the levels of actin stress fibers. These data define a Rac1-dependent pathway wherein fibronectin polymerization promotes the SMC synthetic phenotype by modulating the expression of smooth muscle cell differentiation proteins.
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影响因子：
11.2
作者：
Chung, J;Yoon, S;Mercurio, AM
通讯作者：
Mercurio, AM
纤连蛋白和层粘连蛋白对培养的动脉平滑肌细胞表型特性的各种影响。
影响因子：
7.8
作者：
Hedin, U;Bottger, B A;Forsberg, E;Johansson, S;Thyberg, J
通讯作者：
Thyberg, J
影响因子：
3.3
作者：
Cox, EA;Sastry, SK;Huttenlocher, A
通讯作者：
Huttenlocher, A
影响因子：
5
作者：
Chen, JY;Kitchen, CM;Miano, JM
通讯作者：
Miano, JM
影响因子：
2.9
作者：
HEDIN, U;THYBERG, J
通讯作者：
THYBERG, J