Berk B C, Corson M A, Peterson T E, Tseng H
Department of Medicine, University of Washington, Seattle 98195, USA.
J Biomech. 1995 Dec;28(12):1439-50. doi: 10.1016/0021-9290(95)00092-5.
Fluid shear stress regulates endothelial cell function, but the signal transduction mechanisms involved in mechanotransduction remain unclear. Recent findings demonstrate that several intracellular kinases are activated by mechanical forces. In particular, members of the mitogen-activated protein (MAP) kinase family are stimulated by hyperosmolarity, stretch, and stress such as heat shock. We propose a model for mechanotransduction in endothelial cells involving calcium-dependent and calcium-independent protein kinase pathways. The calcium-dependent pathway involves activation of phospholipase C, hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), increases in intracellular calcium and stimulation of kinases such as calcium-calmodulin and C kinases (PKC). The calcium-independent pathway involves activation of a small GTP-binding protein and stimulation of calcium-independent PKC and MAP kinases. The calcium-dependent pathway mediates the rapid, transient response to fluid shear stress including activation of nitric oxide synthase (NOS) and ion transport. In contrast, the calcium-independent pathway mediates a slower response including the sustained activation of NOS and changes in cell morphology and gene expression. We propose that focal adhesion complexes link the calcium-dependent and calcium-independent pathways by regulating activity of phosphatidylinositol 4-phosphate (PIP) 5-kinase (which regulates PIP2 levels) and p125 focal adhesion kinase (FAK, which phosphorylates paxillin and interacts with cytoskeletal proteins). This model predicts that dynamic interactions between integrin molecules present in focal adhesion complexes and membrane events involved in mechanotransduction will be integrated by calcium-dependent and calcium-independent kinases to generate intracellular signals involved in the endothelial cell response to flow.
流体剪切应力调节内皮细胞功能，但机械转导所涉及的信号转导机制仍不清楚。最近的研究结果表明，几种细胞内激酶可被机械力激活。特别是，丝裂原活化蛋白（MAP）激酶家族的成员受到高渗、拉伸和热休克等应激的刺激。我们提出了一种内皮细胞机械转导模型，该模型涉及钙依赖性和钙非依赖性蛋白激酶途径。钙依赖性途径涉及磷脂酶C的激活、磷脂酰肌醇4,5-二磷酸（PIP2）的水解、细胞内钙的增加以及钙调蛋白和C激酶（PKC）等激酶的刺激。钙非依赖性途径涉及小GTP结合蛋白的激活以及钙非依赖性PKC和MAP激酶的刺激。钙依赖性途径介导对流体剪切应力的快速、瞬时反应，包括一氧化氮合酶（NOS）的激活和离子转运。相比之下，钙非依赖性途径介导较慢的反应，包括NOS的持续激活以及细胞形态和基因表达的变化。我们提出，粘着斑复合物通过调节磷脂酰肌醇4-磷酸（PIP）5-激酶（调节PIP2水平）和p125粘着斑激酶（FAK，使桩蛋白磷酸化并与细胞骨架蛋白相互作用）的活性来连接钙依赖性和钙非依赖性途径。该模型预测，粘着斑复合物中存在的整合素分子与机械转导所涉及的膜事件之间的动态相互作用将通过钙依赖性和钙非依赖性激酶整合，以产生参与内皮细胞对血流反应的细胞内信号。
