Regulation of endothelial cell gap formation and paracellular permeability.
Regulation of endothelial cell gap formation and paracellular permeability.
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发表时间：
1995-04
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通讯作者：
Joe G. N. Garcia;K. Schaphorst
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作者：
Joe G. N. Garcia;K. Schaphorst
对内皮细胞渗透性调节的研究已经得到证据支持EC间隙形成和屏障功能双重调节的概念。在该模型中，EC渗透性的主要决定因素是系留/粘附特性（图1）和拉伸向心力的产生（图2）。肌动蛋白肌球蛋白的相互作用和积极的细胞收缩和力的产生的重要性进行了审查。在凝血酶诱导的EC屏障功能障碍的模型中，MLC物质从未磷酸化的形式强烈转变为二磷酸化的形式，表明MLCK的激活，MLCK是一种在EC收缩中具有重要性的关键酶，已经得到很好的确立。虽然EC和SMC之间存在重要差异，但内皮细胞间隙形成涉及类似于SMC的肌动球蛋白依赖性收缩机制，SMC是MLC磷酸化与张力发展的初始速率相关的细胞系统。MLC磷酸化和等长张力的增加与信号转导的激活介导等长张力通过细胞骨架增加到新水平的“闩锁状态”的假设一致。因此，现有的证据暗示了细胞力的产生和收缩在凝血酶诱导的屏障功能障碍的演变中的重要作用。越来越多的证据还表明，拴系性质的调节，主要是那些涉及细胞-基质和细胞-细胞粘附，也是基础EC屏障性质以及激动剂介导的屏障功能障碍的关键决定因素。因为这些粘着斑成分中的每一种都可能参与建立内皮中的束缚特性，所以它们各自可能参与确定屏障通透性，并且可能参与激动剂介导的屏障功能障碍的演变。因此，除了MLCK依赖性主动张力产生外，激动剂诱导的屏障功能障碍可能通过依赖于MLC磷酸化基础水平的MLCK非依赖性途径或通过影响参与内皮拴系特性的蛋白质而发生，这些蛋白质有助于屏障功能。进一步检查栓系力特性，结合阐明EC松弛通过MLC去磷酸化可能会产生线索，如何维持和血管损伤后恢复这一重要的血管屏障。
Investigation of the regulation of permeability properties of the endothelium has yielded evidence to support the concept of a dual regulation of EC gap formation and barrier function. In this model, the primary determinants of EC permeability are tethering/adhesive properties (Figure 1) and tensile centripetal force generation (Figure 2). The importance of actin-myosin interactions and active cellular contraction and force generation has been reviewed. In the model of thrombin-induced EC barrier dysfunction, there is a strong shift in the MLC species from the unphosphorylated to the diphosphorylated form, indicating activation of MLCK, a key enzyme whose importance in EC contraction has been well established. Although important differences between EC and SMC exist, endothelial cell gap formation involves actomyosin-dependent contractile mechanisms similar to SMC, a cellular system in which MLC phosphorylation correlates with the initial rate of tension development. The increase in MLC phosphorylation and isometric tension is consistent with the hypothesis that activation of signal transduction mediates an increase in isometric tension to a new level of "latch state" through the cytoskeleton. Thus, the available evidence implicates a strong role for cellular force generation and contraction in the evolution of thrombin-induced barrier dysfunction. Accumulating evidence also indicates that modulation of tethering properties, primarily those involving cell-matrix and cell-cell adhesion, is also a key determinant of basal EC barrier properties as well as agonist-mediated barrier dysfunction. Because each of these focal adhesion constituents may be involved in establishing tethering properties in endothelium, they each may be involved in determining barrier permeability and may be involved in the evolution of agonist-mediated barrier dysfunction. Therefore, in addition to MLCK-dependent active tensile force generation, agonist-induced barrier dysfunction may occur via MLCK-independent pathways that rely on basal levels of MLC phosphorylation or by affecting proteins involved in tethering properties of endothelium that contribute to barrier function. Further examination of tethering force properties, combined with elucidation of EC relaxation via MLC dephosphorylation may yield clues as to how this important vascular barrier is maintained and restored after vascular insult.