Endothelial barrier disruption and recovery is controlled by substrate stiffness.
Endothelial barrier disruption and recovery is controlled by substrate stiffness.
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DOI：
10.1016/j.mvr.2012.12.006
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发表时间：
2013-05
影响因子：
3.1
通讯作者：
Birukov, Konstantin G.
中科院分区：
文献类型：
--
作者：
Birukova, Anna A.;Tian, Xinyong;Cokic, Ivan;Beckham, Yvonne;Gardel, Margaret L.;Birukov, Konstantin G.
循环屏障破坏性激动剂结合特异性细胞膜受体并触发信号转导途径，导致细胞收缩性和内皮细胞（EC）渗透性的激活。尽管包括血管EC在内的组织中的所有细胞都被顺应性细胞外基质包围，但基质硬度对激动剂诱导的信号传导、细胞骨架重塑和EC屏障调节的影响还不清楚。本研究探讨了激动剂诱导的细胞骨架和信号转导的变化与EC屏障破坏和恢复使用肺EC上生长的生理相关的（8.6千帕）刚度，非常低（0.55千帕）和非常高（42千帕）刚度顺应性基板。人肺微血管和大血管内皮细胞生长在0.55 kPa的基板上含有一些肌动蛋白应力纤维，而应力纤维的数量增加，增加基质刚度。凝血酶诱导的应力纤维的形成是最大的EC上生长在42 kPa基板上，减少8.6 kPa基板上，是最小的0.55 kPa基板上。这些效应与凝血酶诱导的Rho激酶靶点、肌球蛋白轻链磷酸酶（MYPT 1）和调节性肌球蛋白轻链（MLC）磷酸化的刚度依赖性增加有关。令人惊讶的是，EC屏障恢复和激活Rac GTP酶依赖的屏障保护信号在8.6 kPa的EC中达到最大水平，但在0.55 kPa的基质上没有。总之，这些数据表明，在激动剂诱导的EC渗透性的发作和消退期间，细胞外基质硬度在调节Rac/Rho信号传导平衡中起关键作用。Rho/Rac信号转换的最佳条件，它提供了一个有效的和可逆的EC细胞骨架和渗透性的激动剂的反应，达到在生理相关的刚度的基质上生长的细胞。
Circulating barrier disruptive agonists bind specific cell membrane receptors and trigger signal transduction pathways leading to activation of cell contractility and endothelial cell (EC) permeability. Although all cells in tissues including vascular EC are surrounded by compliant extracellular matrix, the impact of matrix stiffness on agonist-induced signaling, cytoskeletal remodeling and EC barrier regulation is not well understood. This study examined agonist-induced cytoskeletal and signaling changes associated with EC barrier disruption and recovery using pulmonary EC grown on compliant substrates of physiologically relevant (8.6 kPa) stiffness, very low (0.55 kPa) and very high (42 kPa) stiffness. Human pulmonary microvascular and macrovascular EC grown on 0.55 kPa substrate contained a few actin stress fibers, while stress fiber amount increased with increasing matrix stiffness. Thrombin-induced stress fiber formation was maximal in EC grown on 42 kPa substrate, diminished on 8.6 kPa substrate, and was minimal on 0.55 kPa substrate. These effects were linked to a stiffness-dependent increase in thrombin-induced phosphorylation of the Rho kinase target, myosin light chain phosphatase (MYPT1), and regulatory myosin light chains (MLC). Surprisingly, EC barrier recovery and activation of Rac GTPase-dependent barrier protective signaling reached maximal levels in EC grown on 8.6 kPa, but not on 0.55 kPa substrate. In conclusion, these data show a critical role of extracellular matrix stiffness in the regulation of the Rac/Rho signaling balance during onset and resolution of agonist-induced EC permeability. The optimal conditions for the Rho/Rac signaling switch, which provides an effective and reversible EC cytoskeletal and permeability response to agonist, are reached in cells grown on the matrix of physiologically relevant stiffness.
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影响因子：
3.3
作者：
Aratyn-Schaus Y;Oakes PW;Gardel ML
通讯作者：
Gardel ML
DOI：
10.1152/ajplung.00202.2009
发表时间：
2010-11-01
影响因子：
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作者：
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Birukov, Konstantin G.
DOI：
10.1083/jcb.200201105
发表时间：
2002-07-08
期刊：
The Journal of cell biology
影响因子：
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作者：
Katsumi A;Milanini J;Kiosses WB;del Pozo MA;Kaunas R;Chien S;Hahn KM;Schwartz MA
通讯作者：
Schwartz MA
影响因子：
21.3
作者：
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DOI：
10.1152/ajplung.00292.2011
发表时间：
2012-05-01
影响因子：
4.9
作者：
Birukova, Anna A.;Tian, Yufeng;Birukov, Konstantin G.
通讯作者：
Birukov, Konstantin G.