Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity.
Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity.
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DOI：
10.1038/s41467-022-34701-y
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发表时间：
2022-11-19
影响因子：
16.6
通讯作者：
Shenoy, Vivek B.
中科院分区：
文献类型：
--
作者：
McEvoy, Eoin;Sneh, Tal;Moeendarbary, Emad;Javanmardi, Yousef;Efimova, Nadia;Yang, Changsong;Marino-Bravante, Gloria E.;Chen, Xingyu;Escribano, Jorge;Spill, Fabian;Manuel Garcia-Aznar, Jose;Weeraratna, Ashani T.;Svitkina, Tatyana M.;Kamm, Roger D.;Shenoy, Vivek B.
血管内皮间隙的形成和恢复控制着从血管生成到肿瘤细胞外渗的广泛的生理和病理现象。然而，驱动血管内皮细胞动态行为的机械和信号过程之间的相互作用还没有很好地理解。在这项研究中，我们提出了一个化学力学模型来研究依赖于肌动球蛋白收缩性，VE-钙粘蛋白键营业额和肌动蛋白聚合之间的反馈，介导施加在细胞-细胞界面上的力的内皮连接的调节。模拟显示，活跃的细胞张力可以稳定钙粘蛋白键，但过度的RhoA信号可以驱动键解离和连接失败。虽然肌动蛋白聚合有助于间隙闭合，但高水平的Rac 1可诱导连接弱化。结合建模框架与实验，我们的模型预测的药理学治疗对连接状态的影响，并确定RhoA和Rac 1表达之间的关键平衡是需要保持连接稳定性。我们提出的框架可以帮助指导靶向GTP酶的Rho家族和下游主动机械过程的治疗方法的开发。脉管系统中的间隙形成支持免疫和肿瘤细胞浸润。在这里，作者提出了一个化学机械模型来分析机械敏感信号，积极的细胞力和粘附之间的反馈如何控制内皮连接的破裂，恢复和完整性。
The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the regulation of endothelial junctions as dependent on the feedback between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Simulations reveal that active cell tension can stabilize cadherin bonds, but excessive RhoA signaling can drive bond dissociation and junction failure. While actin polymerization aids gap closure, high levels of Rac1 can induce junction weakening. Combining the modeling framework with experiments, our model predicts the influence of pharmacological treatments on the junction state and identifies that a critical balance between RhoA and Rac1 expression is required to maintain junction stability. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes. Gap formation in the vasculature underpins immune and tumour cell infiltration. Here the authors propose a chemo-mechanical model to analyse how feedback between mechanosensitive signalling, active cellular forces and adhesion governs the breakdown, recovery, and integrity of endothelial junctions.
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影响因子：
2.5
作者：
Aslam M;Tanislav C;Troidl C;Schulz R;Hamm C;Gündüz D
通讯作者：
Gündüz D
影响因子：
3.7
作者：
Amado-Azevedo J;de Menezes RX;van Nieuw Amerongen GP;van Hinsbergh VWM;Hordijk PL
通讯作者：
Hordijk PL
影响因子：
11.8
作者：
Acharya, Bipul R.;Nestor-Bergmann, Alexander;Yap, Alpha S.
通讯作者：
Yap, Alpha S.
DOI：
10.1152/ajpheart.00542.2005
发表时间：
2006-01-01
影响因子：
4.8
作者：
Baffert, F;Le, T;McDonald, DM
通讯作者：
McDonald, DM
影响因子：
11.2
作者：
Chang, Yu-Wen E.;Marlin, Jerry W.;Jakobi, Rolf
通讯作者：
Jakobi, Rolf