Modeling the three-way feedback between cellular contractility, actin polymerization, and adhesion turnover resolves the contradictory effects of RhoA and Rac1 on endothelial junction dynamics
Modeling the three-way feedback between cellular contractility, actin polymerization, and adhesion turnover resolves the contradictory effects of RhoA and Rac1 on endothelial junction dynamics
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对细胞收缩性、肌动蛋白聚合和粘附周转之间的三向反馈进行建模，解决了 RhoA 和 Rac1 对内皮连接动力学的矛盾影响
DOI：
10.1101/2021.03.15.435512
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
McEvoy E
中科院分区：
文献类型：
--
作者：
McEvoy E
血管内皮间隙的形成和恢复控制着从血管生成到动脉粥样硬化和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，以调查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，介导的细胞-细胞界面上施加的力之间的串扰内皮连接的维护。我们的理论模型表明，活跃的细胞张力可以稳定粘附内的钙粘蛋白键，但过度的RhoA信号可以驱动键解离和连接失败。虽然Rac 1介导的肌动蛋白聚合有助于间隙闭合，但高水平的Rac 1也可能促进连接弱化。结合新的实验建模框架，我们确定如何动态破裂和愈合周期出现，并进一步描述为什么差距往往定位在多细胞接触。此外，我们的分析还表明，RhoA和Rac 1表达之间的关键平衡是维持连接稳定性和限制内皮功能障碍所必需的。该模型预测了肌动蛋白聚合和细胞收缩性的药理学调节如何影响连接稳定性，随后通过实验验证了预测。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。
The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to atherosclerosis and 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 maintenance of endothelial junctions as dependent on the crosstalk between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Our theoretical model reveals that active cell tension can stabilize cadherin bonds within an adhesion, but excessive RhoA signaling can drive bond dissociation and junction failure. While Rac1-mediated actin polymerization aids gap closure, high levels of Rac1 may also facilitate junction weakening. Combining the modeling framework with novel experiments, we identify how dynamic rupture and heal cycles emerge and, further, describe why gaps tend to localize at multi-cell contacts. Beyond, our analysis also indicates that a critical balance between RhoA and Rac1 expression is required to maintain junction stability and limit endothelial dysfunction. The model predicts how pharmacological modulation of actin polymerization and cell contractility impacts junction stability, with predictions subsequently validated experimentally. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.
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DOI：
10.1007/978-1-0716-1661-1_2
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.9
作者：
Lessey EC;Guilluy C;Burridge K
通讯作者：
Burridge K
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
内皮细胞连接处 VE-钙粘蛋白的定量动力学概览：基本要求和当前概念
DOI：
--
发表时间：
2016
期刊：
Discoveries
影响因子：
--
作者：
J. Seebach;Jiahui Cao;H. Schnittler
通讯作者：
H. Schnittler
影响因子：
3
作者：
Miyaguchi, K
通讯作者：
Miyaguchi, K