Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2022 Nov 19;13(1):7089. doi: 10.1038/s41467-022-34701-y.
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.
血管内皮细胞中间隙的形成和恢复控制着广泛的生理和病理现象，从血管生成到肿瘤细胞外渗。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不是很清楚。在这项研究中，我们提出了一个化学生物力学模型来研究内皮连接的调节，这取决于肌动球蛋白收缩、VE-钙粘蛋白键周转率和肌动蛋白聚合之间的反馈，这些过程介导了作用在细胞-细胞界面上的力。模拟结果表明，细胞的主动张力可以稳定钙粘蛋白键，但过多的 RhoA 信号可以导致键解离和连接失败。虽然肌动蛋白聚合有助于间隙闭合，但高水平的 Rac1 可以诱导连接减弱。将建模框架与实验相结合，我们的模型预测了药物治疗对连接状态的影响，并确定需要 RhoA 和 Rac1 表达之间的临界平衡来维持连接的稳定性。我们提出的框架可以帮助指导针对 Rho 家族 GTP 酶和下游主动机械过程的治疗药物的开发。
