Irons Linda, Huang Huang, Owen Markus R, O'Dea Reuben D, Meininger Gerald A, Brook Bindi S
Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom.
Dalton Cardiovascular Research Center, Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States.
J Theor Biol. 2020 Oct 7;502:110387. doi: 10.1016/j.jtbi.2020.110387. Epub 2020 Jun 27.
Integrins regulate mechanotransduction between smooth muscle cells (SMCs) and the extracellular matrix (ECM). SMCs resident in the walls of airways or blood vessels are continuously exposed to dynamic mechanical forces due to breathing or pulsatile blood flow. However, the resulting effects of these forces on integrin dynamics and associated cell-matrix adhesion are not well understood. Here we present experimental results from atomic force microscopy (AFM) experiments, designed to study the integrin response to external oscillatory loading of varying amplitudes applied to live aortic SMCs, together with theoretical results from a mathematical model. In the AFM experiments, a fibronectin-coated probe was used cyclically to indent and retract from the surface of the cell. We observed a transition between states of firm adhesion and of complete detachment as the amplitude of oscillatory loading increased, revealed by qualitative changes in the force timecourses. Interestingly, for some of the SMCs in the experiments, switching behaviour between the two adhesion states is observed during single timecourses at intermediate amplitudes. We obtain two qualitatively similar adhesion states in the mathematical model, where we simulate the cell, integrins and ECM as an evolving system of springs, incorporating local integrin binding dynamics. In the mathematical model, we observe a region of bistability where both the firm adhesion and detachment states can occur depending on the initial adhesion state. The differences are seen to be a result of mechanical cooperativity of integrins and cell deformation. Switching behaviour is a phenomenon associated with bistability in a stochastic system, and bistability in our deterministic mathematical model provides a potential physical explanation for the experimental results. Physiologically, bistability provides a means for transient mechanical stimuli to induce long-term changes in adhesion dynamics-and thereby the cells' ability to transmit force-and we propose further experiments for testing this hypothesis.
整合素调节平滑肌细胞（SMC）与细胞外基质（ECM）之间的机械转导。存在于气道或血管壁中的SMC由于呼吸或脉动血流而持续暴露于动态机械力。然而，这些力对整合素动力学及相关细胞-基质黏附的最终影响尚未得到充分理解。在此，我们展示了原子力显微镜（AFM）实验的结果，该实验旨在研究整合素对施加于活体主动脉SMC的不同振幅外部振荡负荷的反应，同时还展示了一个数学模型的理论结果。在AFM实验中，使用一个包被纤连蛋白的探针周期性地压入细胞表面并从其表面缩回。随着振荡负荷振幅的增加，我们观察到牢固黏附状态和完全脱离状态之间的转变，这通过力随时间变化曲线的定性变化得以揭示。有趣的是，在实验中的一些SMC中，在单次随时间变化过程中，中等振幅时可观察到两种黏附状态之间的切换行为。在数学模型中，我们获得了两种定性相似的黏附状态，在该模型中，我们将细胞、整合素和ECM模拟为一个不断演化的弹簧系统，并纳入了局部整合素结合动力学。在数学模型中，我们观察到一个双稳态区域，其中牢固黏附状态和脱离状态均可出现，这取决于初始黏附状态。差异被认为是整合素的机械协同作用和细胞变形的结果。切换行为是随机系统中与双稳态相关的一种现象，我们确定性数学模型中的双稳态为实验结果提供了潜在的物理解释。在生理上，双稳态为瞬态机械刺激诱导黏附动力学的长期变化——从而诱导细胞传递力的能力的长期变化——提供了一种方式，并且我们提出了进一步的实验来检验这一假设。
