Andresen Eguiluz Roberto C, Kaylan Kerim B, Underhill Gregory H, Leckband Deborah E
Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
Biomaterials. 2017 Sep;140:45-57. doi: 10.1016/j.biomaterials.2017.06.010. Epub 2017 Jun 9.
The vascular endothelium is subject to diverse mechanical cues that regulate vascular endothelial barrier function. In addition to rigidity sensing through integrin adhesions, mechanical perturbations such as changes in fluid shear stress can also activate force transduction signals at intercellular junctions. This study investigated how extracellular matrix rigidity and intercellular force transduction, activated by vascular endothelial cadherin, coordinate to regulate the integrity of endothelial monolayers. Studies used complementary mechanical measurements of endothelial monolayers grown on patterned substrates of variable stiffness. Specifically perturbing VE-cadherin receptors activated intercellular force transduction signals that increased integrin-dependent cell contractility and disrupted cell-cell and cell-matrix adhesions. Further investigations of the impact of substrate rigidity on force transduction signaling demonstrated how cells integrate extracellular mechanics cues and intercellular force transduction signals, to regulate endothelial integrity and global tissue mechanics. VE-cadherin specific signaling increased focal adhesion remodeling and cell contractility, while sustaining the overall mechanical equilibrium at the mesoscale. Conversely, increased substrate rigidity exacerbates the disruptive effects of intercellular force transduction signals, by increasing heterogeneity in monolayer stress distributions. The results provide new insights into how substrate stiffness and intercellular force transduction coordinate to regulate endothelial monolayer integrity.
血管内皮受到多种调节血管内皮屏障功能的机械信号的影响。除了通过整合素黏附进行刚度感知外，诸如流体剪切应力变化等机械扰动也可在细胞间连接激活力转导信号。本研究调查了由血管内皮钙黏蛋白激活的细胞外基质刚度和细胞间力转导如何协同调节内皮单层的完整性。研究使用了在可变刚度的图案化基质上生长的内皮单层的互补力学测量方法。特异性干扰血管内皮钙黏蛋白受体会激活细胞间力转导信号，这些信号会增加整合素依赖性细胞收缩性并破坏细胞-细胞和细胞-基质黏附。对基质刚度对力转导信号影响的进一步研究表明，细胞如何整合细胞外力学信号和细胞间力转导信号，以调节内皮完整性和整体组织力学。血管内皮钙黏蛋白特异性信号增强了黏着斑重塑和细胞收缩性，同时在中尺度维持了整体力学平衡。相反，增加的基质刚度通过增加单层应力分布的异质性，加剧了细胞间力转导信号的破坏作用。这些结果为基质刚度和细胞间力转导如何协同调节内皮单层完整性提供了新的见解。
