Understanding how matrix rigidity and cytoskeletal crosstalk regulate vascular smooth muscle cell ageing

维持主动脉顺应性，即主动脉随血压变化而改变形状的能力，对健康老龄化至关重要。主动脉壁由弹性和非弹性成分组成。随着年龄的增长，弹性成分退化，增加了硬度，降低了主动脉顺应性。这是许多与年龄有关的疾病的主要风险因素。血管平滑肌细胞（VSMCs）是主动脉壁的主要细胞类型。这些机械敏感细胞感知到增加的主动脉壁硬度，并产生增强的肌动球蛋白驱动的收缩力。这样可以防止主动脉壁变形，进一步降低主动脉顺应性。然而，主动脉壁刚度增加对VSMC力产生的调节机制尚不清楚。该项目旨在解决我们知识上的这一差距，并确定调节这一过程的新途径。最近我们已经表明，生长在刚性表面的vsmc显示微管稳定性下降。我们假设微管分解激活RhoA/GEF-H1信号通路，进而促进肌动蛋白聚合并增强肌动球蛋白衍生的力产生。该项目旨在确定：(1)微管不稳定是否促进了肌动球蛋白力的增强；(2)靶向RhoA/GEF-H1足以缓解肌动球蛋白生成增强；(3) RhoA改变细胞-基质粘附信号通路，以响应基质刚度。

Maintaining aortic compliance, the ability of the aorta to change shape in response to changes in blood pressure, is essential for healthy ageing. The aortic wall is comprised of elastic and non-elastic components. As we age, the elastic components become degraded, increasing the stiffness and reducing aortic compliance. This is a major risk-factor for numerous age-related diseases.Vascular Smooth Muscle Cells (VSMCs) are the predominant cell type of the aortic wall. These mechanosensitive cells sense increased aortic wall stiffness and generate enhanced actomyosin-driven contractile forces. This prevents the deformation of the aortic wall and further reduces aortic compliance. However, mechanisms regulating VSMC force generation in response to increased aortic wall stiffness remain unknown. This studentship seeks to address this gap in our knowledge and identify novel pathways regulating this process.Recently we have shown that VSMCs grown on rigid surfaces display decreased microtubule stability. We hypothesise that microtubule disassembly activates a RhoA/GEF-H1 signalling pathway, which in turn promotes actin polymerisation and enhances actomyosin-derived force production. This project seeks to determine if: (1) microtubule destabilisation promotes enhanced actomyosin force production; (2) targeting RhoA/GEF-H1 is sufficient to alleviate enhanced actomyosin force generation; and (3) RhoA alters cell-matrix adhesion signalling pathways in response to matrix stiffness.