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

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.