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

WARREND_U23DTP

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;
(3) RhoA alters cell-matrix adhesion signalling pathways in response to matrix stiffness.
The Warren Lab is a collaborative and enthusiastic research environment.

This studentship will train you in a range of biomedical (hydrogel-based cell culture, qPCR, Western blotting) and imaging (immunofluorescence, confocal and traction-force microscopy) techniques.

Those interested in cell, molecular, mechano-, and/or vascular biology are encouraged to apply / discuss the project in further detail.

References

Sultan Ahmed*, Robert Johnson*, Reesha Solanki, Teclino Afewerki, Finn Wostear, and Derek Warren. Using polyacrylamide hydrogels to model physiological aortic stiffness reveals that microtubules are critical regulators of isolated smooth muscle cell morphology and contractility. Front. Pharmacol. 13:836710. doi: 10.3389/fphar.2022.836710.

Johnson RT, Solanki R, Warren DT. Mechanical programming of arterial smooth muscle cells in health and ageing. Biophys Rev. 2021 Aug 30;13(5):757-768. doi: 10.1007/s12551-021-00833-6.

Sultan Ahmed and Derek T Warren. Smooth muscle cell contraction and mechanotransduction. Vessel Plus. 2018;2:36. doi:10.20517/2574-1209.2018.51