Understanding how matrix rigidity regulates vascular smooth muscle cell function during ageing

WARREN_U22DTP2

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.

However, preventing the degradation of these elastic components is difficult. The Warren Lab therefore focuses on targeting Vascular Smooth Muscle Cells (VSMCs), the principal cell type of the aortic wall. These mechanosensitive cells regulate aortic compliance by generating actomyosin-driven contractile forces that restore the aorta back to its resting state. As the aortic wall stiffens during ageing, VSMCs respond by producing greater actomyosin-derived forces. Thus, preventing the deformation of the aortic wall and reducing compliance. However, the mechanisms which regulate VSMC force generation in rigid environments are unknown.

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.

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