Improving aortic compliance during ageing: Microtubules regulate smooth muscle cell force generation

WARREN_U21DTP

Maintaining vascular compliance, the ability of blood vessels to change shape in response to changes in blood pressure, is essential for healthy aging. The vascular wall of large arteries, i.e. the aorta, is comprised of elastic and non-elastic components, that respectively provide elasticity and tensile strength to the vascular wall. As we age, the elastic components become degraded. This results in increased vessel stiffness and reduced vascular compliance, a 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 principle cell type of the aortic wall. These mechanosensitive cells respond to changes in aortic shape by producing actomyosin forces that contract the vessel back to its resting state. As the aortic wall stiffens due to aging, VSMCs respond by producing greater actomyosin forces. Thus, preventing the deformation of the vascular wall and reducing vascular compliance.

We have correlated increased VSMC actomyosin force generation with reduced microtubule acetylation, a marker of microtubule instability. This project seeks to understand: (1) the mechanistic relationship between microtubule acetylation and actomyosin force generation; (2) how microtubules regulate VSMCs ability to transfer actomyosin force through cell-matrix adhesion complexes; (3) whether targeted manipulation of microtubule stability can regulate VSMC actomyosin force production? This study has the potential to identify novel targets that will allow the pharmacological manipulation and restoration of aortic compliance during ageing.

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 (confocal, traction force and atomic force microscopy) techniques. Those interested in cell, molecular, mechano- and vascular biology are encouraged to apply.

References:
Lauren J Porter, Rose-Marie Minaisah, Sultan Ahmed, Seema Ali, Rosemary Norton, Qiuping Zhang, Elisa Ferraro, Chris Molenaar, Mark R Holt, Susan Cox, Samuel J Fountain, Catherine M Shanahan & Derek T Warren. SUN1/2 are essential for RhoA/ROCK regulated actomyosin activity in isolated vascular smooth muscle cells. Cells 2020, 9, 132. doi: 10.3390/cells9010132

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

Minaisah RM, Cox S, Warren DT. The Use of Polyacrylamide Hydrogels to Study the Effects of Matrix Stiffness on Nuclear Envelope Properties. Methods Mol Biol. 2016;1411:233-9. doi: 10.1007/978-1-4939-3530-7_15