Unveiling the Mechanisms that Contribute to the Vascular Smooth Muscle Cell Response to Matrix Rigidity

Solanki, Reesha (2024) Unveiling the Mechanisms that Contribute to the Vascular Smooth Muscle Cell Response to Matrix Rigidity. Doctoral thesis, University of East Anglia.

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Abstract

Vascular smooth muscle cells (VSMCs) are the predominant cell type that make up the tunica media in the arterial wall. They exist in a quiescent, contractile state and regulate vascular tone and compliance. In ageing and disease, the extracellular matrix (ECM) stiffens, and vascular compliance is reduced. VSMCs are mechanosensitive and can respond to the stiffened ECM by dedifferentiating to a proliferative phenotype and becoming hypertrophic. The exact mechanism driving this change remains elusive, therefore, our work focuses on the VSMC response to rigid ECM.

We seed human aortic-VSMCs onto polyacrylamide hydrogels (PAHs) of two tensile strengths biomimicking a physiological (12 kPa) and pathological (72 kPa) aorta. In this thesis we have identified multiple VSMC volume regulators. Additionally, we have been able to identify that VSMCs seeded on rigid (72 kPa) PAHs stimulated with angiotensin II or growth media are hypertrophic in nature but also experience increased DNA damage.

We find that HDAC3 inhibition plays a beneficial role in restoring healthy morphology on a rigid matrix, whilst HDAC6 inhibition caused a hypertrophic response in those seeded on a pliable (12 kPa) PAHs as well as greater DNA damage accumulation. We find that microtubule stability does not drive this mechanism as we first hypothesised.

We highlight a novel piezo1/PKC/aquaporin-1 mediated pathway driving VSMC hypertrophy. We find that the pharmacological targeting of this pathway (even in the longer term) inhibits the increased VSMC volume response to ECM rigidity. We utilised the allosteric activator of piezo1, Yoda1, as well as siRNA-mediated knockdown and the inhibition of PKC and aquaporin-1 to determine this result. We also confirm that PKC regulates aquaporin-1 localisation in VSMCs, which was not fully elucidated until now. Our findings provide novel therapeutic targets for stiffness-induced VSMC hypertrophy and dysregulation.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Depositing User:	Kitty Laine
Date Deposited:	11 Jun 2025 09:25
Last Modified:	11 Jun 2025 09:25
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99442
DOI:

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