The effect of matrix stiffness on vascular smooth muscle cell contractility

Ahmed, Sultan (2021) The effect of matrix stiffness on vascular smooth muscle cell contractility. Doctoral thesis, University of East Anglia.

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Vascular smooth muscle cells (VSMCs) typically line the medial layer of the arterial wall, and exist in a quiescent contractile phenotype to regulate vessel tone. However, during ageing and early cardiovascular disease (CVD) development, the arterial wall becomes more rigid, and under these conditions, VSMC de-differentiate into the synthetic proliferative phenotype where they instead contribute to vessel repair. Arterial stiffness is a key predicative biomarker of CVD and our work focuses on the response of the VSMCs to the less compliant extracellular matrix (ECM). We hypothesise aberrations in VSMC structure and function in response to matrix stiffness, and speculate that this may contribute to the pathological vessel wall remodelling typically observed within CVD.
To test this, we fabricated polyacrylamide gels with rigidities representative of both physiological (12kPa) and pathological (72kPa) stiffness. Our work presents an increase in VSMC force generation in response to matrix stiffness via traction force microscopy (TFM). We show this to occur via novel mechanisms and, importantly, highlight the key mechanosensors mediating this. When seeded on that 72kPa hydrogel, quiescent VSMCs were shown to undergo hypertrophy causing increased DNA damage. Our study identifies stretch activated channels (SACs) and N-acetyltransferase 10 (NAT10) as critical mechanosensors that facilitate this, as inhibition of both restored healthy morphology. Importantly, we highlight Piezo1 as a novel SAC within stiffness-induced VSMC dysregulation. Using qPCR, we show Piezo1 gene expression to increase in response to matrix rigidity, and also reveal that its knockdown, via siRNA-mediated methods, can reduce DNA damage accumulation. Due to this, we predict there to be an intricate crosstalk between the cytoskeletal networks and key mechanosensors present at the cell membrane, and introduce Piezo1 and NAT10 as therapeutic targets for stiffness-induced quiescent VSMC dysregulation.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Nicola Veasy
Date Deposited: 30 Mar 2022 08:02
Last Modified: 30 Mar 2022 08:02


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