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Piezo1-mediated microtubule destabilisation promotes extracellular matrix rigidity induced smooth muscle cell hypertrophy
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  • Robert Johnson,
  • Sultan Ahmed,
  • Finn Wostear,
  • Reesha Solanki,
  • Christopher Morris,
  • Stefan Bidula,
  • Derek Warren
Robert Johnson
University of East Anglia

Corresponding Author:[email protected]

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Sultan Ahmed
University of East Anglia
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Finn Wostear
University of East Anglia
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Reesha Solanki
University of East Anglia
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Christopher Morris
University of East Anglia
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Stefan Bidula
University of East Anglia
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Derek Warren
University of East Anglia
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Abstract

Decreased aortic compliance is a precursor to numerous cardiovascular diseases. Compliance is regulated by the rigidity of the aortic wall and the vascular smooth muscle cells (VSMCs) within it. Extracellular matrix stiffening, observed during ageing, reduces compliance and contributes to hypertension. In response to increased rigidity, VSMCs generate enhanced contractile forces that result in VSMC stiffening and a further reduction in compliance. Due to a lack of suitable in vitro models, the mechanisms driving VSMC response to matrix rigidity remain poorly defined. Human aortic-VSMCs were seeded onto polyacrylamide hydrogels whose rigidity mimicked either healthy or aged/diseased aortae. VSMC response to contractile agonist stimulation was measured through changes in cell area and volume. VSMCs were pre-treated with pharmacological agents prior to agonist stimulation to identify regulators of VSMC hypertrophy. VSMCs undergo a differential response to contractile agonist stimulation based on matrix rigidity. On pliable matrices, VSMCs contract, decreasing in cell area. Meanwhile, on rigid matrices VSMCs undergo a hypertrophic response, increasing in area and volume. Piezo1 mediated calcium influx drives VSMC hypertrophy by promoting microtubule destabilisation. Pharmacological stabilisation of microtubules or blocking calcium influx prevented VSMC hypertrophy on rigid matrices whilst maintaining contractility on pliable matrices. In response to extracellular matrix rigidity, VSMCs undergo a hypertrophic response driven by piezo1-mediated microtubule destabilisation. Pharmacological targeting of this response blocks matrix rigidity induced VSMC hypertrophy whilst VSMC contractility on healthy mimicking matrices is unimpeded. Through delineating this rigidity-induced mechanism, we identify novel targets whose pharmacological inhibition may prove beneficial against VSMC-driven cardiovascular disease.
11 Apr 2023Submitted to British Journal of Pharmacology
12 Apr 2023Submission Checks Completed
12 Apr 2023Assigned to Editor
12 Apr 2023Review(s) Completed, Editorial Evaluation Pending
22 Apr 2023Reviewer(s) Assigned
25 May 2023Editorial Decision: Revise Minor
27 Sep 20231st Revision Received
27 Sep 2023Review(s) Completed, Editorial Evaluation Pending
27 Sep 2023Submission Checks Completed
27 Sep 2023Assigned to Editor
03 Oct 2023Reviewer(s) Assigned
29 Oct 2023Editorial Decision: Revise Minor
03 Nov 20232nd Revision Received
07 Nov 2023Submission Checks Completed
07 Nov 2023Assigned to Editor
07 Nov 2023Review(s) Completed, Editorial Evaluation Pending