Piezo1-mediated regulation of smooth muscle cell volume in response to enhanced extracellular matrix rigidity

Johnson, Robert T., Solanki, Reesha, Wostear, Finn, Ahmed, Sultan, Taylor, James C. K., Rees, Jasmine, Abel, Geraad, McColl, James, Jørgensen, Helle F., Morris, Chris J. ORCID: https://orcid.org/0000-0002-7703-4474, Bidula, Stefan ORCID: https://orcid.org/0000-0002-3790-7138 and Warren, Derek T. (2024) Piezo1-mediated regulation of smooth muscle cell volume in response to enhanced extracellular matrix rigidity. British Journal of Pharmacology, 181 (11). pp. 1576-1595. ISSN 0007-1188

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Abstract

Background and Purpose: 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). Extracellular matrix stiffening, observed during ageing, reduces compliance. In response to increased rigidity, VSMCs generate enhanced contractile forces that result in VSMC stiffening and a further reduction in compliance. Mechanisms driving VSMC response to matrix rigidity remain poorly defined. Experimental Approach: Human aortic-VSMCs were seeded onto polyacrylamide hydrogels whose rigidity mimicked either healthy (12 kPa) or aged/diseased (72 kPa) aortae. VSMCs were treated with pharmacological agents prior to agonist stimulation to identify regulators of VSMC volume regulation. Key Results: On pliable matrices, VSMCs contracted and decreased in cell area. Meanwhile, on rigid matrices VSMCs displayed a hypertrophic-like response, increasing in area and volume. Piezo1 activation stimulated increased VSMC volume by promoting calcium ion influx and subsequent activation of PKC and aquaporin-1. Pharmacological blockade of this pathway prevented the enhanced VSMC volume response on rigid matrices whilst maintaining contractility on pliable matrices. Importantly, both piezo1 and aquaporin-1 gene expression were upregulated during VSMC phenotypic modulation in atherosclerosis and after carotid ligation. Conclusions and Implications: In response to extracellular matrix rigidity, VSMC volume is increased by a piezo1/PKC/aquaporin-1 mediated pathway. Pharmacological targeting of this pathway specifically blocks the matrix rigidity enhanced VSMC volume response, leaving VSMC contractility on healthy mimicking matrices intact. Importantly, upregulation of both piezo1 and aquaporin-1 gene expression is observed in disease relevant VSMC phenotypes.

Item Type:	Article
Additional Information:	Research Funding: British Heart Foundation. Grant Number: FS/17/32/32916; Biotechnology and Biological Sciences Research Council. Grant Numbers: BB/T007699/1, BB/T008717/1
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Pathogen Biology Group
Depositing User:	LivePure Connector
Date Deposited:	19 Jan 2024 01:35
Last Modified:	01 Oct 2024 01:56
URI:	https://ueaeprints.uea.ac.uk/id/eprint/94202
DOI:	10.1111/bph.16294

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