Mechanosignals in abdominal aortic aneurysms

Lowis, Christiana; Winaya, Aurellia Ramara; Kumari, Puja; Rivera, Cristobal; Vlahos, John; Hermantara, Rio; Pratama, Muhammad Yogi; Ramkhelawon, Bhama

doi:10.3389/fcvm.2022.1021934

Cited by 9 publications

(10 citation statements)

References 132 publications

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“…8 It was also demonstrated that macrophage-derived signals could regulate the expression of Piezo-1 by the vascular smooth muscle cells in the aorta and that this could play a critical role during vascular matrix remodeling. 9,10 To assess the direct role of macrophage-derived Piezo-1 in adjusting the angiogenic response following hindlimb ischemia, mice with conditional knockdown of Piezo-1 in the myeloid lineage (Piezo1 flox/flox LysM Cre ) were generated. The authors demonstrated that the deficiency of Piezo-1 in myeloid cells improved the reperfusion of blood in the leg of mice after hindlimb ischemia by facilitating the revascularization response locally.…”

Section: See Accompanying Article On Page 504mentioning

confidence: 99%

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Mechanical Reprogramming of Macrophages: A Push for Vascularization

Ramkhelawon

2023

ATVB

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Section: See Accompanying Article On Page 504mentioning

confidence: 99%

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confidence: 99%

Mechanical Reprogramming of Macrophages: A Push for Vascularization

Ramkhelawon

2023

ATVB

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“…Whether VSMCs possess a similar response to ECM rigidity remains unknown, however, VSMCs possess numerous stretch activated ion channels including piezo1 and members of the TRP (transient receptor potential) family (Lowis et al, 2023). In normal physiology, these channels are activated transiently by blood flow derived stretching of the aortic wall (Liu & Lin, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…SAC activation enables mechanical stimuli to be converted into biochemical responses through mediating the diffusion of ions, including calcium ions (Ca 2+ ), across the cell membrane (Kobayashi & Sokabe, 2010). Whether VSMCs possess a similar response to ECM rigidity remains unknown, however, VSMCs possess numerous stretch activated ion channels including piezo1 and members of the TRP (transient receptor potential) family (Lowis et al, 2023). In normal physiology, these channels are activated transiently by blood flow derived stretching of the aortic wall (Liu & Lin, 2022).…”

Section: Introductionmentioning

confidence: 99%

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

Johnson,

Solanki,

Wostear

et al. 2024

British J Pharmacology

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Background and PurposeDecreased 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 ApproachHuman 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 ResultsOn 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 ImplicationsIn 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.

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“…SAC activation enables mechanical stimuli to be converted into biochemical responses through mediating the diffusion of ions, including calcium, across the cell membrane (Kobayashi and Sokabe, 2010). Whether VSMCs possess a similar response to ECM rigidity remains unknown, however, VSMCs possess numerous stretch activated ion channels including piezo1 and members of the TRP (transient receptor potential) family (Lowis et al, 2023). In normal physiology, these channels are activated transiently by blood flow derived stretching of the aortic wall (Liu and Lin, 2022).…”

Section: Introductionmentioning

confidence: 99%

Piezo1-mediated microtubule destabilisation promotes extracellular matrix rigidity induced smooth muscle cell hypertrophy

Johnson

Ahmed

Wostear

et al. 2023

Preprint

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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.

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Mechanosignals in abdominal aortic aneurysms

Cited by 9 publications

References 132 publications

Mechanical Reprogramming of Macrophages: A Push for Vascularization

Mechanical Reprogramming of Macrophages: A Push for Vascularization

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

Piezo1-mediated microtubule destabilisation promotes extracellular matrix rigidity induced smooth muscle cell hypertrophy

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