Microskeletal stiffness promotes aortic aneurysm by sustaining pathological vascular smooth muscle cell mechanosensation via Piezo1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA776527 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16642933.fastq.gz | Fastqsanger.gz | |||
| SRR16642934.fastq.gz | Fastqsanger.gz | |||
| SRR16642935.fastq.gz | Fastqsanger.gz | |||
| SRR16642936.fastq.gz | Fastqsanger.gz | |||
| SRR16642937.fastq.gz | Fastqsanger.gz |
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Project description:Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. Here, we combined novel tweezers-based micromechanical system and single-cell RNA sequencing to map defective mechano-phenotype signatures of VSMC in AAA. Notably, theoretical modelling predicted that cytoskeleton alterations fueled cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which were validated by live micromechanical measurements. Mechanistically, VSMC gradually adopted a mechanically solid-like state by upregulating CSK crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevented mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA.
2021-11-01 | GSE186865 | GEO
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Project description:Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding microenvironment. However, how chronological aging alters VSMCs’ ability to sense and adapt to mechanical perturbations remains unexplored. Here, we show defective VSMC mechanosensation in aging measured with ultrasound tweezers-based micromechanical system, force instantaneous frequency spectrum and transcriptome analyses. The mechanobiological study reveals thataged VSMCs adapt a relatively inert solid-like state with altered actin cytoskeletal integrity, resulting in an impairment in their mechanosensitivity and dynamic mechanoresponse to mechanical perturbations. The aging-associated decline in mechanosensation behaviors is mediated by hyperactivity of Piezo1-dependent calcium signaling. Inhibition of Piezo1 alleviates vascular aging and partially restores the loss in dynamic contractile properties in aged cells. Altogether, our study reveals the novel signaling pathway underlying aging-associated aberrant mechanosensation in VSMC and identifies Piezo1 as a potential therapeutic mechanobiological target to alleviate vascular aging.
2024-02-21 | GSE230805 | GEO
Project description:Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding microenvironment. However, how chronological aging alters VSMCs’ ability to sense and adapt to mechanical perturbations remains unexplored. Here, we show defective VSMC mechanosensation in aging measured with ultrasound tweezers-based micromechanical system, force instantaneous frequency spectrum and transcriptome analyses. The mechanobiological study reveals thataged VSMCs adapt a relatively inert solid-like state with altered actin cytoskeletal integrity, resulting in an impairment in their mechanosensitivity and dynamic mechanoresponse to mechanical perturbations. The aging-associated decline in mechanosensation behaviors is mediated by hyperactivity of Piezo1-dependent calcium signaling. Inhibition of Piezo1 alleviates vascular aging and partially restores the loss in dynamic contractile properties in aged cells. Altogether, our study reveals the novel signaling pathway underlying aging-associated aberrant mechanosensation in VSMC and identifies Piezo1 as a potential therapeutic mechanobiological target to alleviate vascular aging.
2023-11-01 | GSE244111 | GEO
Project description:Although cells of the immune system experience force and pressure throughout their lifecycle, almost nothing is known about how these mechanical processes regulate the immune response. Immune cells in highly mechanical organs, such as the lung, are constantly exposed to tonic and dynamically changing mechanical cues. Here using reverse genetics, we show that myeloid cells respond to force and alterations in cyclical hydrostatic pressure (CHP) via the mechanosensory ion channel (MSIC) PIEZO1. Unbiased RNA-sequencing from macrophages subjected to CHP reveals a striking state of proinflammatory reprogramming. We report a novel mechanosensory-immune signaling circuit which PIEZO1 initiates in response to CHP, activating c-JUN, upregulating Endothelin-1 (EDN1), and stabilizing HIF1α to facilitate a prolonged program of proinflammatory mediators. Using mice conditionally deficient of PIEZO1 in myeloid cells, and cellular depletion assays, we show infiltrating monocytes respond to cyclical force to recruit neutrophils and clear pulmonary Pseudomonas aeruginosa infection. Furthermore, myeloid PIEZO1 also drove lung pathology in a mouse model of pulmonary fibrosis. Our results demonstrate a novel environmental sensory axis that myeloid cells recognize to mount an inflammatory response, and is the first report showing a physiological role for PIEZO1 and mechanosensation in immunity.
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Project description:Synovial resident macrophages in humans play a key role in maintaining tissue and synovial fluid homeostasis and typically exhibit protective phenotypes. However, at the start of rheumatoid arthritis, macrophages can adopt inflammation-permissive phenotypes. The factors that influence macrophage phenotype during the early stages of arthritis are not yet fully understood. Interestingly, in mice, mechanical stress is required for the localization of joint inflammation. Given the critical roles of macrophages, we investigated whether mechanosensation contributes to the regulation of macrophage phenotypes. PIEZO1, a well-established mechanosensor expressed on macrophages, regulates various macrophage functions, including migration and phagocytosis. We found that PIEZO1 activation in macrophages shifted their phenotype to a tissue-resident (MERTKhigh, CD36high), inflammation-permissive phenocopy (TREM2low, VSIG4low), with elevated MHC class II and cytokine secretion. Additionally, in vivo activation of PIEZO1 in mice produced similar effects in synovial tissue macrophages (STMs) and led to increased recruitment of monocytes and neutrophils. By dissecting the PIEZO1 signalling pathway, we were able to restore the protective macrophage phenotype by inhibiting calpain signalling and knocking-out HIF1α, both downstream mediators of PIEZO1 activation. Furthermore, we observed that PIEZO1 expression is present in synovial macrophages from patients with active rheumatoid arthritis and decreases during remission, suggesting a link between macrophage PIEZO1 expression and disease activity
2026-01-31 | E-MTAB-15203 | biostudies-arrayexpress
Project description:Synovial resident macrophages in humans play a key role in maintaining tissue and synovial fluid homeostasis and typically exhibit protective phenotypes. However, at the start of rheumatoid arthritis, macrophages can adopt inflammation-permissive phenotypes. The factors that influence macrophage phenotype during the early stages of arthritis are not yet fully understood. Interestingly, in mice, mechanical stress is required for the localization of joint inflammation. Given the critical roles of macrophages, we investigated whether mechanosensation contributes to the regulation of macrophage phenotypes. PIEZO1, a well-established mechanosensor expressed on macrophages, regulates various macrophage functions, including migration and phagocytosis. We found that PIEZO1 activation in macrophages shifted their phenotype to a tissue-resident (MERTKhigh, CD36high), inflammation-permissive phenocopy (TREM2low, VSIG4low), with elevated MHC class II and cytokine secretion. Additionally, in vivo activation of PIEZO1 in mice produced similar effects in synovial tissue macrophages (STMs) and led to increased recruitment of monocytes and neutrophils. By dissecting the PIEZO1 signalling pathway, we were able to restore the protective macrophage phenotype by inhibiting calpain signalling and knocking-out HIF1α, both downstream mediators of PIEZO1 activation. Furthermore, we observed that PIEZO1 expression is present in synovial macrophages from patients with active rheumatoid arthritis and decreases during remission, suggesting a link between macrophage PIEZO1 expression and disease activity
2026-01-31 | E-MTAB-15200 | biostudies-arrayexpress
Project description:Mechanosensation of Cyclical Force by PIEZO1 is Essential for Innate Immunity
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Project description:Augmented extracellular matrix (ECM) stiffness is a mechanical hallmark of cancer. Mechanotransduction studies have extensively probed the mechanisms by which ECM stiffness regulates intracellular communication. However, the influence of stiffness on intercellular communication aiding tumor progression in three-dimensional microenvironments remains unknown. Small extracellular vesicles (EVs) are communicators of altered biophysical cues to distant sites through EV-ECM interactions and EV-mediated recipient cell-ECM interactions. Here we demonstrate stiffness-mediated modulation of small EVs secretion and cargo from three-dimensional oral squamous cell carcinoma spheroids. Using a spheroid culture platform with varying matrix stiffness properties, we show that small EVs carry parental biomolecular cargo, including mechanosensitive Piezo1 ion channel and adhesion molecule CD44. We comprehensively validate the presence of both markers in our EV populations using proteomic and genetic analysis. Transcriptomic analysis of microRNA and long non-coding RNA cargo of small EVs released from soft and stiff ECM spheroids revealed enrichment of tumorigenic and metastatic profiles in EVs from stiff ECM cultures compared to that of soft ones. Gene set enrichment analysis of a comparative dataset obtained by overlaying spheroid mRNA and EV miRNA profiles identified key oncogenic pathways involved in cell-EV crosstalk in the spheroid model.
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