The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease

Cell, Journal Year: 2020, Volume and Issue: 182(2), P. 270 - 296

Published: July 1, 2020

Language: Английский

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Discoveries in structure and physiology of mechanically activated ion channels

Nature, Journal Year: 2020, Volume and Issue: 587(7835), P. 567 - 576

Published: Nov. 25, 2020

Language: Английский

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Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 31, 2021

Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine role mechanically activated cation channel Piezo1 in polarization sensing microenvironmental stiffness. We show that macrophages lacking exhibit reduced inflammation enhanced wound healing responses. Additionally, expressing transgenic Ca2+ reporter, Salsa6f, reveal influx is dependent on Piezo1, modulated soluble signals, stiff substrates. Furthermore, stiffness-dependent changes function, both vitro response subcutaneous implantation biomaterials vivo, require Piezo1. Finally, positive feedback between actin drives activation. Together, our studies a mechanosensor stiffness macrophages, its activity modulates

Language: Английский

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The mechanosensitive Piezo1 channel is required for bone formation

eLife, Journal Year: 2019, Volume and Issue: 8

Published: July 10, 2019

Mechanical load of the skeleton system is essential for development, growth, and maintenance bone. However, molecular mechanism by which mechanical stimuli are converted into osteogenesis bone formation remains unclear. Here we report that Piezo1, a bona fide mechanotransducer critical various biological processes, plays role in formation. Knockout Piezo1 osteoblast lineage cells disrupts osteoblasts severely impairs structure strength. Bone loss induced unloading blunted knockout mice. Intriguingly, simulated microgravity treatment reduced function suppressing expression Piezo1. Furthermore, osteoporosis patients show closely correlated with dysfunction. These data collectively suggest functions as key conferring mechanosensitivity to determining mechanical-load-dependent formation, represents novel therapeutic target treating or unloading-induced severe loss.

Language: Английский

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Mechanical regulation of bone remodeling

Bone Research, Journal Year: 2022, Volume and Issue: 10(1)

Published: Feb. 18, 2022

Abstract Bone remodeling is a lifelong process that gives rise to mature, dynamic bone structure via balance between formation by osteoblasts and resorption osteoclasts. These opposite processes allow the accommodation of bones mechanical forces, altering mass in response changing conditions. Mechanical forces are indispensable for homeostasis; skeletal formation, resorption, adaptation dependent on signals, loss stimulation can therefore significantly weaken structure, causing disuse osteoporosis increasing risk fracture. The exact mechanisms which body senses transduces regulate have long been an active area study among researchers clinicians. Such research will lead deeper understanding disorders identify new strategies rejuvenation. Here, we discuss properties, mechanosensitive cell populations, mechanotransducive signaling pathways system.

Language: Английский

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Force Sensing by Piezo Channels in Cardiovascular Health and Disease

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2019, Volume and Issue: 39(11), P. 2228 - 2239

Published: Sept. 19, 2019

Mechanical forces are fundamental in cardiovascular biology, and deciphering the mechanisms by which they act remains a testing frontier research. Here, we raise awareness of 2 recently discovered proteins, Piezo1 Piezo2, assemble as transmembrane triskelions to combine exquisite force sensing with regulated calcium influx. There is emerging evidence for their importance endothelial shear stress secretion, NO generation, vascular tone, angiogenesis, atherosclerosis, permeability remodeling, blood pressure regulation, insulin sensitivity, exercise performance, baroreceptor reflex, there early suggestions relevance cardiac fibroblasts myocytes. Human genetic analysis points significance lymphatic disease, anemia, varicose veins, potentially heart failure, hypertension, aneurysms, stroke. These channels appear be versatile sensors, used creatively inform various force-sensing situations. We discuss emergent concepts controversies suggest that potential new important understanding substantial.

Language: Английский

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Endothelial cell Piezo1 mediates pressure-induced lung vascular hyperpermeability via disruption of adherens junctions

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(26), P. 12980 - 12985

Published: June 11, 2019

Significance Increased hydrostatic pressure in lung capillaries experienced during high altitude, head trauma, and left heart failure can lead to disruption of endothelial barrier edema formation. We identified Piezo1 as a mechanical sensor responsible for breakdown (barotrauma) secondary reduced expression the adherens junction proteins VE-cadherin, β-catenin, p120-catenin. Endothelial-specific deletion or pharmacological inhibition prevented capillary leakage, suggesting therapeutic approach preventing associated failure.

Language: Английский

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Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Cell, Journal Year: 2019, Volume and Issue: 179(2), P. 340 - 354

Published: Oct. 1, 2019

Language: Английский

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The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 8, 2021

Abstract The beating heart possesses the intrinsic ability to adapt cardiac output changes in mechanical load. century-old Frank–Starling law and Anrep effect have documented that stretching during diastolic filling increases its contractile force. However, molecular mechanotransduction mechanism impact on health disease remain elusive. Here we show mechanically activated Piezo1 channel converts stretch of cardiomyocytes into Ca 2+ reactive oxygen species (ROS) signaling, which critically determines activity heart. Either cardiac-specific knockout or overexpression mice results defective ROS signaling development cardiomyopathy, demonstrating a homeostatic role Piezo1. is pathologically upregulated both mouse human diseased hearts via an autonomic response cardiomyocytes. Thus, serves as key mechanotransducer for initiating mechano-chemo transduction consequently maintaining normal function, might represent novel therapeutic target treating diseases.

Language: Английский

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Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(13)

Published: March 23, 2021

Significance Osteoarthritis is a global health problem that affects load-bearing joints, causing loss of mobility and enormous healthcare costs. However, disease-modifying approaches are lacking. Here, we report cellular mechanism inflammatory signaling in chondrocytes, the component cartilage. We show how osteoarthritis-relevant levels interleukin-1α reprogram articular chondrocytes so they become more susceptible to mechanical trauma, which sense via Piezo1/2-mechanosensitive ion channels. uncover IL-1α enhances gene expression P iezo 1 primary underlying Piezo1 enhanced function. elucidate from membrane nucleus, including transcription factors enhance expression. also define consequences increased Piezo1, for mechanotransduction at rest, implicate this reprogramming osteoarthritis pathogenesis.

Language: Английский

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