Force Sensing by Piezo Channels in Cardiovascular Health and Disease

Beech, David J.; Kalli, Antreas C.

doi:10.1161/atvbaha.119.313348

Cited by 182 publications

(168 citation statements)

References 103 publications

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“…(ii) Piezo1-mediated depolarization in SMCs activates voltage-operated calcium influx and vasoconstriction whereas TRPV4 -mediates vasodilation (92), and (iii) TRPV1 mediates contraction whereas TRPV4 mediates dilation of the ciliary muscle (93). We propose that Piezo1 and TRPV4 channels in TM cells are coupled to distinct microdomains and/or downstream Ca 2+ effectors.…”

Section: Discussionmentioning

confidence: 88%

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Yarishkin

Phuong

Baumann

et al. 2020

Preprint

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AbstractMechanosensitivity of the trabecular meshwork (TM) is a key determinant of intraocular pressure (IOP) yet our understanding of the molecular mechanisms that subserve it remains in its infancy. Here, we show that mechanosensitive Piezo1 channels modulate the TM pressure response via calcium signaling and dynamics of the conventional outflow pathway. Pressure steps evoked fast, inactivating cation currents and calcium signals that were inhibited by Ruthenium Red, GsMTx4 and Piezo1 shRNA. Piezo1 expression was confirmed by transcript and protein analysis, and by visualizing Yoda1-mediated currents and [Ca2+]i elevations in primary human TM cells. Piezo1 activation was obligatory for transduction of physiological shear stress and was coupled to reorganization of F-actin cytoskeleton and focal adhesions. The importance of Piezo1 channels as pressure sensors was shown by the GsMTx4 -dependence of the pressure-evoked current and conventional outflow function. We also demonstrate that Piezo1 collaborates with the stretch-activated TRPV4 channel, which mediated slow, delayed currents to pressure steps. Collectively, these results suggest that TM mechanosensitivity utilizes kinetically, regulatory and functionally distinct pressure transducers to inform the cells about force-sensing contexts. Piezo1-dependent control of shear flow sensing, calcium homeostasis, cytoskeletal dynamics and pressure-dependent outflow suggests a novel potential therapeutic target for treating glaucoma.Significance StatementTrabecular meshwork (TM) is a highly mechanosensitive tissue in the eye that regulates intraocular pressure through the control of aqueous humor drainage. Its dysfunction underlies the progression of glaucoma but neither the mechanisms through which TM cells sense pressure nor their role in aqueous humor outflow are understood at the molecular level. We identified the Piezo1 channel as a key TM transducer of tensile stretch, shear flow and pressure. Its activation resulted in intracellular signals that altered organization of the cytoskeleton and cell-extracellular matrix contacts, and modulated the trabecular component of aqueous outflow whereas another channel, TRPV4, mediated a delayed mechanoresponse. These findings provide a new mechanistic framework for trabecular mechanotransduction and its role in the regulation of fast fluctuations in ocular pressure, as well as chronic remodeling of TM architecture that epitomizes glaucoma.

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Section: Discussionmentioning

confidence: 88%

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Yarishkin

Phuong

Baumann

et al. 2020

Preprint

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“…These are known as Piezo channels, and they are blocked by GsMTx-4 and Gd 3+ (Coste et al 2010). The channels are widely expressed and are important to the normal function of multiple tissues, including from the cardiovascular system (Beech and Kalli 2019). The channels display rapid voltagedependent inactivation in patch-clamped and whole-cell mechanical assays (Coste 2012;Coste et al 2010;Murthy et al 2017;Wu et al 2017).…”

Section: Stretch-activated Nonspecific Cation Channelsmentioning

confidence: 99%

Stretch modulation of cardiac contractility: importance of myocyte calcium during the slow force response

et al. 2020

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The mechanical response of the heart to myocardial stretch has been understood since the work of muscle physiologists more than 100 years ago, whereby an increase in ventricular chamber filling during diastole increases the subsequent force of contraction. The stretch-induced increase in contraction is biphasic. There is an abrupt increase in the force that coincides with the stretch (the rapid response), which is then followed by a slower response that develops over several minutes (the slow force response, or SFR). The SFR is associated with a progressive increase in the magnitude of the Ca 2+ transient, the event that initiates myocyte cross-bridge cycling and force development. However, the mechanisms underlying the stretch-dependent increase in the Ca 2+ transient are still debated. This review outlines recent literature on the SFR and summarizes the different stretch-activated Ca 2+ entry pathways. The SFR might result from a combination of several different cellular mechanisms initiated in response to activation of different cellular stretch sensors.

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“…The molecular and functional studies required to test these ideas will take time to complete. Moreover, our studies have shown the importance of understanding PIEZO1 in its native membrane environment because the native endothelial and red blood cell environments profoundly alter the gating characteristics of PIEZO1 18,27,44,45 . We do not yet know whether endothelial cell dysfunction affects the properties of PIEZO1, but any changes could be relevant to COVID-19 and its progression to fatality.…”

Section: Discussionmentioning

confidence: 93%

Genetic variants of PIEZO1 associate with COVID-19 fatality

Cheng

Deivasikamani

Ludlow

et al. 2020

Preprint

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COVID-19, caused by the SARS-CoV-2 virus, carries significant risk of mortality and has spread globally with devastating societal consequences. Endothelial infection has been identified as a feature of the disease and so there is motivation to determine the relevance of endothelial membrane mechanisms affecting viral entry and response. Here, through a study of patient data in UK Biobank released on 16 April 2020, we suggest relevance of PIEZO1, a non-selective cation channel protein that both mediates endothelial responses to mechanical force and unusually indents the cell membrane. PIEZO1 notably has roles that may also be relevant in red blood cell function, pulmonary inflammation, bacterial infection and fibrotic auto-inflammation. We provide evidence that single nucleotide polymorphisms (SNPs) in the gene encoding PIEZO1 are more common in individuals who test positive for SARS-CoV-2 regardless of pre-existing hypertension, myocardial infarction, stroke, diabetes mellitus or arthritis. Some of these SNPs are more common in African and Caribbean populations, which are groups that were recently shown to have greater susceptibility to infection. One of the SNPs is a missense mutation that results in an amino acid change in an evolutionarily conserved and previously unexplored N-terminal region PIEZO1. The data support the notion of genetic factors influencing SARS-CoV-2 infection and suggest a specific role for PIEZO1.

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Force Sensing by Piezo Channels in Cardiovascular Health and Disease

Cited by 182 publications

References 103 publications

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Stretch modulation of cardiac contractility: importance of myocyte calcium during the slow force response

Genetic variants of PIEZO1 associate with COVID-19 fatality

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