Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Iring, András; Jin, Young-June; Albarrán-Juárez, Julian; Siragusa, Mauro; Wang, Shengpeng; Dancs, Péter T.; Nakayama, Akiko; Tonack, Sarah; Chen, Min; Künne, Carsten; Sokòl, Anna M.; Günther, Stefan; Martı́nez, Alfredo; Fleming, Ingrid; Wettschureck, Nina; Graumann, Johannes; Weinstein, Lee S.; Offermanns, Stefan

doi:10.1172/jci123825

Cited by 146 publications

(169 citation statements)

References 79 publications

(96 reference statements)

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“…Since the cardiovascular system develops early during embryonic development, being functional approximately around 10 weeks of gestation, mechanosensitivity may play an important role during prenatal and postnatal vascular morphogenesis as well as during adulthood. Recent studies have shown that the endothelial cell (EC) sensitivity to WSS is involved in several developmental and physiological vascular processes such as angiogenesis and vascular morphogenesis, vascular remodeling, and vascular tone (Chen and Tzima, 2009;Franco et al, 2015;Carter et al, 2016;Poduri et al, 2017;John et al, 2018;Iring et al, 2019). In contrast with barosensitivity, which involves central control by the brainstem of the heart activity and the peripheral arterial resistance and endocrine blood volume control, shear stress sensitivity seems to be determined and act locally.…”

Section: Introductionmentioning

confidence: 99%

Fluid Shear Stress Sensing by the Endothelial Layer

et al. 2020

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Blood flow produces mechanical frictional forces, parallel to the blood flow exerted on the endothelial wall of the vessel, the so-called wall shear stress (WSS). WSS sensing is associated with several vascular pathologies, but it is first a physiological phenomenon. Endothelial cell sensitivity to WSS is involved in several developmental and physiological vascular processes such as angiogenesis and vascular morphogenesis, vascular remodeling, and vascular tone. Local conditions of blood flow determine the characteristics of WSS, i.e., intensity, direction, pulsatility, sensed by the endothelial cells that, through their effect of the vascular network, impact WSS. All these processes generate a local-global retroactive loop that determines the ability of the vascular system to ensure the perfusion of the tissues. In order to account for the physiological role of WSS, the so-called shear stress set point theory has been proposed, according to which WSS sensing acts locally on vessel remodeling so that WSS is maintained close to a set point value, with local and distant effects of vascular blood flow. The aim of this article is (1) to review the existing literature on WSS sensing involvement on the behavior of endothelial cells and its short-term (vasoreactivity) and longterm (vascular morphogenesis and remodeling) effects on vascular functioning in physiological condition; (2) to present the various hypotheses about WSS sensors and analyze the conceptual background of these representations, in particular the concept of tensional prestress or biotensegrity; and (3) to analyze the relevance, explanatory value, and limitations of the WSS set point theory, that should be viewed as dynamical, and not algorithmic, processes, acting in a self-organized way. We conclude that this dynamic set point theory and the biotensegrity concept provide a relevant explanatory framework to analyze the physiological mechanisms of WSS sensing and their possible shift toward pathological situations.

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Section: Introductionmentioning

confidence: 99%

Fluid Shear Stress Sensing by the Endothelial Layer

et al. 2020

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“…TRPV4, a polymodal nonselective cation channel, mediates the TM Ca 2+ influx in response to stretch and contributes to cell remodeling in the presence of chronic pressure/strain (15,17) but the mechanotransduction mechanism that mediates the homeostatic adjustment to pressure fluctuations has remained unknown. Potential candidates are Piezo channels, which have been recently implicated in dynamic regulation of pressure-induced lung vascular hyperpermeability and shear-stress induced endothelial signaling (18,19). Piezo 1 and 2 are large, conserved trimeric channels that mediate rapidly inactivating, small conductance (~25 -35 pS), low-threshold (~0.6 kBT/nm 2 ) currents in response to membrane tension (~1 -3 mN/m), indentation, shear stress (~10 dyn/cm 2 ) and/or stretch (20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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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“…A prior report has suggested lack of specificity of Yoda1 for Piezo1 channels 40 but the GsMTx4 toxin used as the basis of this proposal has limited value as a tool for evaluating Piezo1. Other prior studies have shown that genetic deletion of Piezo1 abolishes Yoda1's effects 10,36,41,42 and that Piezo1 knockdown by RNA interference suppresses its effects 14,30,[43][44][45][46] , consistent with Yoda1 having only Piezo1-mediated effects. Specific structure-activity requirements of Yoda1 at Piezo1 have been observed 24 and it does not activate Piezo2 21 .…”

Section: Discussionmentioning

confidence: 52%

Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression

Beech

Caolo

Debant

et al. 2019

Preprint

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Mechanical force has emerged as a determinant of Notch signalling but the mechanisms of force sensing and coupling to Notch are unclear. Here we propose a role for Piezo1 channels, the recently identified mechanosensors of mammalian systems. Piezo1 channel opening in response to shear stress or a chemical agonist led to activation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca 2+ -regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation there was increased Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, -secretase. Endothelial-specific disruption of Piezo1 in mice led to decreased Notch1-regulated gene expression in hepatic vasculature, consistent with prior evidence that Notch1 controls hepatic perfusion. The data suggest Piezo1 as a mechanism for coupling physiological force at the endothelium to ADAM10, Notch1, gene expression and vascular function.

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Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Cited by 146 publications

References 79 publications

Fluid Shear Stress Sensing by the Endothelial Layer

Fluid Shear Stress Sensing by the Endothelial Layer

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression

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