Feeling force: physical and physiological principles enabling sensory mechanotransduction.

Organisms as diverse as microbes, roundworms, insects, and mammals detect and respond to applied force. In animals, this ability depends on ionotropic force receptors, known as mechanoelectrical transduction (MeT) channels, that are expressed by specialized mechanoreceptor cells embedded in diverse tissues and distributed throughout the body. These cells mediate hearing, touch, and proprioception and play a crucial role in regulating organ function. Here, we attempt to integrate knowledge about the architecture of mechanoreceptor cells and their sensory organs with principles of cell mechanics, and we consider how engulfing tissues contribute to mechanical filtering. We address progress in the quest to identify the proteins that form MeT channels and to understand how these channels are gated. For clarity and convenience, we focus on sensory mechanobiology in nematodes, fruit flies, and mice. These themes are emphasized: asymmetric responses to applied forces, which may reflect anisotropy of the structure and mechanics of sensory mechanoreceptor cells, and proteins that function as MeT channels, which appear to have emerged many times through evolution.

The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation.

Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of noninvasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1 was studied through a conditional knockout mouse model as a major mediator for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout (P1KO) in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement, and muscle electromyogram (EMG) responses. We also detected higher Piezo1 expression in the central amygdala (CEA), which was found to be more sensitive to ultrasound stimulation than the cortex was. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation, while knocking out astrocytic Piezo1 showed no-obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.

Mechanoelectric coupling and arrhythmogenesis in cardiomyocytes contracting under mechanical afterload in a 3D viscoelastic hydrogel.

The heart pumps blood against the mechanical afterload from arterial resistance, and increased afterload may alter cardiac electrophysiology and contribute to life-threatening arrhythmias. However, the cellular and molecular mechanisms underlying mechanoelectric coupling in cardiomyocytes remain unclear. We developed an innovative patch-clamp-in-gel technology to embed cardiomyocytes in a three-dimensional (3D) viscoelastic hydrogel that imposes an afterload during regular myocyte contraction. Here, we investigated how afterload affects action potentials, ionic currents, intracellular Ca2+ transients, and cell contraction of adult rabbit ventricular cardiomyocytes. We found that afterload prolonged action potential duration (APD), increased transient outward K+ current, decreased inward rectifier K+ current, and increased L-type Ca2+ current. Increased Ca2+ entry caused enhanced Ca2+ transients and contractility. Moreover, elevated afterload led to discordant alternans in APD and Ca2+ transient. Ca2+ alternans persisted under action potential clamp, indicating that the alternans was Ca2+ dependent. Furthermore, all these afterload effects were significantly attenuated by inhibiting nitric oxide synthase 1 (NOS1). Taken together, our data reveal a mechano-chemo-electrotransduction (MCET) mechanism that acutely transduces afterload through NOS1-nitric oxide signaling to modulate the action potential, Ca2+ transient, and contractility. The MCET pathway provides a feedback loop in excitation-Ca2+ signaling-contraction coupling, enabling autoregulation of contractility in cardiomyocytes in response to afterload. This MCET mechanism is integral to the individual cardiomyocyte (and thus the heart) to intrinsically enhance its contractility in response to the load against which it has to do work. While this MCET is largely compensatory for physiological load changes, it may also increase susceptibility to arrhythmias under excessive pathological loading.

Expression patterns of mechanosensitive ion channel PIEZOs in irreversible pulpitis.

BACKGROUND: Mechanosensitive ion channel PIEZOs have been widely reported to involve inflammation and pain. This study aimed to clarify expression patterns of PIEZOs and their potential relations to irreversible pulpitis. MATERIALS AND METHODS: Normal pulp tissues (n = 29) from patients with impacted third molars and inflamed pulp tissues (n = 23) from patients with irreversible pulpitis were collected. Pain levels were assessed using a numerical rating scale. PIEZO expressions were measured using real-time PCR and then confirmed using GEO datasets GSE77459, immunoblot, and immunohistochemistry staining. Correlations of PIEZO mRNA expression with inflammatory markers, pain markers, or clinical pain levels were evaluated using Spearman's correlation analysis. Univariate analysis was conducted to analyze PIEZO expressions based on pain description and clinical examinations of cold test, percussion, palpation, and bite test. RESULTS: Compared with normal pulp tissues, mRNA expression levels of PIEZO1 were significantly increased in inflamed pulp tissues, while PIEZO2 was significantly decreased, which was further confirmed in GSE77459 and on a protein and histological level. The positive correlation of the mRNA expression levels between PIEZO1 and inflammatory markers, as well as between PIEZO2 and pain markers, was verified. PIEZO2 expression was also positively correlated with pain levels. Besides, irreversible pulpitis patients who reported continuous pain and who detected a positive response to cold stimulus exhibited a higher expression level of PIEZO2 in the inflamed pulp tissues. By contrast, patients reporting pain duration of more than one week showed a higher expression level of PIEZO1. CONCLUSIONS: This study demonstrated the upregulation of PIEZO1 and the downregulation of PIEZO2 in irreversible pulpitis and revealed the potential relation of PIEZO1 and PIEZO2 to inflammation and pain. These findings suggested that PIEZOs might play critical roles in the progression of irreversible pulpitis and paved the way for further investigations aimed at novel therapies of irreversible pulpitis by targeting PIEZOs.

Sonogenetics for Monitoring and Modulating Biomolecular Function by Ultrasound.

Ultrasound technology, synergistically harnessed with genetic engineering and chemistry concepts, has started to open the gateway to the remarkable realm of sonogenetics-a pioneering paradigm for remotely orchestrating cellular functions at the molecular level. This fusion not only enables precisely targeted imaging and therapeutic interventions, but also advances our comprehension of mechanobiology to unparalleled depths. Sonogenetic tools harness mechanical force within small tissue volumes while preserving the integrity of the surrounding physiological environment, reaching depths of up to tens of centimeters with high spatiotemporal precision. These capabilities circumvent the inherent physical limitations of alternative in vivo control methods such as optogenetics and magnetogenetics. In this review, we first discuss mechanosensitive ion channels, the most commonly utilized sonogenetic mediators, in both mammalian and non-mammalian systems. Subsequently, we provide a comprehensive overview of state-of-the-art sonogenetic approaches that leverage thermal or mechanical features of ultrasonic waves. Additionally, we explore strategies centered around the design of mechanochemically reactive macromolecular systems. Furthermore, we delve into the realm of ultrasound imaging of biomolecular function, encompassing the utilization of gas vesicles and acoustic reporter genes. Finally, we shed light on limitations and challenges of sonogenetics and present a perspective on the future of this promising technology.

The role of PIEZO ion channels in the musculoskeletal system.

PIEZO1 and PIEZO2 are mechanosensitive cation channels that are highly expressed in numerous tissues throughout the body and exhibit diverse, cell-specific functions in multiple organ systems. Within the musculoskeletal system, PIEZO1 functions to maintain muscle and bone mass, sense tendon stretch, and regulate senescence and apoptosis in response to mechanical stimuli within cartilage and the intervertebral disc. PIEZO2 is essential for transducing pain and touch sensations as well as proprioception in the nervous system, which can affect musculoskeletal health. PIEZO1 and PIEZO2 have been shown to act both independently as well as synergistically in different cell types. Conditions that alter PIEZO channel mechanosensitivity, such as inflammation or genetic mutations, can have drastic effects on these functions. For this reason, therapeutic approaches for PIEZO-related disease focus on altering PIEZO1 and/or PIEZO2 activity in a controlled manner, either through inhibition with small molecules, or through dietary control and supplementation to maintain a healthy cell membrane composition. Although many opportunities to better understand PIEZO1 and PIEZO2 remain, the studies summarized in this review highlight how crucial PIEZO channels are to musculoskeletal health and point to promising possible avenues for their modulation as a therapeutic target.

De Novo Cloning and Functional Characterization of a Mechanosensitive Piezo-Like Ion Channel in the Crayfish.

BACKGROUND/AIMS: Mechanosensitive ion channels are the principal elements in the transduction of mechanical force to neural activity. To date, considerably fewer studies have been published about the molecular and structural properties of mechanosensitive channels. Piezo channels are the only ion channel family in eukaryotes which is selectively gated by the membrane tension. Piezo channels have been described in mammals and some other eukaryotes. However, not much information is available for the crustaceans. METHODS: Conventional cloning methods were used to clone the putative PIEZO channel mRNA in crayfish ganglia samples. HEK293T cells were transfected by the plasmid of the cloned gene for functional studies. The CDS of the mRNA translated into the protein sequence and three-dimensional structure of the channel has been calculated. RESULTS: An mRNA, 9378 bp, was firstly cloned from crayfish which codes a 2674 residues protein. The cloned sequence is similar to the piezo channel mRNAs reported in the other species. The sequence of the coded protein has been analyzed, and some functional domains have been identified. A three-dimensional structure of the coded protein was successfully calculated in reference to mouse piezo 1 channel protein data. A plasmid with a fluorescent protein indicator was synthesized for heterologous expression in HEK293T cells. The evoked calcium response to mechanical stimulation was not different from those observed in the control cells. However, the transfected cells were more sensitive to the gating modifier YODA-1. CONCLUSION: Based on the apparent similarity in sequence, structure and functional properties to other known piezo channels, it has been proposed that cloned mRNA may code a piezo-like ion channel in crayfish.

Differential expression of PIEZO1 and PIEZO2 mechanosensitive channels in ocular tissues implicates diverse functional roles.

PIEZO1 and PIEZO2 are mechanosensitive ion channels that regulate many important physiological processes including vascular blood flow, touch, and proprioception. As the eye is subject to mechanical stress and is highly perfused, these channels may play important roles in ocular function and intraocular pressure regulation. PIEZO channel expression in the eye has not been well defined, in part due to difficulties in validating available antibodies against PIEZO1 and PIEZO2 in ocular tissues. It is also unclear if PIEZO1 and PIEZO2 are differentially expressed. To address these questions, we used single-molecule fluorescence in situ hybridization (smFISH) together with transgenic reporter mice expressing PIEZO fusion proteins under the control of their endogenous promoters to compare the expression and localization of PIEZO1 and PIEZO2 in mouse ocular tissues relevant to glaucoma. We detected both PIEZO1 and PIEZO2 expression in the trabecular meshwork, ciliary body, and in the ganglion cell layer (GCL) of the retina. Piezo1 mRNA was more abundantly expressed than Piezo2 mRNA in these ocular tissues. Piezo1 but not Piezo2 mRNA was detected in the inner nuclear layer and outer nuclear layer of the retina. Our results suggest that PIEZO1 and PIEZO2 are differentially expressed and may have distinct roles as mechanosensors in glaucoma-relevant ocular tissues.

Magnetic Ion Channel Activation (MICA)-Enabled Screening Assay: A Dynamic Platform for Remote Activation of Mechanosensitive Ion Channels.

This study reports results of a mechanical platform-based screening assay (MICA) to evaluate the remote activation of mechanosensitive ion channels. Here, we studied ERK pathway activation and the elevation in intracellular Ca2+ levels in response to the MICA application using the Luciferase assay and Fluo-8AM assay, respectively. Functionalised magnetic nanoparticles (MNPs) targeting membrane-bound integrins and mechanosensitive TREK1 ion channels were studied with HEK293 cell lines under MICA application. The study demonstrated that active targeting of mechanosensitive integrins via RGD (Arginylglycylaspartic acid) motifs or TREK1 (KCNK2, potassium channel subfamily K member 2) ion channels can stimulate the ERK pathway and intracellular calcium levels compared to non-MICA controls. This screening assay offers a powerful tool, which aligns with existing high-throughput drug screening platforms for use in the assessment of drugs that interact with ion channels and influence ion channel-modulated diseases.

Functional Expression of Mechanosensitive Piezo1/TRPV4 Channels in Mouse Osteoblasts.

Mechanical stress is an important regulatory factor in bone homeostasis. Mechanical stimulation of osteoblasts has been shown to elicit an increase in the concentration of intracellular free Ca2+ ([Ca2+]i). The pattern of functional expression of mechanosensitive ion channels remains unclear, however. Therefore, the purpose of this study was to investigate the pharmacological characteristics of [Ca2+]i in response to direct mechanical stimulation in osteoblasts. The morphological expression of mechanosensitive ion channels was also examined. Mouse osteoblast-like cells (MC3T3-E1 cells) were loaded with fura-2-acetoxymethyl ester, after which [Ca2+]i was measured. Increased levels of [Ca2+]i were observed in MC3T3-E1 cells in response to direct mechanical stimulation by means of a glass micropipette, but no desensitization. Application of a hypotonic solution also induced an increase in [Ca2+]i but was accompanied by a desensitizing effect. Extracellular Gd3+, GsMTx4, or RN-1734 reversibly inhibited this mechanical stimulation-induced increase in [Ca2+]i, whereas no inhibitory effect was observed with HC030031 or clemizole. When osteoblasts were stimulated with Yoda1, an increase was observed in [Ca2+]i together with a significant desensitizing effect. Immunoreactivity against Piezo1 and TRPV4 channel antibodies was detected in MC3T3-E1 cells. These results suggest that osteoblasts express Piezo1 and TRPV4 channels, which are involved in mechanosensitive processes during mechanical stress.

Identification and functional characterization of the Piezo1 channel pore domain.

Mechanotransduction is the process by which cells convert physical forces into electrochemical responses. On a molecular scale, these forces are detected by mechanically activated ion channels, which constitute the basis for hearing, touch, pain, cold, and heat sensation, among other physiological processes. Exciting high-resolution structural details of these channels are currently emerging that will eventually allow us to delineate the molecular determinants of gating and ion permeation. However, our structural-functional understanding across the family remains limited. Piezo1 is one of the largest and least understood of these channels, with various structurally identified features within its trimeric assembly. This study seeks to determine the modularity and function of Piezo1 channels by constructing deletion proteins guided by cryo EM structural knowledge. Our comprehensive functional study identified, for the first time, the minimal amino acid sequence of the full-length Piezo1 that can fold and function as the channel's pore domain between E2172 and the last residue E2547. While the addition of an anchor region has no effect on permeation properties. The Piezo1 pore domain is not pressure-sensitive and the appending of Piezo Repeat-A did not restore pressure-dependent gating, hence the sensing module must exist between residues 1 to 1952. Our efforts delineating the permeation and gating regions within this complex ion channel have implications in identifying small molecules that exclusively regulate the activity of the channel's pore module to influence mechanotransduction and downstream processes.

Short-Duration High Frequency MegaHertz-Order Nanomechanostimulation Drives Early and Persistent Osteogenic Differentiation in Mesenchymal Stem Cells.

Stem cell fate can be directed through the application of various external physical stimuli, enabling a controlled approach to targeted differentiation. Studies involving the use of dynamic mechanical cues driven by vibrational excitation to date have, however, been limited to low frequency (Hz to kHz) forcing over extended durations (typically continuous treatment for >7 days). Contrary to previous assertions that there is little benefit in applying frequencies beyond 1 kHz, we show here that high frequency MHz-order mechanostimulation in the form of nanoscale amplitude surface reflected bulk waves are capable of triggering differentiation of human mesenchymal stem cells from various donor sources toward an osteoblast lineage, with early, short time stimuli inducing long-term osteogenic commitment. More specifically, rapid treatments (10 min daily over 5 days) of the high frequency (10 MHz) mechanostimulation are shown to trigger significant upregulation in early osteogenic markers (RUNX2, COL1A1) and sustained increase in late markers (osteocalcin, osteopontin) through a mechanistic pathway involving piezo channel activation and Rho-associated protein kinase signaling. Given the miniaturizability and low cost of the devices, the possibility for upscaling the platform toward practical bioreactors, to address a pressing need for more efficient stem cell differentiation technologies in the pursuit of translatable regenerative medicine strategies, is ensivaged.

Emerging roles of mechanosensitive ion channels in acute lung injury/acute respiratory distress syndrome.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating respiratory disorder with high rates of mortality and morbidity, but the detailed underlying mechanisms of ALI/ARDS remain largely unknown. Mechanosensitive ion channels (MSCs), including epithelial sodium channel (ENaC), Piezo channels, transient receptor potential channels (TRPs), and two-pore domain potassium ion (K2P) channels, are highly expressed in lung tissues, and the activity of these MSCs can be modulated by mechanical forces (e.g., mechanical ventilation) and other stimuli (e.g., LPS, hyperoxia). Dysfunction of MSCs has been found in various types of ALI/ARDS, and MSCs play a key role in regulating alveolar fluid clearance, alveolar epithelial/endothelial barrier function, the inflammatory response and surfactant secretion in ALI/ARDS lungs. Targeting MSCs exerts therapeutic effects in the treatment of ALI/ARDS. In this review, we summarize the structure and functions of several well-recognized MSCs, the role of MSCs in the pathogenesis of ALI/ARDS and recent advances in the pharmacological and molecular modulation of MSCs in the treatment of ALI/ARDS. According to the current literature, targeting MSCs might be a very promising therapeutic approach against ALI/ARDS.

Fluorescence-coupled micropipette aspiration assay to examine calcium mobilization caused by red blood cell mechanosensing.

Mechanical stimuli such as tension, compression, and shear stress play critical roles in the physiological functions of red blood cells (RBCs) and their homeostasis, ATP release, and rheological properties. Intracellular calcium (Ca2+) mobilization reflects RBC mechanosensing as they transverse the complex vasculature. Emerging studies have demonstrated the presence of mechanosensitive Ca2+ permeable ion channels and their function has been implicated in the regulation of RBC volume and deformability. However, how these mechanoreceptors trigger Ca2+ influx and subsequent cellular responses are still unclear. Here, we introduce a fluorescence-coupled micropipette aspiration assay to examine RBC mechanosensing at the single-cell level. To achieve a wide range of cell aspirations, we implemented and compared two negative pressure adjusting apparatuses: a homemade water manometer (- 2.94 to 0 mmH2O) and a pneumatic high-speed pressure clamp (- 25 to 0 mmHg). To visualize Ca2+ influx, RBCs were pre-loaded with an intensiometric probe Cal-520 AM, then imaged under a confocal microscope with concurrent bright-field and fluorescent imaging at acquisition rates of 10 frames per second. Remarkably, we observed the related changes in intracellular Ca2+ levels immediately after aspirating individual RBCs in a pressure-dependent manner. The RBC aspirated by the water manometer only displayed 1.1-fold increase in fluorescence intensity, whereas the RBC aspirated by the pneumatic clamp showed up to threefold increase. These results demonstrated the water manometer as a gentle tool for cell manipulation with minimal pre-activation, while the high-speed pneumatic clamp as a much stronger pressure actuator to examine cell mechanosensing directly. Together, this multimodal platform enables us to precisely control aspiration and membrane tension, and subsequently correlate this with intracellular calcium concentration dynamics in a robust and reproducible manner.

Involvement of mechanosensitive ion channels in the effects of mechanical stretch induces osteogenic differentiation in mouse bone marrow mesenchymal stem cells.

Bone marrow mesenchymal stem cells (BMSCs) can be induced to process osteogenic differentiation with appropriate mechanical and/or chemical stimuli. The present study described the successful culture of murine BMSCs under mechanical strain. BMSCs were subjected to 0%, 3%, 8%, 13%, and 18% cyclic tensile strain at 0.5 Hz for 8 hr/day for 3 days. The expression of osteogenic markers and mechanosensitive ion channels was evaluated with real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. The expression of alkaline phosphatase (ALP) and matrix mineralization were evaluated with histochemical staining. To investigate the effects of mechanosensitive ion channel expression on cyclic tensile strain-induced osteogenic differentiation, the expression of osteogenic markers was evaluated with real-time RT-PCR in the cells without mechanosensitive ion channel expression. This study revealed a significant augment in osteogenic marker in BMSC strained at 8% compared to other treatments; therefore, an 8% strain was used for further investigations. The ALP expression and matrix mineralization were enhanced in osteogenic induced BMSCs subjected to 8% strain after 7 and 14 days, respectively. Under the same conditions, the osteogenic marker and mechanosensitive ion channel expression were significantly promoted. However, the loss function of mechanosensitive ion channels resulted in the inhibition of osteogenic marker expression. This study demonstrated that strain alone can successfully induce osteogenic differentiation in BMSCs and the expression of mechanosensitive ion channels was involved in the process. The current findings suggest that mechanical stretch could function as efficient stimuli to induce the osteogenic differentiation of BMSCs via the activation of mechanosensitive ion channels.

Exploring the diversity of mechanosensitive channels in bacterial genomes.

Mechanosensitive ion channels are responsible for touch sensation and proprioception in higher level organisms such as humans and recovery after osmotic stress in bacteria. Bacterial mechanosensitive channels are homologous to either the mechanosensitive channel of large conductance (MscL) or the mechanosensitive channel of small conductance (MscS). In the E. coli genome there are seven unique mechanosensitive channels, a single MscL homologue, and six MscS homologues. The six MscS homologues are members of the diverse MscS superfamily of ion channels, and these channels show variation on both the N and C termini when compared to E. coli MscS. In bacterial strains with phenotypic analysis of the endogenous mechanosensors, the quantity of MscS superfamily members in the genome range from 2 to 6 and all of the strains contain a copy of MscL. Here, we show an in-depth analysis of over 150 diverse bacterial genomes, encompassing nine phyla, to determine the number of genomes that contain an MscL homologue and the average number of MscS superfamily members per genome. We determined that the average genome contains 4 ± 3 MscS homologues and 67% of bacterial genomes encode for a MscL homologue.

Insights into the model of non-perfect osmometer cells for cryopreservation: A parametric sweep analysis.

Recently, a mathematical model able to describe the non-perfect osmotic behavior of cells during cryopreservation was proposed. The model improves the two-parameter formalism typically adopted in cryopreservation literature by allowing the transmembrane permeation of ions/salt, through the temporary opening of mechanosensitive channels whenever membrane stretching occurs: cells can reach an equilibrium volume different from the initial one, when isotonic conditions are re-established after contacting with impermeant or permeant solutes, such as sucrose or a cryoprotectant agent like dimethyl sulfoxide, respectively. Although the model was conceived as a conservative development of the two-parameter formalism to avoid over-parameterization, a complex picture of the system emerges. To describe this, first an appropriate non-dimensional version of the model equations is derived. Then, a parametric sweep analysis is performed and discussed to highlight the features of the novel model in comparison with the two-parameter formalism: the conditions by which the first reduces to the second are identified. Only equilibrium equations with impermeant sucrose may be analytically derived from the model: their validity is here extended much more than originally assumed. When permeant dimethyl sulfoxide comes into play, the temporary opening of mechanosensitive channels is difficult to predict and prevents the derivation of the equilibrium equations: in this case, a numerical integration of system dynamics up to steady state is required to determine the cell volume at equilibrium. In conclusion, cell volume at equilibrium depends on the position of the temporal window of mechanosensitive channels opening, which, in general, is a complex function of model parameters and operating conditions.

Cardiovascular mechanosensitive ion channels-Translating physical forces into physiological responses.

Cells and tissues are constantly exposed to mechanical stress. In order to respond to alterations in mechanical stimuli, specific cellular machinery must be in place to rapidly convert physical force into chemical signaling to achieve the desired physiological responses. Mechanosensitive ion channels respond to such physical stimuli in the order of microseconds and are therefore essential components to mechanotransduction. Our understanding of how these ion channels contribute to cellular and physiological responses to mechanical force has vastly expanded in the last few decades due to engineering ingenuities accompanying patch clamp electrophysiology, as well as sophisticated molecular and genetic approaches. Such investigations have unveiled major implications for mechanosensitive ion channels in cardiovascular health and disease. Therefore, in this chapter I focus on our present understanding of how biophysical activation of various mechanosensitive ion channels promotes distinct cell signaling events with tissue-specific physiological responses in the cardiovascular system. Specifically, I discuss the roles of mechanosensitive ion channels in mediating (i) endothelial and smooth muscle cell control of vascular tone, (ii) mechano-electric feedback and cell signaling pathways in cardiomyocytes and cardiac fibroblasts, and (iii) the baroreflex.

Cross-Talk between Mechanosensitive Ion Channels and Calcium Regulatory Proteins in Cardiovascular Health and Disease.

Mechanosensitive ion channels are widely expressed in the cardiovascular system. They translate mechanical forces including shear stress and stretch into biological signals. The most prominent biological signal through which the cardiovascular physiological activity is initiated or maintained are intracellular calcium ions (Ca2+). Growing evidence show that the Ca2+ entry mediated by mechanosensitive ion channels is also precisely regulated by a variety of key proteins which are distributed in the cell membrane or endoplasmic reticulum. Recent studies have revealed that mechanosensitive ion channels can even physically interact with Ca2+ regulatory proteins and these interactions have wide implications for physiology and pathophysiology. Therefore, this paper reviews the cross-talk between mechanosensitive ion channels and some key Ca2+ regulatory proteins in the maintenance of calcium homeostasis and its relevance to cardiovascular health and disease.

It takes more than two to tango: mechanosignaling of the endothelial surface.

The endothelial surface is a highly flexible signaling hub which is able to sense the hemodynamic forces of the streaming blood. The subsequent mechanosignaling is basically mediated by specific structures, like the endothelial glycocalyx building the top surface layer of endothelial cells as well as mechanosensitive ion channels within the endothelial plasma membrane. The mechanical properties of the endothelial cell surface are characterized by the dynamics of cytoskeletal proteins and play a key role in the process of signal transmission from the outside (lumen of the blood vessel) to the interior of the cell. Thus, the cell mechanics directly interact with the function of mechanosensitive structures and ion channels. To precisely maintain the vascular tone, a coordinated functional interdependency between endothelial cells and vascular smooth muscle cells is necessary. This is given by the fact that mechanosensitive ion channels are expressed in both cell types and that signals are transmitted via autocrine/paracrine mechanisms from layer to layer. Thus, the outer layer of the endothelial cells can be seen as important functional mechanosensitive and reactive cellular compartment. This review aims to describe the known mechanosensitive structures of the vessel building a bridge between the important role of physiological mechanosignaling and the proper vascular function. Since mutations and dysfunction of mechanosensitive proteins are linked to vascular pathologies such as hypertension, they play a potent role in the field of channelopathies and mechanomedicine.