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Endothelial cells lining blood vessels are essential for maintaining vascular homeostasis and mediate several pathological and physiological processes. Mechanical stresses generated by blood flow and other biomechanical factors significantly affect endothelial cell activity. Here, we review how mechanical stresses, both in situ and in vitro, affect endothelial cells. We review the basic principles underlying the cellular response to mechanical stresses. We also consider the implications of these findings for understanding the mechanisms of mechanotransducer and mechano-signal transduction systems by cytoskeletal components.

Background Mechanical stress plays a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). The mechanosensitive Piezo1 ion channel can sense the changes in mechanical stress and convert the mechanical signals into chemical signals. This study aims to investigate the effect of Piezo1 on the mechanical stress-induced IVDD and explore the possible mechanism. Methods The expression of Piezo1 and collagen II in immunohistochemical staining, cervical curvature, and the stiffness of nucleus pulpous (NP) were performed in normal and degenerated human intervertebral discs. In the experiment, high-intensity compression was applied to mimic the mechanical environment of IVDD. The cell viability, matrix macromolecules, and pro-inflammatory cytokines were examined to investigate the effect of Piezo1 on mechanical stress-treated NP cells. Additionally, autophagy condition of NP cells was detected within high-intensity compression and/or the inhibitor of Piezo1, GsMTx4. Results The up-expression of Piezo1, down-expression of Col II, elevated stiffness of NP, and poor kyphosis were observed in degenerated human intervertebral discs. High-intensity stress significantly decreased cell viability and the synthesis of extracellular matrix but increased the expression of senescence-associated proteins (p53 and p16) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) by mitochondrial dysfunction and suppression of autophagy. However, GsMTx4 can partly attenuate these effects. Conclusion Piezo1 upregulation under excessive mechanical stress promotes the apoptosis, senescence, and pro-inflammatory cytokines of NP and leads to the loss of extracellular matrix by mitochondrial dysfunction and the suppression of autophagy; on the other hand, the inhibition of Piezo1 can partly alleviate these effects.

Microenvironment can influence cell fate and behavior; for example, extracellular matrix (ECM) stiffness increases cell proliferation, and ECM rigidity induces disorders in tissue morphogenesis by increasing cell tension. Swift et al. ( 1240104 ; see the Perspective by Bainer and Weaver ) used proteomics to identify molecules that are mechanical sensors for tissue elasticity in the nucleus and discovered that expression of lamin-A levels apparently functions as a “mechanostat.” Tissues that need to remain stiff under stress rely on lamin-A to keep the cell nucleus whole. [Also see Perspective by Bainer and Weaver ] Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue mechanics and differentiation is unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, E , as did levels of collagens in the extracellular matrix that determine E . Stem cell differentiation into fat on soft matrix was enhanced by low lamin-A levels, whereas differentiation into bone on stiff matrix was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and, although lamin-A transcription was regulated by the vitamin A/retinoic acid (RA) pathway with broad roles in development, nuclear entry of RA receptors was modulated by lamin-A protein. Tissue stiffness and stress thus increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination.

The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.

Significance Cartilage, a mechanically sensitive tissue that covers joints, is essential for vertebrate locomotion by sustaining skeletal mobility. Transduction of mechanical stimuli by cartilage cells, chondrocytes, leads to biochemical–metabolic responses. Such mechanotransduction can be beneficial for tissue maintenance when evoked by low-level mechanical stimuli, or can have health-adverse effects via cartilage-damaging high-strain mechanical stress. Thus, high-strain mechanotransduction by cartilage mechanotrauma is relevant for the pathogenesis of osteoarthritis. Molecular mechanisms of high-strain mechanotransduction of chondrocytes have been elusive. Here we identify Piezo1 and Piezo2 mechanosensitive ion channels in chondrocytes as transduction channels for high-strain mechanical stress. We verify their functional link to the cytoskeleton as important for their concerted function and offer a remedial strategy by application of a Piezo1/2 blocking peptide, GsMTx4, from tarantula venom. Diarthrodial joints are essential for load bearing and locomotion. Physiologically, articular cartilage sustains millions of cycles of mechanical loading. Chondrocytes, the cells in cartilage, regulate their metabolic activities in response to mechanical loading. Pathological mechanical stress can lead to maladaptive cellular responses and subsequent cartilage degeneration. We sought to deconstruct chondrocyte mechanotransduction by identifying mechanosensitive ion channels functioning at injurious levels of strain. We detected robust expression of the recently identified mechanosensitive channels, PIEZO1 and PIEZO2. Combined directed expression of Piezo1 and -2 sustained potentiated mechanically induced Ca ²⁺ signals and electrical currents compared with single-Piezo expression. In primary articular chondrocytes, mechanically evoked Ca ²⁺ transients produced by atomic force microscopy were inhibited by GsMTx4, a PIEZO-blocking peptide, and by Piezo1- or Piezo2-specific siRNA. We complemented the cellular approach with an explant-cartilage injury model. GsMTx4 reduced chondrocyte death after mechanical injury, suggesting a possible therapy for reducing cartilage injury and posttraumatic osteoarthritis by attenuating Piezo-mediated cartilage mechanotransduction of injurious strains.

• Secondary cell walls (SCWs) in stem xylem vessel and fibre cells enable plants to withstand the enormous compressive forces associated with upright growth. It remains unclear if xylem vessel and fibre cells can directly sense mechanical stimuli and modify their SCW during development. • We provide evidence that Arabidopsis SCW-specific Fasciclin-Like Arabinogalactan-proteins 11 (FLA11) and 12 (FLA12) are possible cell surface sensors regulating SCW development in response to mechanical stimuli. Plants overexpressing FLA11 (OE-FLA11) showed earlier SCW development compared to the wild-type (WT) and altered SCW properties that phenocopy WT plants under compression stress. By contrast, OE-FLA12 stems showed higher cellulose content compared to WT plants, similar to plants experiencing tensile stress. • fla11, OE-FLA11, fla12, and OE-FLA12 plants showed altered SCW responses to mechanical stress compared to the WT. Quantitative polymerase chain reaction (qPCR) and RNA-seq analysis revealed the up-regulation of genes and pathways involved in stress responses and SCW synthesis and regulation. Analysis of OE-FLA11 nst1 nst3 plants suggests that FLA11 regulation of SCWs is reliant on classical transcriptional networks. • Our data support the involvement of FLA11 and FLA12 in SCW sensing complexes to fine-tune both the initiation of SCW development and the balance of lignin and cellulose synthesis/deposition in SCWs during development and in response to mechanical stimuli.

During the formation of tissues, cells organize collectively by cell division and apoptosis. The multicellular dynamics of such systems is influenced by mechanical conditions and can give rise to cell rearrangements and movements. We develop a continuum description of tissue dynamics, which describes the stress distribution and the cell flow field on large scales. In the absence of division and apoptosis, we consider the tissue to behave as an elastic solid. Cell division and apoptosis introduce stress sources that, in general, are anisotropic. By combining cell number balance with dynamic equations for the stress source, we show that the tissue effectively behaves as a viscoelastic fluid with a relaxation time set by the rates of division and apoptosis. If the system is confined in a fixed volume, it reaches a homeostatic state in which division and apoptosis balance. In this state, cells undergo a diffusive random motion driven by the stochasticity of division and apoptosis. We calculate the expression for the effective diffusion coefficient as a function of the tissue parameters and compare our results concerning both diffusion and viscosity to simulations of multicellular systems using dissipative particle dynamics.

Although the effects of kinetics on crystal growth are well understood, the role of substrate curvature is not yet established. We studied rigid, two-dimensional colloidal crystals growing on spherical droplets to understand how the elastic stress induced by Gaussian curvature affects the growth pathway. In contrast to crystals grown on flat surfaces or compliant crystals on droplets, these crystals formed branched, ribbon-like domains with large voids and no topological defects. We show that this morphology minimizes the curvature-induced elastic energy. Our results illustrate the effects of curvature on the ubiquitous process of crystallization, with practical implications for nanoscale disorder-order transitions on curved manifolds, including the assembly of viral capsids, phase separation on vesicles, and crystallization of tetrahedra in three dimensions.

Cell migration plays a major role in many fundamental biological processes, such as morphogenesis, tumor metastasis, and wound healing. As they anchor and pull on their surroundings, adhering cells actively probe the stiffness of their environment. Current understanding is that traction forces exerted by cells arise mainly at mechanotransduction sites, called focal adhesions, whose size seems to be correlated to the force exerted by cells on their underlying substrate, at least during their initial stages. In fact, our data show by direct measurements that the buildup of traction forces is faster for larger substrate stiffness, and that the stress measured at adhesion sites depends on substrate rigidity. Our results, backed by a phenomenological model based on active gel theory, suggest that rigidity-sensing is mediated by a large-scale mechanism originating in the cytoskeleton instead of a local one. We show that large-scale mechanosensing leads to an adaptative response of cell migration to stiffness gradients. In response to a step boundary in rigidity, we observe not only that cells migrate preferentially toward stiffer substrates, but also that this response is optimal in a narrow range of rigidities. Taken together, these findings lead to unique insights into the regulation of cell response to external mechanical cues and provide evidence for a cytoskeleton-based rigidity-sensing mechanism.

Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space. In nanotoxicology studies, this lung mimic revealed that cyclic mechanical strain accentuates toxic and inflammatory responses of the lung to silica nanoparticles. Mechanical strain also enhances epithelial and endothelial uptake of nanoparticulates and stimulates their transport into the underlying microvascular channel. Similar effects of physiological breathing on nanoparticle absorption are observed in whole mouse lung. Mechanically active \"organ-on-a-chip\" microdevices that reconstitute tissue-tissue interfaces critical to organ function may therefore expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.