Role Of Shear Stress Research Articles

Time-Lapse Live-Cell Imaging Using Fluorescent Protein Sensors in Outflow Pathway Cells Under Fluid Flow Conditions.

The role of shear stress in regulating aqueous humor (AH) outflow and intraocular pressure (IOP) in the trabecular meshwork (TM) and Schlemm's canal (SC) of the eye is an emerging field. Shear stress has been shown to activate mechanosensitive ion channels in TM cells and induce nitric oxide production in SC cells, which can affect outflow resistance and lower IOP. Live-cell imaging using fluorescent protein sensors has provided real-time data to investigate the physiological relationship between fluid flow and shear stress in the outflow pathway cells. The successful application of time-lapse live-cell imaging in primary cultured cells has led to the identification of key cellular and molecular mechanisms involved in regulating AH outflow and IOP, including the role of autophagy and primary cilia as mechanosensors. This chapter presents a detailed protocol for conducting time-lapse live-cell imaging under fluid flow conditions in the outflow pathway cells.

The Role of Shear Stress in Coronary Artery Disease.

Coronary artery disease is the leading cause of morbidity and mortality worldwide, especially in developed countries, with an increasing incidence in developing countries. Despite the advances in cardiology, there are yet many unanswered questions about the natural history of coronary atherosclerosis. However, it has not been fully explained why some coronary artery plaques remain quiescent over time, whereas others evolve to a high-risk, "vulnerable" plaque with a predisposition to destabilize and induce a cardiac event. Furthermore, approximately half of the patients with acute coronary syndromes demonstrate no prior symptoms of ischemia or angiographically evident disease. Recent findings have indicated that apart from cardiovascular risk factors, genetics, and other unknown factors, local hemodynamic forces, such as endothelial shear stress, blood flow patterns, and endothelial dysfunction of the epicardial and microvascular coronary arteries, are associated with the progression of coronary plaque and the development of cardiovascular complications with complex interactions. In this review article, we summarize the mechanisms that affect coronary artery plaque progression, indicating the importance of endothelial shear stress, endothelial dysfunction of epicardial and microvascular vessels, inflammation, and their complex associations, underlying in parallel the clinical perspectives of these findings.

Influence of the fluid polarity on shear strength of sodium montmorillonite clay: A steered molecular dynamics study

Smectite clay minerals such as sodium montmorillonite (NaMt) are some of the main constituents of expansive clays. This work evaluated the mechanical response of NaMt intercalated with fluids having a wide range of polarities under various magnitudes of compression and fluid content using steered molecular dynamics (SMD) simulations. The shear strength parameters of the clay at the molecular scale, cohesion, and friction angle were quantitively evaluated. The simulation results indicated that the polarity of the fluids and the fluid content in the clay interlayer space played a vital role in shear stress versus shear strain response, the shear strength parameters, and nonbonded interactions energies upon mechanical loading of externally applied compressive stresses followed by shearing. The expansive clay's shear stress versus shear strain response depended on the normal stress and fluid polarity. This study showed the profound influence of the polarity of the fluids on the molecular shear strength behavior of swelling clays. Incorporating the clay-fluid molecular interactions and their role in shear response at the molecular scale is crucial for developing robust theories and tools for accurately predicting the shear strength properties of swelling clays for geotechnical and geoenvironmental applications.

New In Vitro Model to Study Multicellular and Flow Control of Blood‐Brain Barrier

Brain endothelial cells of the blood‐brain barrier (BBB) have been shown to be regulated by supportive cells, such as pericytes and astrocytes, and shear stress exposure. However, studies investigating the impact of pericytes and astrocytes on brain endothelial cell function have identified both beneficial and detrimental results. Additionally, most studies investigating the relationship between shear stress and brain endothelial cell function lack physiological relevance via the use of sub‐physiological shear stress magnitudes and/or via the absence of pericytes and astrocytes. In this study, we developed a millifluidic device compatible with standard transwell inserts to investigate BBB function. In contrast to standard polydimethylsiloxane (PDMS) microfluidic devices, this model allows for easy, reproducible shear stress exposure without common limitations of PDMS devices such as inadequate nutrient diffusion and air bubble formation. In no‐flow conditions, we first used the device to examine the impact of primary human pericytes and astrocytes on human brain microvascular endothelial cell (HBMEC) barrier integrity. We found that astrocytes, pericytes, and a 1:1 ratio of both cell types increased HBMEC barrier integrity via reduced permeability to 40 kDa fluorescent dextran, which was associated with increased expression of tight junction protein, claudin‐5. Interestingly, we also observed a significantly lower permeability to 3 kDa dextran in HBMEC‐pericyte co‐cultures compared to HBMEC‐astrocyte and HBMEC‐astrocyte‐pericyte co‐cultures. Based on these findings, we hypothesize pericytes may be providing increased barrier support to the BBB model compared to astrocytes although they both function as permeability reducers. After using the device to generate 24‐hour flow at 12 dynes/cm2, we observed that shear stress exposure significantly reduced dextran permeability in HBMEC monolayers, but not in tri‐culture models consisting of HBMECs, pericytes, and astrocytes. These results indicate that co‐cultures may demonstrate a more pronounced impact on overall BBB permeability than flow exposure. In both cases, flow exposure was interestingly associated with reduced expression of both claudin‐5 and occludin. However, ZO‐1 expression, and localization at cell‐cell junctions increased in the tri‐culture but exhibited no apparent change in the HBMEC monolayer. Under flow conditions, we also observed alignment of HBMECs in the tri‐culture while no such phenomenon was observed in HBMEC monolayers, indicating supportive cells and flow are both essential to observe brain endothelial cell alignment in vitro. Collectively, these results support the necessity of physiologically relevant, multicellular BBB models when investigating brain endothelial cell function in relation to the BBB. Additionally, our findings provide clues on the role of shear stress and supportive cells within the BBB, a critical step to elucidating the physiology of the neurovascular unit.

Cancer Stem Cells in Ovarian Cancer-A Source of Tumor Success and a Challenging Target for Novel Therapies.

Ovarian cancer is the most lethal neoplasm of the female genital organs. Despite indisputable progress in the treatment of ovarian cancer, the problems of chemo-resistance and recurrent disease are the main obstacles for successful therapy. One of the main reasons for this is the presence of a specific cell population of cancer stem cells. The aim of this review is to show the most contemporary knowledge concerning the biology of ovarian cancer stem cells (OCSCs) and their impact on chemo-resistance and prognosis in ovarian cancer patients, as well as to present the treatment options targeted exclusively on the OCSCs. The review presents data concerning the role of cancer stem cells in general and then concentrates on OCSCs. The surface and intracellular OCSCs markers and their meaning both for cancer biology and clinical prognosis, signaling pathways specifically activated in OCSCs, the genetic and epigenetic regulation of OCSCs function including the recent studies on the non-coding RNA regulation, cooperation between OCSCs and the tumor microenvironment (ovarian cancer niche) including very specific environment such as ascites fluid, the role of shear stress, autophagy and metabolic changes for the function of OCSCs, and finally mechanisms of OCSCs escape from immune surveillance, are described and discussed extensively. The possibilities of anti-OCSCs therapy both in experimental settings and in clinical trials are presented, including the recent II phase clinical trials and immunotherapy. OCSCs are a unique population of cancer cells showing a great plasticity, self-renewal potential and resistance against anti-cancer treatment. They are responsible for the progression and recurrence of the tumor. Several completed and ongoing clinical trials have tested different anti-OCSCs drugs which, however, have shown unsatisfactory efficacy in most cases. We propose a novel approach to ovarian cancer diagnosis and therapy.

Agitation-dependent biomechanical forces modulate GPVI receptor expression and platelet adhesion capacity during storage

BackgroundContinuous agitation during storage slows down the platelet storage lesions. However, in special circumstances, manual-mixing can be alternatively used to store products for short time periods without compromising platelet quality. Based on this finding, and given the role of shear stress in modulating receptor expression, we were interested in comparing the levels of platelet adhesion receptor, GPVI and platelet adhesion capacity under each storage condition.MethodsPlatelet concentrates (PCs) were divided into three groups: continuously-agitated PCs (CAG-PCs) with or without PP2 (Src kinase inhibitor) and manually-mixed PCs (MM-PCs). Platelet count/MPV, swirling, GPVI and P-selectin expression, GPVI shedding, platelet adhesion/spreading to collagen were examined during 5 days of storage.ResultsWhile MM- and CAG-PCs showed similar levels of P-selectin expression, GPVI expression was significantly elevated in MM-PCs with lower GPVI shedding/expression ratios, enhanced platelet adhesion/spreading and swirling in manually-mixed PCs. Of note, CAG-PCs treated with PP2 also demonstrated lower P-selectin expression and GPVI shedding, higher GPVI expression and attenuated swirling and spreading capability.ConclusionGiven the comparable platelet activation state in MM and CAG-PCs as indicated by P-selectin expression, enhanced platelet adhesion/spreading in MM-PCs, along with relatively higher GPVI expression here, supports previous studies demonstrating a role for biomechanical forces in modulating GPVI-dependent function. Thus, lower GPVI expression in CAG-PCs may be due to shear forces induced by agitation, which keeps this receptor down-regulated while also attenuating platelet adhesion/spreading capacities during storage. Low platelet function in PP2-CAG-PCs also highlights the importance of Src-kinases threshold activity in maintaining platelets quality.

Superhardness Induced by Grain Boundary Vertical Sliding in (001)-textured ZrB[formula omitted] and TiB[formula omitted] Nano Films

Superhardness up to 50 and 60 GPa has been achieved recently in orientationally (001)-textured ZrB2 and TiB2 films composed of nano columnar grains, which almost double those in common TMB2 (TM=Zr, Ti). But the atomic origin, especially the role of shear stresses under indentation on grain boundaries (GBs), remains largely unknown. In this work, we report the identification of the experimentally observed GBs as Σ13 [001] tilt GB by first-principles calculations. The calculated formation energies of the GBs and TM vacancies on the GBs explain well the experimental results. Under shear stresses beneath indentors, the GB motion transforms the accumulated shear stresses parallel to (001) plane into a vertical sliding of the nano grains in [001] direction, while maintaining the GB structure unchanged. This special mode of shear plastic deformation correlates their hardness to the compressive strengths in [001] direction, instead of to the shear strengths on (001) plane as in bulk crystals, with the calculated compressive strengths well accounting for the measured superhardness in these (001)-textured nano ultra-high temperature ceramics.

Role of Shear Stress on Renal Proximal Tubular Cells for Nephrotoxicity Assays.

Drug-induced nephrotoxicity causes huge morbidity and mortality at massive financial cost. The greatest burden of drug-induced acute kidney injury falls on the proximal tubular cells. To maintain their structure and function, renal proximal tubular cells need the shear stress from tubular fluid flow. Diverse techniques to reintroduce shear stress have been studied in a variety of proximal tubular like cell culture models. These studies often have limited replicates because of the huge cost of equipment and do not report all relevant parameters to allow reproduction and comparison of studies between labs. This review codifies the techniques used to reintroduce shear stress, the cell lines utilized, and the biological outcomes reported. Further, we propose a set of interventions to enhance future cell biology understanding of nephrotoxicity using cell culture models.

Role of Shear Stress and tPA Concentration in the Fibrinolytic Potential of Thrombi.

The resolution of arterial thrombi is critically dependent on the endogenous fibrinolytic system. Using well-established and complementary whole blood models, we investigated the endogenous fibrinolytic potential of the tissue-type plasminogen activator (tPA) and the intra-thrombus distribution of fibrinolytic proteins, formed ex vivo under shear. tPA was present at physiologically relevant concentrations and fibrinolysis was monitored using an FITC-labelled fibrinogen tracer. Thrombi were formed from anticoagulated blood using a Chandler Loop and from non-anticoagulated blood perfused over specially-prepared porcine aorta strips under low (212 s−1) and high shear (1690 s−1) conditions in a Badimon Chamber. Plasminogen, tPA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured by ELISA. The tPA–PAI-1 complex was abundant in Chandler model thrombi serum. In contrast, free tPA was evident in the head of thrombi and correlated with fibrinolytic activity. Badimon thrombi formed under high shear conditions were more resistant to fibrinolysis than those formed at low shear. Plasminogen and tPA concentrations were elevated in thrombi formed at low shear, while PAI-1 concentrations were augmented at high shear rates. In conclusion, tPA primarily localises to the thrombus head in a free and active form. Thrombi formed at high shear incorporate less tPA and plasminogen and increased PAI-1, thereby enhancing resistance to degradation.

Flow shear stress controls the initiation of neovascularization via heparan sulfate proteoglycans within a biomimetic microfluidic model.

Endothelial cells (ECs) in vivo are subjected to three forms of shear stress induced by luminal blood flow, transendothelial flow and interstitial flow simultaneously. It is controversial that shear stress, especially the component induced by luminal flow, was thought to inhibit the initialization of angiogenesis and trigger arteriogenesis. Here, we combined microfabrication techniques and delicate numerical simulations to reconstruct the initial physiological microenvironment of neovascularization in vitro, where ECs experience high luminal shear stress, physiological transendothelial flow and various vascular endothelial growth factor (VEGF) distributions simultaneously. With the biomimetic microfluidic model, cell alignment and endothelial sprouting assays were carried out. We found that luminal shear stress inhibits endothelial sprouting and tubule formation in a dose-dependent manner. Although a high concentration of VEGF increases EC sprouting, neither a positive nor a negative VEGF gradient additionally affects the degree of sprouting, and luminal shear stress significantly attenuates neovascularization even in the presence of VEGF. Heparinase was used to selectively degrade the heparan sulfate proteoglycan (HSPG) coating on ECs and messenger RNA profiles in ECs were analyzed. It turned out that HSPGs could act as a mechanosensor to sense the change of fluid shear stress, modulate multiple EC gene expressions, and hence affect neovascularization. In summary, distraction from the stabilized state, such as decreased luminal shear stress, increased VEGF and the destructed mechanotransduction of HSPGs would induce the initiation of neovascularization. Our study highlights the key role of the magnitude and forms of shear stress in neovascularization.

Higher-order semi-layerwise models for doubly curved delaminated composite shells

This work deals w ith the development and extension of higher-order models for delaminated doubly curved composite shells with constant radii of curvatures. The mechanical model is based on the method of four equivalent single layers and the system of exact kinematic conditions. A remarkable addition of this work compared to some previous ones, is a modified and improved continuity condition between the delaminated and undelaminated parts of the shell. Using the principle of virtual work, the equilibrium equations of the shell systems are brought to the stage and solved by using the classical Lévy plate formulation under simply supported conditions. Four different scenarios of elliptic and hyperbolic delaminated shells are investigated providing the solutions for the mechanical fields as well as for the J-integral. The analytical results are compared to 3D finite element calculations, and excellent agreement was obtained for the displacement components and normal stresses. On the contrary, it was found that the transverse shear stresses are captured quite differently by the proposed method and the finite element models. Although the role of shear stresses should not be underrated, they seem to be marginal because the distributions of the J-integral components are in very good agreement with the numerically determined energy release rates.

Abstract 5012: Exercise as a novel method of tumor vascular remodeling

Abstract Chemotherapy efficacy is reliant upon access to tumor cells. One method of increasing chemotherapy response is to enhance delivery of chemotherapy to the tumor by vascular normalization. Tumor vasculature is largely dysfunctional, leading to poor delivery of chemotherapy. Vascular normalization, the remodeling of tumor vessels to increase functionality, has been shown to improve drug delivery and response in patients with glioblastoma, ovarian and colorectal cancers. Current normalization strategies using anti-angiogenic agents have a narrow dose and time therapeutic window. Therefore, it is imperative to identify other methods of inducing tumor vessel normalization to enhance the delivery and efficacy of chemotherapy. Vascular development, and endothelial cell (EC) signaling, is controlled by shear stress. Shear stress is the mechanical force exerted on ECs by blood flow through the vessel lumen. The role of shear stress in tumor vessel development is poorly understood. Tumors have heterogeneous, low levels of vascular shear stress. Heterogeneous, low shear stress causes hyper-permeable vessels that inefficiently deliver blood throughout the tumor. Aerobic exercise is a well-studied method for increasing vascular shear stress. We demonstrated in mouse models of Ewing sarcoma and melanoma that increasing shear stress via moderate exercise caused improved tumor vascular function including reduced hyper-permeability. This correlated with significantly increased chemotherapy delivery and efficacy; doxorubicin was significantly more effective against both tumor models when combined with exercise. The molecular mechanisms of tumor vascular remodeling in response to exercise, particularly the decrease in vessel permeability leading to better drug delivery, are unclear. Vascular permeability is regulated in part via Sphingosine-1-Phosphate Receptors 1 and 2 (S1PR1, S1PR2) on ECs, which have contrasting effects on angiogenesis. S1PR1 signaling increases adherens junctions, decreasing vascular permeability. In contrast, S1PR2 signaling increases vessel permeability. We found that S1PR1 was increased while S1PR2 was decreased on tumor endothelium of exercised mice. We have now identified the novel regulator of tumor endothelial permeability, ERK5, as a key mediator of improved tumor vascular function in response to exercise. Pharmacologic activation of S1PR1 by SEW2871 or activation of ERK5 signaling by p90RSK decreased tumor vascular hyper-permeability and increased doxorubicin efficacy, mimicking the exercise effect. Ongoing work using inducible S1PR1 or ERK5 knockout mice will determine whether this pathway is essential for exercise-induced tumor vascular remodeling and improved chemotherapeutic efficacy. Citation Format: Hannah Savage, Enrica Marmonti, Claudia Bedoya, Miriam Garcia, Keri Schadler. Exercise as a novel method of tumor vascular remodeling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5012.

Bio-mimicking Shear Stress Environments for Enhancing Mesenchymal Stem Cell Differentiation.

Mesenchymal stem cells (MSCs) are multipotent stromal cells, with the ability to differentiate into mesodermal (e.g., adipocyte, chondrocyte, hematopoietic, myocyte, osteoblast), ectodermal (e.g., epithelial, neural) and endodermal (e.g., hepatocyte, islet cell) lineages based on the type of induction cues provided. As compared to embryonic stem cells, MSCs hold a multitude of advantages from a clinical translation perspective, including ease of isolation, low immunogenicity and limited ethical concerns. Therefore, MSCs are a promising stem cell source for different regenerative medicine applications. The in vitro differentiation of MSCs into different lineages relies on effective mimicking of the in vivo milieu, including both biochemical and mechanical stimuli. As compared to other biophysical cues, such as substrate stiffness and topography, the role of fluid shear stress (SS) in regulating MSC differentiation has been investigated to a lesser extent although the role of interstitial fluid and vascular flow in regulating the normal physiology of bone, muscle and cardiovascular tissues is well-known. This review aims to summarise the current state-of-the-art regarding the role of SS in the differentiation of MSCs into osteogenic, cardiovascular, chondrogenic, adipogenic and neurogenic lineages. We will also highlight and discuss the potential of employing SS to augment the differentiation of MSCs to other lineages, where SS is known to play a role physiologically but has not yet been successfully harnessed for in vitro differentiation, including liver, kidney and corneal tissue lineage cells. The incorporation of SS, in combination with biochemical and biophysical cues during MSC differentiation, may provide a promising avenue to improve the functionality of the differentiated cells by more closely mimicking the in vivo milieu.

SIRT1 Inhibits High Shear Stress-Induced Apoptosis in Rat Cortical Neurons.

Sirtuin1 (SIRT1), one of NAD+-dependent protein deacetylases, is proved to be neuroprotective in aging diseases, but its effect on neuronal apoptosis has not been clarified. To investigate the role of SIRT1 in inhibiting neuronal apoptosis, SIRT1 was interfered or overexpressed in cortical neurons. We exerted overloading laminar shear stress with 10 dyn/cm2 for 4, 8, and 12 h on neurons to cause cortical neuronal apoptosis, and the apoptosis percentage was tested by TUNEL assay. The adenovirus plasmids containing SIRT1 RNA interference or SIRT1 wild type gene were transfected into neurons before shear stress loading. SIRT1 mRNA and protein level were tested by Real-time PCR, immunofluorescence and western blots assay. SIRT1 was primarily expressed in nucleus of cortical neurons, and its mRNA level was significantly increased after 4 h stimulation. SIRT1 RNAi cortical neurons had higher TUNEL positive cells, while SIRT1 overexpression significantly decreased the percentage of died cells induced by shear stress compared to control group. SIRT1 plays a neuroprotective role in shear stress induced apoptosis and could be as potential pharmacological targets against neuronal degeneration in future.

Role of shear stress at rest on the viscoelastic response of fresh cement pastes

Fresh concrete is composed of aggregates and cement paste, which itself is a dense suspension that exhibits a yield stress and serves as a binder that solidifies through cement hydration. Although there is relatively little reaction during the fresh state (i.e., before setting), there is still the formation of early hydration products that will influence the paste rheology. Nonzero stress at rest widely exists in concrete practice, e.g., interruption during pumping, static formwork casting, and 3D concrete printing, but its impact on eventual viscoelastic properties is not well understood. In this study, we investigated the influence of different levels of applied shear stress at rest on fresh cement pastes and show that it dramatically alters the eventual solid performance (i.e., static yield stress and stiffness). With increasing applied shear stress at rest, the cement paste exhibited increasing static yield stress and increasingly elastic behavior, where the origin was tied to the progression of hydration. Cement pastes were compared against magnesium oxide suspensions, which served as an inert model system, and an accelerated rate of static yield stress increase over time was observed in the former but not in the latter. This highlights the role of early cement hydration on the solidification behavior of fresh cement pastes in the presence of nonzero shear stress at rest. We further support this by showing that the structural evolution of cement paste under applied stress can primarily be attributed to an enhanced elastic limit, which is associated with early hydration. The influence of two common viscosity modifying admixtures, nanoclay and diutan gum, on these properties was also examined. This work demonstrates the importance of taking the shear stress at rest into consideration for laboratory rheological experiments and industrial concrete applications, as it can substantially impact the eventual solidification behavior.

PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1.

PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence-myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.

P721Shear stress induced unfolding of von willebrand factor may be involved in the premature development of myocardial infarction

Abstract Background Normally, von Willebrand factor (vWF) becomes highly reactive with platelets upon unfolding into a fibrillar conformation at critical shear rate (more than 5000 s–1), that may occur in stenotic arteries. At shear rates below critical value (1200–1300 s–1), which occur in intact coronary arteries, normally there is no conformational rearrangement of vWF. Pathologic unfolding of vWF at shear rates below critical value may increase a risk of the development of coronary thrombosis. There is little information on the role of shear stress induced conformational rearrangement of vWF in the development of myocardial infarction in young individuals. Purpose To investigate vWF-dependent platelet adhesion of patients with premature myocardial infarction at shear rates below critical value (1200–1300 s–1). Methods Using a microfluidic system, we measured platelet adhesion to a fibrinogen-coated optical surface at shear rates of 1200–1300 s–1 during 10 minutes. We assessed platelet-rich plasma of 8 male persons 40–52 years old, who had previous myocardial infarction at the age of 34–39. The control group comprised 6 healthy male volunteers 30–55 years old. We compared the intensity of scattered laser light measured in volts (V) at 10th minute. To study vWF-dependent platelet adhesion, we blocked GPIb receptor with monoclonal antibody to inhibit platelet interaction with vWF. To compare the intensity of vWF-dependent platelet adhesion with normally occurring adhesion to fibrinogen, we blocked GPIIb/IIIa receptor with monoclonal antibody. Results The inhibition of GPIb vWF-receptor decreased platelet adhesion to fibrinogen surface at shear rates of 1200–1300 s–1 by 17.8±4.7% in healthy volunteers and by 92±2.8% in persons with premature myocardial infarction (p<0.05). Inhibition of GPIIb/IIIa receptor decreased platelet adhesion by 91.5±3.8% in healthy volunteers and by 97.3±3.2% in persons with premature myocardial infarction. Conclusion Pathologic unfolding of vWF at shear rates below critical value may be involved in the development of premature myocardial infarction. Acknowledgement/Funding This work was supported by the grant of the Russian Science Foundation (project #16-15-10098)

The Role of Shear Stress in Atherosclerotic Plaque Progression, Destabilization and Rupture

The pathophysiology of atherosclerosis is complex and multifactorial, involving systemic risk factors and biomechanical stimuli. Atherosclerotic plaques predominantly form in regions that are exposed to low shear stress of the blood at the vessel wall, whereas regions of moderate and high shear stress are generally protected. For more than 20 years, my research group performs studies to investigate the role of shear stress in atherosclerotic plaque formation and rupture in coronary and carotid arteries of patients and laboratory animals. For that reason, new technology was developed to 3D reconstruct arteries based on fusion of multiple invasive and non-invasive imaging modalities. These 3D reconstructions were used as input for computational fluid mechanics to derive the local shear stress. We noticed that if the lumen was not affected by the disease, because of outward remodeling, plaques were mainly located at low shear stress regions. However, at later stages of the disease if lumen narrowing occurred, the plaque is also exposed to high shear stress. Until now it is not fully clear, what the influence is of high shear stress on these advanced lumen intruding plaques. Evidence is accumulating for a role of high shear stress in changes in plaque composition towards plaque destabilization and eventually plaque rupture. Moreover, not much studies investigated the influence of multidirectional shear stress on plaque progression and destabilization. In this lecture I will present the research that my group performed to investigate the role of (multidirectional) shear stress on plaque progression, destabilization and rupture at different stages of the atherosclerotic disease.

Low-level shear stress induces differentiation of liver cancer stem cells via the Wnt/β-catenin signalling pathway

Shear stress-activated cellular signalling is involved in cellular migration, proliferation and differentiation. However, it remains unclear about the effects of shear stress on the differentiation of liver cancer stem cells (LCSCs). In this study, using a parallel plated flow chamber system, we found that low-shear stress loading (2 dyne/cm2) for 48 h could significantly inhibit the sphere-forming ability, increase the chemotherapeutic drug sensitivity, downregulate cancer stem cell marker expression and suppress the in vivo tumorigenicity potential of LCSCs. Moreover, using an atomic force microscope (AFM), we found that shear stress increased the Young's modulus of LCSCs. These results indicate LCSC's differentiation after shear stress exposure. In addition, low-shear stress loading suppressed the β-catenin expression in LCSCs. More importantly, pharmacological activation of Wnt/β-catenin signalling restored the shear stress-suppressed β-catenin expression in LCSCs, and abolished the shear stress-altered sphere-forming ability, chemotherapeutic drug sensitivity, cancer stem cell marker expression, Young's modulus and in vivo tumorigenicity potential of LCSCs. Our results suggest that low shear stress could induce LCSC differentiation via the Wnt/β-catenin signalling pathways, providing a new insight into the role of shear stress in cancer cell biological behaviors that might contribute to the development of new therapeutic strategies for liver cancer treatment.

The Role of Shear Stress in Fault Healing and Frictional Aging

AbstractThe seismic cycle involves repeated failure and strength recovery of tectonic faults, known as fault healing. In Earth's crust, where fault strength is dominated by friction, frictional healing is the primary agent of fault healing. Laboratory studies document the role of contact aging and cementation as key mechanisms of frictional healing; however, the role of shear stress is not well understood. We describe a laboratory study of frictional healing as a function of shear stress for bare granite surfaces and simulated fault gouge composed of Westerly granite and quartz. Faults are sheared at normal stresses of 5–25 MPa, 100% relative humidity and room temperature. We quantify frictional healing in slide‐hold‐slide tests for shear stresses from 0 to the sliding friction value and monitor the amplitude of elastic waves propagating across the fault zone. Healing of gouge shows a strong negative dependence on shear stress, whereas healing of bare surfaces does not vary systematically with shear stress. In gouge, frictional healing involves shear stress‐dependent compaction and particle rearrangement, while for bare surfaces frictional strength is derived primarily from contact area evolution. The magnitude of compaction in gouge varies with shear stress, which explains the dependence of healing on shear stress. Elastic wave amplitude increases with hold time and varies inversely with shear stress, consistent with fault zone compaction, shear dilatancy, and their impact on strength evolution and healing. Fault zone compaction during shear unloading and reloading operates with contact aging to dictate frictional healing and fault restrengthening following shear failure.