Oscillatory Shear Stress Research Articles

Computationally Enhanced, Haemodynamic Case Study of Neointimal Hyperplasia Development in a Dialysis Access Fistula.

Oscillatory wall shear stress and related metrics have been identified as potential predictors of dialysis access outcomes; however, the absence of a simple non-invasive method for measuring these haemodynamic forces has been prohibitive to their adoption into routine clinical practice. We present a computationally enhanced, single patient case study, offering a unique insight into the haemodynamic environment surrounding the development of flow limiting neointimal hyperplasia within the efferent vein of a previously functional arteriovenous fistula (AVF). Computational fluid dynamics (CFD) simulations were used to create a quantitative map of oscillatory shear stress as well as enabling visualisation of streamline patterns within the AVF. CFD data was compared to ultrasound-based turbulence quantification and examined alongside structural and functional changes in the access site over time. This work further supports the notion that flow limiting neointimal hyperplasia development in vascular access fistulae, occurs in response to oscillatory wall shear stress, and provides proof of concept for the idea that non-invasive ultrasound turbulence quantification tools could play a role in predicting vascular access outcomes. In addition to providing insight into the haemodynamic environment surrounding the development of flow limiting neointimal hyperplasia, we hope that this paper will promote discussion and further thinking about how our learnings from in-silico studies can be incorporated into clinical practice through novel uses of existing diagnostic tools.

Disturbed flow impairs MerTK-mediated efferocytosis in aortic endothelial cells during atherosclerosis.

Background: MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. MerTK is mainly expressed in macrophages and immature dendritic cells. There are very limited reports focused on MerTK biology in aortic endothelial cells (ECs). It remains unclear for the role of blood flow patterns in regulating MerTK-mediated efferocytosis in aortic ECs. This study was designed to investigate whether endothelial MerTK and EC efferocytosis respond to blood flow patterns during atherosclerosis. Methods: Big data analytics, RNA-seq and proteomics combined with our in vitro and in vivo studies were applied to reveal the potential molecular mechanisms. Partial carotid artery ligation combined with AAV-PCSK9 and high fat diet were used to set up acute atherosclerosis in 4 weeks. Results: Our data showed that MerTK is sensitive to blood flow patterns and is inhibited by disturbed flow and oscillatory shear stress in primary human aortic ECs (HAECs). The RNA-seq data in HAECs incubated with apoptotic cells showed that d-flow promotes pro-inflammatory pathway and senescence pathway. Our in vivo data of proteomics and immunostaining showed that, compared with WT group, MerTK-/- aggravates atherosclerosis in d-flow areas through upregulation of endothelial dysfunction markers (e.g. IL-1β, NF-κB, TLR4, MAPK signaling, vWF, VCAM-1 and p22phox) and mitochondrial dysfunction. Interestingly, MerTK-/-induces obvious abnormal endothelial thickening accompanied with decreased endothelial efferocytosis, promoting the development of atherosclerosis. Conclusions: Our data suggests that blood flow patterns play an important role in regulating MerTK-mediated efferocytosis in aortic ECs, revealing a new promising therapeutic strategy with EC efferocytosis restoration to against atherosclerosis.

Molecular profiling of sponge deflation reveals an ancient relaxant-inflammatory response

A hallmark of animals is the coordination of whole-body movement. Neurons and muscles are central to this, yet coordinated movements also exist in sponges that lack these cell types. Sponges are sessile animals with a complex canal system for filter-feeding. They undergo whole-body movements resembling "contractions" that lead to canal closure and water expulsion. Here, we combine live 3D optical coherence microscopy, pharmacology, and functional proteomics to elucidate the sequence and detail of shape changes, the tissues and molecular physiology involved, and the control of these movements. Morphometric analysis and targeted perturbation suggest that the movement is driven by the relaxation of actomyosin stress fibers in epithelial canal cells, which leads to whole-body deflation via collapse of the incurrent and expansion of the excurrent canal system. Thermal proteome profiling and quantitative phosphoproteomics confirm the control of cellular relaxation by an Akt/NO/PKG/PKA pathway. Agitation-induced deflation leads to differential phosphorylation of proteins forming epithelial cell junctions, implying their mechanosensitive role. Unexpectedly, untargeted metabolomics detect a concomitant decrease in antioxidant molecules during deflation, reflecting an increase in reactive oxygen species. Together with the secretion of proteinases, cytokines, and granulin, this indicates an inflammation-like state of the deflating sponge reminiscent of vascular endothelial cells experiencing oscillatory shear stress. These results suggest the conservation of an ancient relaxant-inflammatory response of perturbed fluid-carrying systems in animals and offer a possible mechanism for whole-body coordination through diffusible paracrine signals and mechanotransduction.

Identification of Signature Gene Relate to Oscillatory Shear Stress Based on Machine Learning

Identification of Signature Gene Relate to Oscillatory Shear Stress Based on Machine Learning

Amplitude of heat and mass transfer of gravity-driven convective oscillatory flow along inclined heated plate under reduced gravity and viscosity

As gravitation grows, the impact of interaction across two particles improves. The force of gravity is a critical process of transferring material along an angled surface. The main importance of present research is to generate wave oscillations in concentrating particles along an angled surface under weak gravitational pressure. Main goal of thermo-viscosity in current model is to produce maximum movement in concentrated particles for significant oscillating heat transport along buoyancy-based plate. The governing mathematical model is constructed for numerical and graphical outcomes of present mechanism under weak gravity and variable viscosity. To generate pertinent parameters, the model is changed into non-dimension form by using suitable variables. To observe oscillatory and amplitude sequence of results, the model is formulated into steady, real and imaginary equations. For programming sequence in FORTRAN tool, the primitive coefficients are used. The primitive based equations are solved by applying implicit form of finite difference method and Gaussian elimination scheme. The steady results such as fluid velocity, temperature variations and concentration profiles are observed for different physical factor under defined boundaries. The amplitude of oscillatory shear stress, oscillatory heat transport and oscillatory mass transport are explored by using steady results. It is noticed that the velocity of fluid enhances as viscosity decreases. It is found that the temperature variation grows as Schmidt number enhances but concentration profile decreases. It is observed that the prominent wave oscillations in heat transfer increases as Prandtl number enhances.

Unsteady Flow of Casson Fluid between Two Side Walls over an Infinite Plate

In the present study, the velocity field corresponding to the unsteady flow of Casson fluid between two parallel side walls perpendicular to an infinite plate that exerts an oscillating shear stress to the fluid is determined with the help of Fourier sine and cosine transforms. Exact solutions are obtained and given in simple form as a combination of transient and steady-state solutions, which satisfy the governing equation and all imposed initial and boundary conditions. These solutions are reduced to the similar solutions corresponding to the motion over an infinite plate, when and Newtonian fluid by making Casson parameter Furthermore, effect of side walls on the motion of fluid, the time which is required to attain the steady state and the distance between the side walls for which their presence can be ignored are graphically determined.

Oscillatory shear stress is elevated in patients with bicuspid aortic valve and aortic regurgitation: a 4D flow cardiovascular magnetic resonance cross-sectional study.

Patients with bicuspid aortic valve (BAV) and aortic regurgitation have higher rate of aortic complications compared with patients with BAV and stenosis, as well as BAV without valvular disease. Aortic regurgitation alters blood haemodynamics not only in systole but also during diastole. We therefore sought to investigate wall shear stress (WSS) during the whole cardiac cycle in BAV with aortic regurgitation. Fifty-seven subjects that underwent 4D flow cardiovascular magnetic resonance imaging were included: 13 patients with BAVs without valve disease, 14 BAVs with aortic regurgitation, 15 BAVs with aortic stenosis, and 22 normal controls with tricuspid aortic valve. Peak and time averaged WSS in systole and diastole and the oscillatory shear index (OSI) in the ascending aorta were computed. Student's t-tests were used to compare values between the four groups where the data were normally distributed, and the non-parametric Wilcoxon rank sum tests were used otherwise. BAVs with regurgitation had similar peak and time averaged WSS compared with the patients with BAV without valve disease and with stenosis, and no regions of elevated WSS were found. BAV with aortic regurgitation had twice as high OSI as the other groups (P ≤ 0.001), and mainly in the outer mid-to-distal ascending aorta. OSI uniquely characterizes altered WSS patterns in BAVs with aortic regurgitation, and thus could be a haemodynamic marker specific for this specific group that is at higher risk of aortic complications. Future longitudinal studies are needed to verify this hypothesis.

Dill Extract Preserves Dermal Elastic Fiber Network and Functionality: Implication of Elafin

Introduction: Elastic skin fibers lose their mechanical properties during aging due to enzymatic degradation, lack of maturation, or posttranslational modifications. Dill extract has been observed to increase elastin protein expression and maturation in a 3D skin model, to improve mechanical properties of the skin, to increase elastin protein expression in vascular smooth muscle cells, to preserve aortic elastic lamella, and to prevent glycation. Objective: The aim of the study was to highlight dill actions on elastin fibers during aging thanks to elastase digestion model and the underlying mechanism. Methods: In this study, elastic fibers produced by dermal fibroblasts in 2D culture model were injured by elastase, and we observed the action of dill extract on elastic network by elastin immunofluorescence. Then action of dill extract was examined on mice skin by injuring elastin fibers by intradermal injection of elastase. Then elastin fibers were observed by second harmonic generation microscopy, and their functionality was evaluated by oscillatory shear stress tests. In order to understand mechanism by which dill acted on elastin fibers, enzymatic tests and real-time qPCR on cultured fibroblasts were performed. Results: We evidence in vitro that dill extract is able to prevent elastin from elastase digestion. And we confirm in vivo that dill extract treatment prevents elastase digestion, allowing preservation of the cutaneous elastic network in mice and preservation of the cutaneous elastic properties. Although dill extract does not directly inhibit elastase activity, our results show that dill extract treatment increases mRNA expression of the endogenous inhibitor of elastase, elafin. Conclusion: Dill extract can thus be used to counteract the negative effects of elastase on the cutaneous elastic fiber network through modulation of PI3 gene expression.

Platelet and endothelial cell responses under concurrent shear stress and tensile strain

Thrombosis can lead to significant mortality and morbidity. Both platelets and vascular endothelial cells play significant roles in thrombosis. Platelets' response to blood flow-induced shear stress can vary greatly depending on shear stress magnitude, pattern and shear exposure time. Endothelial cells are also sensitive to the biomechanical environment. Endothelial cell activation and dysfunction can occur under low oscillatory shear stress and low tensile strain. Platelet and endothelial cell interaction can also be affected by mechanical conditions. The goal of this study was to investigate how blood flow-induced shear stress, vascular wall tensile strain, platelet-endothelial cell stress history, and platelet-endothelial cell interaction affect platelet thrombogenicity. Platelets and human coronary artery endothelial cells were pretreated with physiological and pathological shear stress and/or tensile strain separately. The pretreated cells were then put together and exposed to pulsatile shear stress and cyclic tensile strain simultaneously in a shearing-stretching device. Following treatment, platelet thrombin generation rate, platelet and endothelial cell activation, and platelet adhesion to endothelial cells was measured. The results demonstrated that shear stress pretreatment of endothelial cells and platelets caused a significant increase in platelet thrombin generation rate, cell surface phosphatidylserine expression, and adhesion to endothelial cells. Shear stress pretreatment of platelets and endothelial cells attenuated endothelial cell ICAM-1 expression under stenosis conditions, as well as vWF expression under recirculation conditions. These results indicate that platelets are sensitized by prior shearing, while in comparison, the interaction with shear stress-pretreated platelets may reduce endothelial cell sensitivity to pathological shear stress and tensile strain.

ENOS Regulates Lymphatic Valve Specification by Controlling β-Catenin Signaling During Embryogenesis in Mice.

Lymphatic valves play a critical role in ensuring unidirectional lymph transport. Loss of lymphatic valves or dysfunctional valves are associated with several diseases including lymphedema, lymphatic malformations, obesity, and ileitis. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. In blood vessels, eNOS (endothelial NO synthase; gene name: Nos3) is a well-characterized shear stress signaling effector, but its role in lymphatic valve development remains unexplored. We used global Nos3-/- mice and cultured human dermal lymphatic endothelial cells to investigate the role of eNOS in lymphatic valve development, which requires oscillatory shear stress signaling. Our data reveal a 45% reduction in lymphatic valve specification cell clusters and that loss of eNOS protein inhibited activation of β-catenin and its nuclear translocation. Genetic knockout or knockdown of eNOS led to downregulation of β-catenin target proteins in vivo and in vitro. However, pharmacological inhibition of NO production did not reproduce these effects. Co-immunoprecipitation and proximity ligation assays reveal that eNOS directly binds to β-catenin and their binding is enhanced by oscillatory shear stress. Finally, genetic ablation of the Foxo1 gene enhanced FOXC2 expression and partially rescued the loss of valve specification in the eNOS knockouts. In conclusion, we demonstrate a novel, NO-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS directly binds β-catenin to regulate its nuclear translocation and thereby transcriptional activity.

Aneurysmal growth in type-B aortic dissection: assessing the impact of patient-specific inlet conditions on key haemodynamic indices.

Type-B aortic dissection is a cardiovascular disease in which a tear develops in the intimal layer of the descending aorta, allowing pressurized blood to delaminate the layers of the vessel wall. In medically managed patients, long-term aneurysmal dilatation of the false lumen (FL) is considered virtually inevitable and is associated with poorer disease outcomes. While the pathophysiological mechanisms driving FL dilatation are not yet understood, haemodynamic factors are believed to play a key role. Computational fluid dynamics (CFD) and 4D-flow MRI (4DMR) analyses have revealed correlations between flow helicity, oscillatory wall shear stress and aneurysmal dilatation of the FL. In this study, we compare CFD simulations using a patient-specific, three-dimensional, three-component inlet velocity profile (4D IVP) extracted from 4DMR data against simulations with flow rate-matched uniform and axial velocity profiles that remain widely used in the absence of 4DMR. We also evaluate the influence of measurement errors in 4DMR data by scaling the 4D IVP to the degree of imaging error detected in prior studies. We observe that oscillatory shear and helicity are highly sensitive to inlet velocity distribution and flow volume throughout the FL and conclude that the choice of IVP may greatly affect the future clinical value of simulations.

Permanent Solutions for MHD Motions of Generalized Burgers’ Fluids Adjacent to an Unbounded Plate Subjected to Oscillatory Shear Stresses

Closed-form expressions have been obtained to characterize the non-dimensional velocity and corresponding non-trivial shear stress in the context of two magnetohydrodynamic (MHD) motions exhibited by incompressible generalized Burgers’ fluids. These motions occur over an infinite plate, which subjects the fluid to oscillatory shear stresses. The obtained solutions represent the first exact analytical solutions for MHD motions of such fluids under the condition of shear stress prescribed along the boundary. The establishment of these solutions relies upon the utilization of a perfect symmetry existing between the governing equations of fluid velocity and shear stress. To validate the results, a comprehensive analysis has been undertaken using two distinct methods. This validation process is further substantiated through graphical representation, demonstrating the congruence between the obtained solutions. Additionally, the convergence of the initial solutions, obtained through numerical techniques, towards their corresponding permanent counterparts has been visually established. This graphical depiction not only substantiates the accuracy of the solutions but also provides insights into the temporal evolution of the system toward its permanent state. An insight to characterize the non-dimensional shear stresses in the context of two values of the magnetic parameter is to identify that the permanent state is reached at an earlier time and the absolute magnitude of fluid velocity is reduced in the presence of an applied magnetic field.

Differential Expression of the MiT/TFE Transcription Factor Family in Vascular Endothelial Cells under Low Oscillatory Shear Stress

Low Oscillating Shear Stress (LOSS) is known to promote inflammation and atherosclerosis, impacting the phenotype and function of Vascular Endothelial Cells (VECs). The microphthalmia/transcription factor E (MiT/TFE) family of transcription factors regulates autophagy and lysosomal biogenesis in response to internal and external stressors. However, whether LOSS affects the expression of MiT/TFE family members in Human Umbilical Vein Endothelial Cells (HUVECs) has remained unclear. In this study, we utilized qPCR and WB to examine how LOSS influenced the mRNA and protein expression of MiT/TFE family members (MITF, TFEB, TFEC, and TFE3) in HUVECs in vitro. The in vitro findings were further confirmed using immunohistochemistry in a mouse model with a partially ligated carotid artery. Our results showed that LOSS down-regulated the expressions of TFEC and TFE3, while having no impact on MITF and TFEB expressions in HUVECs, the down-regulated expression of TFE3 were validated in the animal model. In conclusion, this study systematically explored the expression patterns of the MiT/TFE family in VECs under LOSS, providing new insights into the molecular mechanisms of abnormal hemodynamics-induced vascular endothelial inflammation-related diseases like atherosclerosis.

Oscillatory shear stress-induced downregulation of TET1s injures vascular endothelial planar cell polarity by suppression of actin polymerization.

Vascular endothelial polarity induced by blood flow plays crucial roles in the development of atherosclerosis. Loss of endothelial polarity leads to an increase in permeability and leukocyte recruitment, which are crucial hallmarks of atherosclerotic initiation. Endothelial cells exhibit a morphological adaptation to hemodynamic shear stress and possesses planar cell polarity to the direction of blood flow. However, the mechanism of how hemodynamic shear stress regulates endothelial planar cell polarity has not been firmly established. Here, we found that TET1s, a short isoform of Tet methylcytosine dioxygenase 1, was a mediator in the regulation of the planar cell polarity in endothelial cells in response to hemodynamic shear stress. In the process, low expression of TET1s induced by oscillatory shear stress led to the endothelial planar polarity damage through inhibition of F-actin polymerization. TET1s can regulate demethylation level of the sFRP-1 promoter to alter the expression of sFRP-1, which affects the interaction of sFRP-1/Fzd4 and F-actin polymerization. Our study revealed the mechanism of how TET1s mediates endothelial planar cell polarity in response to hemodynamic shear stress and provides a new insight for the prevention of atherosclerosis.

The interleukin-1 receptor type-1 in disturbed flow-induced endothelial mesenchymal activation.

Atherosclerosis is a progressive disease that develops in areas of disturbed flow (d-flow). Progressive atherosclerosis is characterized by bulky plaques rich in mesenchymal cells and high-grade inflammation that can rupture leading to sudden cardiac death or acute myocardial infarction. In response to d-flow, endothelial cells acquire a mesenchymal phenotype through endothelial-to-mesenchymal transition (EndMT). However, the signaling intermediaries that link d-flow to EndMT are incompletely understood. In this study we found that in human atherosclerosis, cells expressing SNAI1 (Snail 1, EndMT transcription factor) were highly expressed within the endothelial cell (EC) layer and in the pre-necrotic areas in unstable lesions, whereas stable lesions did not show any SNAI1 positive cells, suggesting a role for EndMT in lesion instability. The interleukin-1 (IL-1), which signals through the type-I IL-1 receptor (IL-1R1), has been implicated in plaque instability and linked to EndMT formation in vitro. Interestingly, we observed an association between SNAI1 and IL-1R1 within ECs in the unstable lesions. To establish the causal relationship between EndMT and IL-1R1 expression, we next examined IL-1R1 levels in our Cre-lox endothelial-specific lineage tracing mice. IL-1R1 and Snail1 were highly expressed in ECs under atheroprone compared to athero-protective areas, and oscillatory shear stress (OSS) increased IL-1R1 protein and mRNA levels in vitro. Exposure of ECs to OSS resulted in loss of their EC markers and higher induction of EndMT markers. By contrast, genetic silencing of IL-1R1 significantly reduced the expression of EndMT markers and Snail1 nuclear translocation, suggesting a direct role for IL-1R1 in d-flow-induced EndMT. In vivo, re-analysis of scRNA-seq datasets in carotid artery exposed to d-flow confirmed the IL-1R1 upregulation among EndMT population, and in our partial carotid ligation model of d-flow, endothelial cell specific IL-1R1 KO significantly reduced SNAI1 expression. Global inhibition of IL-1 signaling in atherosclerosis as a therapeutic target has recently been tested in the completed CANTOS trial, with promising results. However, the data on IL-1R1 signaling in different vascular cell-types are inconsistent. Herein, we show endothelial IL-1R1 as a novel mechanosensitive receptor that couples d-flow to IL-1 signaling in EndMT.

Calculation of internal-wave-driven instability and vortex shedding along a flat bottom

The instability and vortex shedding in the bottom boundary layer caused by internal solitary waves of depression propagating along a shallow pycnocline of a fluid are computed by finite-volume code in two dimensions. The calculated transition to instability agrees very well with laboratory experiments (Carret al.,Phys. Fluids, vol. 20, issue 6, 2008, 06603) but disagrees with existing computations that give a very conservative instability threshold. The instability boundary expressed by the amplitude depends on the depth$d$of the pycnocline divided by the water depth$H$, and decays by a factor of 2.2 when$d/H$is 0.21, and by a factor of 1.6 when$d/H$is 0.16, and the stratification Reynolds number increases by a factor of 32. The instability occurs at moderate amplitude at large scale. The calculated oscillatory bed shear stress is strong in the wave phase and increases with the scale. Its non-dimensional magnitude at stratification Reynolds number 650 000 is comparable to the turbulent stress that can be extracted from field measurements of internal solitary waves of similar nonlinearity, moving along a pycnocline of similar relative depth.

Oscillatory shear stress-mediated aberrant O-GlcNAc SIRT3 accelerates glycocalyx inflammatory injury via LKB1/p47phox/Hyal2 signaling

Glycocalyx coating on endothelial surface layer helps to sense shear forces and maintain endothelial function. However, the underlying mechanism of endothelial glycocalyx degradation upon disordered shear stress stimulation is not fully understood. SIRT3, a major NAD+-dependent protein deacetylases, is required for protein stability during vascular homeostasis and partly involved in atherosclerotic process. While few studies showed that SIRT3 is responsible for endothelial glycocalyx homeostasis under shear stress, the underlying mechanisms remain largely unknown. Here, we demonstrated that oscillatory shear stress (OSS) induces glycocalyx injury by activating LKB1/p47phox/Hyal2 axis both in vivo and in vitro. And O-GlcNAc modification served to prolong SIRT3 deacetylase activity and stabilized p47/Hyal2 complex. OSS could decrease SIRT3 O-GlcNAcylation to activate LKB1, further accelerated endothelial glycocalyx injury in inflammatory microenvironment. SIRT3Ser329 mutation or inhibition of SIRT3 O-GlcNAcylation strongly promoted glycocalyx degradation. On the contrary, overexpression of SIRT3 reverse glycocalyx damage upon OSS treatment. Together, our findings indicated that targeting O-GlcNAcylation of SIRT3 could prevent and/or treat diseases whereby glycocalyx injured.

Effect of heart rate on the hemodynamics in healthy and stenosed carotid arteries

Stenosis in the internal carotid arteries is a serious cardiovascular condition. It is well-reported that low and oscillatory wall shear stress enhances the risk of stenosis progression. However, the effects of increased heart rates in highly stenosed arteries are not well explored. A detailed understanding of the flow features and stress distribution in stenosed carotid arteries at different heart rates may help clinicians to prescribe better exercise schedules for patients. In this study, we probe the effects of elevated heart rates on the hemodynamics in healthy and stenosed carotid arterial geometries using an immersed boundary method-based computational framework. Our results reveal that a strong recirculation, secondary velocity, and oscillatory shear index (OSI) zone develop inside a severely stenosed carotid artery at normal heart rate. Higher heart rates may potentially improve arterial health by reducing OSI only for the healthy and mild stenosis carotid arteries. However, the increased heart rates worsen the arterial health of severely stenosed arteries by onsetting flow instabilities, enhancing the spread and severity of the recirculation zone and the magnitude of the secondary velocity, the pressure drops across the stenosis, and the spread of high OSI (≥0.2) zone downstream. Furthermore, in the case of severe stenosis, the wall shear stress at the stenosis throat rises significantly, which can contribute to plaque rupture and thrombus development. Here, we report in detail the behavior of stress levels and pressure fluctuations in the carotid artery model at different stenosis levels for normal and elevated heart rates.

P21: Generalized blood rheological model for analyzing thrombus formation in venous valve architecture

The health impact of venous thromboembolism (VTE), a major cause of morbidity and mortality, can be appreciated from the large number of people affected, 1 million Americans and > 700,000 Europeans annually. The economic impacts of this have been the focus of several studies, with the annual cost to the US healthcare system of incident VTE being estimated at up to $10 billion. The non-Newtonian, shear-thinning blood rheology plays a major role in determining the shape and duration of stagnant fluid zones arising within the venous valve leaflet pockets where the thrombi occur. It has also been suggested that valve compression treatment ensuring oscillating shear stress at the vein wall within the pocket can prevent the formation of clots. Many models have been proposed for blood rheology, some with yield stress and others not, and these have been used extensively to model wall shear stress in models of coronary arteries, with a view to determining the likelihood of stenoses. In this new work, we propose a new non-Newtonian model whose parameters can be readily determined using a capillary rheometer. The model takes the form σ = σ0 + k εn + µ∞ ε where σ is the shear stress and is the ε shear strain rate. σ0 is the yield stress and the fluid viscosity at a high shear strain rate. This generalizes three of the existing models and eliminates the unphysical characteristics of each individual model. This model incorporates the Herschel-Bulkley, Casson, and K-L models as special cases. The overall aim of the work is to determine the effect of venous valve geometry on the likelihood of clot formation, using a realistic description of blood rheology.

Flow-inducedreprogramming of endothelial cells in atherosclerosis.

Atherosclerotic diseases such as myocardial infarction, ischaemic stroke and peripheral artery disease continue to be leading causes of death worldwide despite the success of treatments with cholesterol-lowering drugs and drug-eluting stents, raising the need to identify additional therapeutic targets. Interestingly, atherosclerosis preferentially develops in curved and branching arterial regions, where endothelial cells are exposed to disturbed blood flow with characteristic low-magnitude oscillatory shear stress. By contrast, straight arterial regions exposed to stable flow, which is associated with high-magnitude, unidirectional shear stress, are relatively well protected from the disease through shear-dependent, atheroprotective endothelial cell responses. Flow potently regulates structural, functional, transcriptomic, epigenomic and metabolic changes in endothelial cells through mechanosensors and mechanosignal transduction pathways. A study using single-cell RNA sequencing and chromatin accessibility analysis in a mouse model of flow-induced atherosclerosis demonstrated that disturbed flow reprogrammes arterial endothelial cells in situ from healthyphenotypes to diseased ones characterized by endothelial inflammation, endothelial-to-mesenchymal transition, endothelial-to-immune cell-like transition and metabolic changes. In this Review, we discuss this emerging concept of disturbed-flow-induced reprogramming of endothelial cells (FIRE) as a potential pro-atherogenic mechanism. Defining the flow-induced mechanisms through which endothelial cells are reprogrammed to promote atherosclerosis is a crucial area of research that could lead to the identification of novel therapeutic targets to combat the high prevalence of atherosclerotic disease.