Hemodynamic Shear Stress Research Articles

Relative Residence Time Can Account for Half of the Anatomical Variation in Fatty Streak Prevalence Within the Right Coronary Artery.

The patchy anatomical distribution of atherosclerosis has been attributed to variation in haemodynamic wall shear stress (WSS). The consensus is that low WSS and a high Oscillatory Shear Index (OSI) trigger the disease. We found that atherosclerosis at aortic branch sites correlates threefold better with transverse WSS (transWSS), a metric which quantifies multidirectional near-wall flow. Coronary artery disease has greater clinical significance than aortic disease but computation of WSS metrics is complicated by the substantial vessel motion occurring during each cardiac cycle. Here we present the first comparison of the distribution of atherosclerosis with WSS metrics computed for moving coronary arteries. Maps of WSS metrics were computed using dynamic geometries reconstructed from angiograms of ten non-stenosed human right coronary arteries (RCAs). They were compared with maps of fatty streak prevalence derived from a previous study of 1852 RCAs. Time average WSS (TAWSS), OSI, transWSS and the cross-flow index (CFI), a non-dimensional form of the transWSS, gave non-significant or significant but low spatial correlations with lesion prevalence. The highest correlation coefficient (0.71) was for the relative residence time (RRT), a metric that decreases with TAWSS and increases with OSI. The coefficient was not changed if RRT was calculated using CFI, which captures multidirectional WSS only, rather than OSI, which encompasses both multidirectional and oscillatory WSS. Contrary to our earlier findings in the aorta, low WSS in combination with highly multidirectional flow correlates best with lesion location in the RCA, explaining approximately half of its anatomical variation.

Dysfunctional mechanotransduction regulates the progression of PIK3CA-driven vascular malformations.

Somatic activating mutations in PIK3CA are common drivers of vascular and lymphatic malformations. Despite common biophysical signatures of tissues susceptible to lesion formation, including compliant extracellular matrix and low rates of perfusion, lesions vary in clinical presentation from localized cystic dilatation to diffuse and infiltrative vascular dysplasia. The mechanisms driving the differences in disease severity and variability in clinical presentation and the role of the biophysical microenvironment in potentiating progression are poorly understood. Here, we investigate the role of hemodynamic forces and the biophysical microenvironment in the pathophysiology of vascular malformations, and we identify hemodynamic shear stress and defective endothelial cell mechanotransduction as key regulators of lesion progression. We found that constitutive PI3K activation impaired flow-mediated endothelial cell alignment and barrier function. We show that defective shear stress sensing in PIK3CA E542K endothelial cells is associated with reduced myosin light chain phosphorylation, junctional instability, and defective recruitment of vinculin to cell-cell junctions. Using 3D microfluidic models of the vasculature, we demonstrate that PIK3CA E542K microvessels apply reduced traction forces and are unaffected by flow interruption. We further found that draining transmural flow resulted in increased sprouting and invasion responses in PIK3CA E542K microvessels. Mechanistically, constitutive PI3K activation decreased cellular and nuclear elasticity resulting in defective cellular tensional homeostasis in endothelial cells which may underlie vascular dilation, tissue hyperplasia, and hypersprouting in PIK3CA-driven venous and lymphatic malformations. Together, these results suggest that defective nuclear mechanics, impaired cellular mechanotransduction, and maladaptive hemodynamic responses contribute to the development and progression of PIK3CA-driven vascular malformations.

Microfluidics as a Powerful Tool to Investigate Microvascular Dysfunction in Trauma Conditions: A Review of the State-of-the-Art.

Skeletal muscle trauma such as fracture or crush injury can result in a life-threatening condition called acute compartment syndrome (ACS), which involves elevated compartmental pressure within a closed osteo-fascial compartment, leading to collapse of the microvasculature and resulting in necrosis of the tissue due to ischemia. Diagnosis of ACS is complex and controversial due to the lack of standardized objective methods, which results in high rates of misdiagnosis/late diagnosis, leading to permanent neuro-muscular damage. ACS pathophysiology is poorly understood at a cellular level due to the lack of physiologically relevant models. In this context, microfluidics organ-on-chip systems (OOCs) provide an exciting opportunity to investigate the cellular mechanisms of microvascular dysfunction that leads to ACS. In this article, the state-of-the-art OOCs designs and strategies used to investigate microvasculature dysfunction mechanisms is reviewed. The differential effects of hemodynamic shear stress on endothelial cell characteristics such as morphology, permeability, and inflammation, all of which are altered during microvascular dysfunction is highlighted. The article then critically reviews the importance of microfluidics to investigate closely related microvascular pathologies that cause ACS. The article concludes by discussing potential biomarkers of ACS with a special emphasis on glycocalyx and providing a future perspective.

Description of the local hemodynamic environment in intracranial aneurysm wall subdivisions.

Intracranial aneurysms (IAs) pose severe health risks influenced by hemodynamics. This study focuses on the intricate characterization of hemodynamic conditions within the IA walls and their influence on bleb development, aiming to enhance understanding of aneurysm stability and the risk of rupture. The methods emphasized utilizing a comprehensive dataset of 359 IAs and 213 IA blebs from 268 patients to reconstruct patient-specific vascular models, analyzing blood flow using finite element methods to solve the unsteady Navier-Stokes equations, the segmentation of aneurysm wall subregions and the hemodynamic metrics wall shear stress (WSS), its metrics, and the critical points in WSS fields were computed and analyzed across different aneurysm subregions defined by saccular, streamwise, and topographical divisions. The results revealed significant variations in these metrics, correlating distinct hemodynamic environments with wall features on the aneurysm walls, such as bleb formation. Critical findings indicated that regions with low WSS and high OSI, particularly in the body and central regions of aneurysms, are prone to conditions that promote bleb formation. Conversely, areas exposed to high WSS and positive divergence, like the aneurysm neck, inflow, and outflow regions, exhibited a different but substantial risk profile for bleb development, influenced by flow impingements and convergences. These insights highlight the complexity of aneurysm behavior, suggesting that both high and low-shear environments can contribute to aneurysm pathology through distinct mechanisms.

P300 Modulates Endothelial Mechanotransduction of Fluid Shear Stress.

P300 is a lysine acetyltransferase that plays a significant role in regulating transcription and the nuclear acetylome. While P300 has been shown to be required for the transcription of certain early flow responsive genes, relatively little is known about its role in the endothelial response to hemodynamic fluid stress. Here we sought to define the role of P300 in mechanotransduction of fluid shear stress in the vascular endothelium. To characterize cellular mechanotransduction and physical properties after perturbation of P300, we performed bulk RNA sequencing, confocal and Brillouin microscopy, and functional assays on HUVEC. Inhibition of P300 in HUVEC triggers a hyper-alignment phenotype, with cells aligning to flow sooner and more uniformly in the presence of the P300 inhibitor A-485 compared to load controls. Bulk transcriptomics revealed differential expression of genes related to the actin cytoskeleton and migration in cells exposed to A-485. Scratch wound and bead sprouting assays demonstrated that treatment with A-485 increased 2D and 3D migration of HUVEC. Closer examination of filamentous actin revealed the presence of a perinuclear actin cap in both P300 knockdown HUVEC and HUVEC treated with A-485. Interrogation of cell mechanical properties via Brillouin microscopy demonstrated that HUVEC treated with A-485 had lower Brillouin shifts in both the cell body and the nucleus, suggesting that P300 inhibition triggers an increase in cellular and nuclear compliance. Together, these results point to a novel role of P300 in modulating endothelial cell mechanics and mechanotransduction of hemodynamic shear stress. The online version contains supplementary material available at 10.1007/s12195-024-00805-2.

Distinguishing high-metastasis-potential circulating tumor cells through fluidic shear stress in a bloodstream-like microfluidic circulatory system.

Circulating tumor cells (CTCs) play a critical role as initiators in tumor metastasis, which unlocks an irreversible process of cancer progression. Regarding the fluid environment of intravascular CTCs, a comprehensive understanding of the impact of hemodynamic shear stress on CTCs is of profound significance but remains vague. Here, we report a microfluidic circulatory system that can emulate the CTC microenvironment to research the responses of typical liver cancer cells to varying levels of fluid shear stress (FSS). We observe that HepG2 cells surviving FSS exhibit a marked overexpression of TLR4 and TPPP3, which are shown to be associated with the colony formation, migration, and anti-apoptosis abilities of HepG2. Furthermore, overexpression of these two genes in another liver cancer cell line with normally low TLR4 and TPPP3 expression, SK-Hep-1 cells, by lentivirus-mediated transfection also confirms the critical role of TLR4 and TPPP3 in improving colony formation, migration, and survival capability under a fluid environment. Interestingly, in vivo experiments show SK-Hep-1 cells, overexpressed with these genes, have enhanced metastatic potential to the liver and lungs in mouse models via tail vein injection. Mechanistically, TLR4 and TPPP3 upregulated by FSS may increase FSS-mediated cell survival and metastasis through the p53-Bax signaling pathway. Moreover, elevated levels of these genes correlate with poorer overall survival in liver cancer patients, suggesting that our findings could offer new therapeutic strategies for early cancer diagnosis and targeted treatment development.

Insights from Murine Studies on the Site Specificity of Atherosclerosis.

Atherosclerosis is an inflammatory reaction that develops at specific regions within the artery wall and at specific sites of the arterial tree over a varying time frame in response to a variety of risk factors. The mechanisms that account for the interaction of systemic factors and atherosclerosis-susceptible regions of the arterial tree to mediate this site-specific development of atherosclerosis are not clear. The dynamics of blood flow has a major influence on where in the arterial tree atherosclerosis develops, priming the site for interactions with atherosclerotic risk factors and inducing cellular and molecular participants in atherogenesis. But how this accounts for lesion development at various locations along the vascular tree across differing time frames still requires additional study. Currently, murine models are favored for the experimental study of atherogenesis and provide the most insight into the mechanisms that may contribute to the development of atherosclerosis. Based largely on these studies, in this review, we discuss the role of hemodynamic shear stress, SR-B1, and other factors that may contribute to the site-specific development of atherosclerosis.

Activation of heme oxygenase-1 by laminar shear stress ameliorates high glucose-induced endothelial cell and smooth muscle cell dysfunction.

High glucose (HG)-induced endothelial cell (EC) and smooth muscle cell (SMC) dysfunction is critical in diabetes-associated atherosclerosis. However, the roles of heme oxygenase-1 (HO-1), a stress-response protein, in hemodynamic force-generated shear stress and HG-induced metabolic stress remain unclear. This investigation examined the cellular effects and mechanisms of HO-1 under physiologically high shear stress (HSS) in HG-treated ECs and adjacent SMCs. We found that exposure of human aortic ECs to HSS significantly increased HO-1 expression; however, this upregulation appeared to be independent of adenosine monophosphate-activated protein kinase, a regulator of HO-1. Furthermore, HSS inhibited the expression of HG-induced intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and reactive oxygen species (ROS) production in ECs. In an EC/SMC co-culture, compared with static conditions, subjecting ECs close to SMCs to HSS and HG significantly suppressed SMC proliferation while increasing the expression of physiological contractile phenotype markers, such as α-smooth muscle actin and serum response factor. Moreover, HSS and HG decreased the expression of vimentin, an atherogenic synthetic phenotypic marker, in SMCs. Transfecting ECs with HO-1-specific small interfering (si)RNA reversed HSS inhibition on HG-induced inflammation and ROS production in ECs. Similarly, reversed HSS inhibition on HG-induced proliferation and synthetic phenotype formation were observed in co-cultured SMCs. Our findings provide insights into the mechanisms underlying EC-SMC interplay during HG-induced metabolic stress. Strategies to promote HSS in the vessel wall, such as continuous exercise, or the development of HO-1 analogs and mimics of the HSS effect, could provide an effective approach for preventing and treating diabetes-related atherosclerotic vascular complications.

Mechanobiological stimulation in organ-on-a-chip systems reduces hepatic drug metabolic capacity in favor of regenerative specialization.

Hepatic physiology depends on the liver's complex structural composition which among others, provides high oxygen supply rates, locally differential oxygen tension, endothelial paracrine signaling, as well as residual hemodynamic shear stress to resident hepatocytes. While functional improvements were shown by implementing these factors into hepatic culture systems, direct cause-effect relationships are often not well characterized-obfuscating their individual contribution in more complex microphysiological systems. By comparing increasingly complex hepatic in vitro culture systems that gradually implement these parameters, we investigate the influence of the cellular microenvironment to overall hepatic functionality in pharmacological applications. Here, hepatocytes were modulated in terms of oxygen tension and supplementation, endothelial coculture, and exposure to fluid shear stress delineated from oxygen influx. Results from transcriptomic and metabolomic evaluation indicate that particularly oxygen supply rates are critical to enhance cellular functionality-with cellular drug metabolism remaining comparable to physiological conditions after prolonged static culture. Endothelial signaling was found to be a major contributor to differential phenotype formation known as metabolic zonation, indicated by WNT pathway activity. Lastly, oxygen-delineated shear stress was identified to direct cellular fate towards increased hepatic plasticity and regenerative phenotypes at the cost of drug metabolic functionality - in line with regenerative effects observed in vivo. With these results, we provide a systematic evaluation of critical parameters and their impact in hepatic systems. Given their adherence to physiological effects in vivo, this highlights the importance of their implementation in biomimetic devices, such as organ-on-a-chip systems. Considering recent advances in basic liver biology, direct translation of physiological structures into in vitro models is a promising strategy to expand the capabilities of pharmacological models.

Transducing Force into Procoagulation: PIEZO1-TMEM16F Functional Coupling in Blood Lining Cells

Thrombosis is a major global disease burden that accounts for 1 in 4 deaths worldwide. Hypertension and preeclampsia greatly increase thrombotic risks by imposing high blood pressure and abnormal hemodynamic shear stress on blood-lining cells, namely endothelial cells (ECs) and placental syncytiotrophoblasts (STBs) in pregnant women. Nonetheless, it remains elusive how abnormal mechanical forces under hypertensive conditions promote coagulation. PIEZO1 mechanosensitive ion channel is a major force sensor in a wide variety of cells, including red blood cells (RBCs) and endothelial cells (ECs), where it transduces mechanical forces into chemical signals through its ion permeability to calcium. On the other hand, TMEM16F is a calcium-activated lipid scramblase (CaPLSase) that translocates phosphatidylserine (PS), an important procoagulant factor, to the cell surfaces of blood cells and endothelial cells. We recently discovered that TMEM16F is the sole CaPLSase in placental trophoblasts and RBCs. Our preliminary results show that PIEZO1 and TMEM16F are functionally coupled in RBCs, and calcium entry through PIEZO1 activates TMEM16F, leading to PS exposure. Based on all these, we hypothesize that in the blood lining cells, PIEZO1-TMEM16F coupling is responsible for transducing mechanical forces into PS exposure, a critical procoagulant signal for blood coagulation. By employing immunostaining, patch clamp electrophysiology, and a fluorescence microscopy-based scrambling assay, we show that PIEZO1 is functionally expressed in placental trophoblasts, including STBs. We further demonstrate that PIEZO1 activation, either stimulated by its agonist Yoda1 or by shear stress, induces PS exposure in BeWo human trophoblast cell line and human umbilical vein endothelial cell line (HUVEC) but not the TMEM16F deficient cell lines. In addition, using chromogenic tenase and prothrombinase, and fluorescence fibrin assays, we show that PIEZO1 activation by its agonist, Yoda1, triggered coagulation activities in a TMEM16F-dependent fashion in trophoblasts. Our study thus discovers the functional expression of the PIEZO1 mechanosensitive channel in placental trophoblasts and elucidates a novel force-induced procoagulant mechanism in blood-lining cells. In this mechanism, PIEZO1-TMEM16F coupling transduces mechanical forces into procoagulant PS exposure on the blood lining cells. Enhanced PIEZO1-TMEM16F coupling may contribute to hypercoagulable states in hypertension and preeclampsia, and breaking the coupling is therefore a potential therapeutic strategy to prevent thrombotic risks associated with these diseases.

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.

Preoperative higher right ventricular stroke work index increases the risk of de novo aortic insufficiency after continuous-flow left ventricular assist device implantation

During continuous-flow left ventricular assist device (CF-LVAD) support, hemodynamic shear stress causes a burden on aortic valve (AV) leaflets, leading to de novo aortic insufficiency (AI). This study investigated the influence of preoperative hemodynamic parameters on de novo AI in CF-LVAD recipients. We reviewed 125 patients who underwent CF-LVAD implantation without concomitant AV surgery between 2005 and 2018. De novo AI was defined as moderate or severe AI in those with none or trivial preoperative AI. During mean 30 ± 16 months of CF-LVAD support, de novo AI-free rate was 86% and 67% at 1 and 2 years, respectively. Multivariable analysis showed that higher right ventricular stroke work index (RVSWI) (hazard ratio, 1.12 /g/m2/beat; 95% confidence interval, 1.00–1.20; p = 0.047) and trivial grade AI (hazard ratio, 2.8; 95% confidence interval, 1.2–6.4; p = 0.020) were independent preoperative risk factors for de novo AI. The longitudinal analysis using generalized mixed effects model showed that higher RVSWI was associated with continuous AV closure after LVAD implantation (Odd ratio, 1.20/g/m2/beat; 95% confidence interval, 1.00–1.43 /g/m2/beat; p = 0.047). Right heart catheterization revealed that preoperative RVSWI was positively correlated with postoperative pump flow index in patients with continuously closed AV (r = 0.44, p = 0.04, n = 22). Preoperative higher RVSWI was a significant risk factor for de novo AI following CF-LVAD implantation. In patients with preserved right ventricular function, postoperative higher pump flow may affect AI development via hemodynamic stress on the AV.

Blood–brain barrier microfluidic chips and their applications

As a natural dynamic barrier separating blood from brain parenchyma, the blood–brain barrier (BBB) is mainly composed of brain microvascular endothelial cells (BMECs), pericytes, astrocytes, and a variety of neurons. The BBB regulates the highly selective transport of various substances between the brain and blood and maintains the stability of the central nervous system (CNS). Owing to this tight control, the BBB represents a formidable challenge for the delivery of drugs and other exogenous compounds into the CNS, which has bottlenecked the development of many drugs for CNS diseases. Therefore, efficient and precise in vitro models of the BBB are needed to assess the efficacy and toxicity of drugs targeting the CNS to inform drug design and to improve the success rate of agents that enter clinical evaluation. In vitro BBB models have rapidly advanced from the early two-dimensional (2D) static models to the current three-dimensional (3D) dynamic microfluidic chips. Although the commonly used, static, in vitro BBB models are simple to construct and TEER values are convenient to detect, the static models do not provide an ideal (i.e., accurate) BBB environment, since they lack the correct physiological size/scale and hemodynamic shear stress, both of which play substantial roles in promoting and maintaining EC differentiation into a specific BBB phenotype. Compared with traditional static models, 3D microfluidic models thus enable cells to react in a manner more closely resembling in vivo behavior by simulating a microenvironment with more natural signal transduction. As a result, the dynamic 3D BBB model can more accurately recapitulate the structure and function of the human BBB. Here we summarize the recent progress in in vitro microfluidic BBB chips and their research applications as well as discuss the prospects and challenges for where the technology is headed.

Intraluminal Thrombus Characteristics in AAA Patients: Non-Invasive Diagnosis Using CFD.

Abdominal aortic aneurysms (AAA) continue to pose a high mortality risk despite advances in medical imaging and surgery. Intraluminal thrombus (ILT) is detected in most AAAs and may critically impact their development. Therefore, understanding ILT deposition and growth is of practical importance. To assist in managing these patients, the scientific community has been researching the relationship between intraluminal thrombus (ILT) and hemodynamic parameters wall shear stress (WSS) derivatives. This study analyzed three patient-specific AAA models reconstructed from CT scans using computational fluid dynamics (CFD) simulations and a pulsatile non-Newtonian blood flow model. The co-localization and relationship between WSS-based hemodynamic parameters and ILT deposition were examined. The results show that ILT tends to occur in regions of low velocity and time-averaged WSS (TAWSS) and high oscillation shear index (OSI), endothelial cell activation potential (ECAP), and relative residence time (RRT) values. ILT deposition areas were found in regions of low TAWSS and high OSI independently of the nature of flow near the wall characterized by transversal WSS (TransWSS). A new approach is suggested which is based on the estimation of CFD-based WSS indices specifically in the thinnest and thickest ILT areas of AAA patients; this approach is promising and supports the effectiveness of CFD as a decision-making tool for clinicians. Further research with a larger patient cohort and follow-up data are needed to confirm these findings.

EVA1A (Eva-1 Homolog A) Promotes Endothelial Apoptosis and Inflammatory Activation Under Disturbed Flow Via Regulation of Autophagy.

Hemodynamic wall shear stress (WSS) exerted on the endothelium by flowing blood determines the spatial distribution of atherosclerotic lesions. Disturbed flow (DF) with a low WSS magnitude and reversing direction promotes atherosclerosis by regulating endothelial cell (EC) viability and function, whereas un-DF which is unidirectional and of high WSS magnitude is atheroprotective. Here, we study the role of EVA1A (eva-1 homolog A), a lysosome and endoplasmic reticulum-associated protein linked to autophagy and apoptosis, in WSS-regulated EC dysfunction. The effect of WSS on EVA1A expression was studied using porcine and mouse aortas and cultured human ECs exposed to flow. EVA1A was silenced in vitro in human ECs and in vivo in zebrafish using siRNA (small interfering RNA) and morpholinos, respectively. EVA1A was induced by proatherogenic DF at both mRNA and protein levels. EVA1A silencing resulted in decreased EC apoptosis, permeability, and expression of inflammatory markers under DF. Assessment of autophagic flux using the autolysosome inhibitor, bafilomycin coupled to the autophagy markers LC3-II (microtubule-associated protein 1 light chain 3-II) and p62, revealed that EVA1A knockdown promotes autophagy when ECs are exposed to DF, but not un-DF . Blocking autophagic flux led to increased EC apoptosis in EVA1A-knockdown cells exposed to DF, suggesting that autophagy mediates the effects of DF on EC dysfunction. Mechanistically, EVA1A expression was regulated by flow direction via TWIST1 (twist basic helix-loop-helix transcription factor 1). In vivo, knockdown of EVA1A orthologue in zebrafish resulted in reduced EC apoptosis, confirming the proapoptotic role of EVA1A in the endothelium. We identified EVA1A as a novel flow-sensitive gene that mediates the effects of proatherogenic DF on EC dysfunction by regulating autophagy.

Modification of the swirling well cell culture model to alter shear stress metrics.

Effects of hemodynamic shear stress on endothelial cells have been extensively investigated using the "swirling well" method, in which cells are cultured in dishes or multiwell plates placed on an orbital shaker. A wave rotates around the well, producing complex patterns of shear. The method allows chronic exposure to flow with high throughput at low cost but has two disadvantages: a number of shear stress characteristics change in a broadly similar way from the center to the edge of the well, and cells at one location in the well may release mediators into the medium that affect the behavior of cells at other locations, exposed to different shears. These properties make it challenging to correlate cell properties with shear. The present study investigated simple alterations to ameliorate these issues. Flows were obtained by numerical simulation. Increasing the volume of fluid in the well-altered dimensional but not dimensionless shear metrics. Adding a central cylinder to the base of the well-forced fluid to flow in a square toroidal channel and reduced multidirectionality. Conversely, suspending a cylinder above the base of the well made the flow highly multidirectional. Increasing viscosity in the latter model increased the magnitude of dimensional but not dimensionless metrics. Finally, tilting the well changed the patterns of different wall shear stressmetrics in different ways. Collectively, these methods allow similar flows over most of the cells cultured and/or allow the separation of different shear metrics. A combination of the methods overcomes the limitations of the baseline model.

Magnetic resonance imaging-based hemodynamic wall shear stress alters aortic wall tissue biomechanics in bicuspid aortic valve patients

ObjectiveIn this study we aimed to conclusively determine whether altered aortic biomechanics are associated with wall shear stress (WSS) independent of region of tissue collection. Elevated WSS in the ascending aorta of patients with bicuspid aortic valve has been shown to contribute to local maladaptive aortic remodeling and might alter biomechanics. MethodsPreoperative 4-dimensional flow magnetic resonance imaging was performed on 22 patients who underwent prophylactic aortic root and/or ascending aorta replacement. Localized elevated WSS was identified in patients using age-matched healthy atlases (n = 60 controls). Tissue samples (n = 78) were collected and categorized according to WSS (elevated vs normal) and region. Samples were subjected to planar biaxial testing. To fully quantify the nonlinear biomechanical response, the tangential modulus (local stiffness) at a low-stretch (LTM) and high-stretch (HTM) linear region and the onset (TZo) and end stress of the nonlinear transition zone were measured. A linear mixed effect models was implemented to determine statistical relationships. ResultsA higher LTM in the circumferential and axial direction was associated with elevated WSS (P = .007 and P = .018 respectively) independent of collection region. Circumferential TZo and HTM were higher with elevated WSS (P = .024 and P = .003); whereas the collection region was associated with variations in axial TZo (P = .013), circumferential HTM (P = .015), and axial HTM (P = .001). ConclusionsThis study shows strong evidence that biomechanical changes in the aorta are strongly associated with hemodynamics, and not region of tissue collection for bicuspid valve aortopathy patients. Elevated WSS is associated with tissue behavior at low stretch ranges (ie, LTM and TZo).

The effect of shear stress on the expression of apelin in trophoblast using microfluidic system

The apelin/APJ(apelin receptor) system is being considered to play a crucial role in cardiovascular function. It is regulated by hemodynamic shear stress and involved in many physiological and pathological processes. Apelin/APJ ,which is found to be highly expressed in placenta, are implicated in the pathophysiology of preeclampsia. In preeclampsia, the process of spiral artery invasion is attenuated, resulting in underperfusion and the elevation of shear stress in placenta. This study is to evaluate the effect of shear stress on the expression of apelin/APJ system using microfluidic system. In this study, microfluidic channels were designed to mimic the shape of the intervillous space, where the shear depend on flow rate of the microchannels. In experiment about time, HTR-8/SV neo cells were exposed to shear stress (0.5, 1.0 or 5.0 dyne/cm2) for 15min, 30min, 1h, 2h, 3h or 4h. Changes in the level of apelin were investigated using ELISA in response to applied shear stresses in a continuous cycling system through microfluidic channels. Apelin in HTR-8/SV neo cells was confirmed in all culture media. The level of apelin in culture media decreased after exposure to shear stress of 5.0 dyne/cm2 compared to exposure to shear stress of 0.5 or 1.0 dyne/cm2. The level of apelin in culture media decreased as the time for exposure to shear stress increased. Our results demonstrate that increased shear stress downregulated the expression of apelin in placenta suggesting the expression of apelin in placenta through shear stress may be involved in the pathogenesis of preeclampsia.

Restoring endothelial function: shedding light on cardiovascular stent development.

Complete endothelialization is highly important for maintaining long-term patency and avoiding subsequent complications in implanting cardiovascular stents. It not only refers to endothelial cells (ECs) fully covering the inserted stents, but also includes the newly formed endothelium, which could exert physiological functions, such as anti-thrombosis and anti-stenosis. Clinical outcomes have indicated that endothelial dysfunction, especially the insufficiency of antithrombotic and barrier functions, is responsible for stent failure. Learning from vascular pathophysiology, endothelial dysfunction on stents is closely linked to the microenvironment of ECs. Evidence points to inflammatory responses, oxidative stress, altered hemodynamic shear stress, and impaired endothelial barrier affecting the normal growth of ECs, which are the four major causes of endothelial dysfunction. The related molecular mechanisms and efforts dedicated to improving the endothelial function are emphasized in this review. From the perspective of endothelial function, the design principles, advantages, and disadvantages behind current stents are introduced to enlighten the development of new-generation stents, aiming to offer new alternatives for restoring endothelial function.

Endothelial TAZ inhibits capillarization of liver sinusoidal endothelium and damage-induced liver fibrosis via nitric oxide production.

Background: Endothelial dysfunction is a systemic disorder and is involved in the pathogenesis of several human diseases. Hemodynamic shear stress plays an important role in vascular homeostasis including nitric oxide (NO) production. Impairment of NO production in endothelial cells stimulates the capillarization of liver sinusoidal endothelial cells, followed by hepatic stellate cell activation, inducing liver fibrosis. However, the detailed mechanism underlying NO production is not well understood. In hepatocytes, transcriptional co-activator with PDZ-binding motif (TAZ) has been reported to be involved in liver fibrosis. However, the role of endothelial TAZ in liver fibrosis has not been investigated. In this study, we uncovered the role TAZ in endothelial cell NO production, and its subsequent effects on liver fibrosis. Methods: TAZ-floxed mice were crossed with Tie2-cre transgenic mice, to generate endothelium-specific TAZ-knockout (eKO) mice. To induce liver damage, a 3,5-diethoxycarboncyl-1,4-dihydrocollidine, methionine-choline-deficient diet, or partial hepatectomy was applied. Liver fibrosis and endothelial dysfunction were analyzed in wild-type and eKO mice after liver damage. In addition, liver sinusoidal endothelial cell (LSEC) was used for in vitro assays of protein and mRNA levels. To study transcriptional regulation, chromatin immunoprecipitation and luciferase reporter assays were performed. Results: In liver of eKO mice, LSEC capillarization was observed, evidenced by loss of fenestrae and decreased LSEC-specific marker gene expression. LSEC capillarization of eKO mouse is caused by downregulation of endothelial nitric oxide synthase expression and subsequent decrease in NO concentration, which is transcriptionally regulated by TAZ-KLF2 binding to Nos3 promoter. Diminished NO concentration by TAZ knockout in endothelium accelerates liver fibrosis induced by liver damages. Conclusions: Endothelial TAZ inhibits damage-induced liver fibrosis via NO production. This highlights an unappreciated role of TAZ in vascular health and liver diseases.