Albumin permeability across endothelial monolayers under pulsatile shear stress

Recent studies suggest that the temporal gradient of shear stress that is generated by blood flow plays an important role in the pathology of arteriosclerosis. We focused on the temporal gradient of shear stress and measured the permeability of albumin under steady or pulsatile shear stress conditions. Porcine aortic endothelial cells were seeded on a membrane filter and subjected to steady or pulsatile shear stress (1 Hz) at 1 Pa for 48 h, and the permeability of albumin was measured over time. The permeability increased gradually under steady flow but increased acutely under pulsatile shear stress. In particular, the maximum permeability of albumin differed under these conditions. The value was 4.2 × 10^?5 cm/s at 18 h under pulsatile shear stress and 2.8 × 10^?5 cm/s at 48 h under steady shear stress. The permeable route of albumin was examined using isoproterenol, which decreases junctional permeability. The increase in albumin permeability with pulsatile shear stress was decreased by isoproterenol. These results suggest that the increased permeability of albumin with pulsatile shear stress was related to trafficking through paracellular junctions. Thus, pulsation may promote a mechanotransduction process that differs from that of steady shear stress, and these pulsation effects likely play an important role in the permeability of macromolecules.     

A boundary layer model for wall shear stress in arterial stenosis

This paper proposes a model for wall shear stress in arterial stenosis based on boundary layer theory. Wall shear stress estimates are obtained by solving the momentum integral equation using the method proposed by Walz and applying this method to various stenosis geometries for Reynolds numbers (Re) of Re = 59-1000. Elevated wall shear stress may be of importance when considering thrombosis and vascular erosion in stenosis, as well as the potential for debris from the stenotic area to 'break away' and cause further pathology. The values of shear stress obtained using the model in this study agree well with published values of wall shear stress. When compared to a previously published boundary layer model utilizing the Thwaites method (Reese and Thompson, 1998), the model proposed herein performs better at higher Re while the model utilizing the Thwaites method performs better at lower Re. Wall shear stresses are shown to increase with increasing stenosis (increased area reduction) for a given stenosis length, increase with increasing Re for a given stenosis geometry, and increase for steeper stenosis of the same constriction. The boundary layer model proposed can be easily implemented by clinical researchers to provide in vivo estimates of wall shear stress through arterial stenoses.     

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

Hyperglycemia is associated with generation of reactive oxygen species (ROS), and this action may contribute to accelerated atherogenesis. We tested the hypothesis that hyperglycemia produces alterations in left anterior descending coronary artery (LAD) wall shear stress concomitant with endothelial dysfunction and ROS production in dogs (n = 12) instrumented for measurement of LAD blood flow, velocity, and diameter. Dogs were randomly assigned to receive vehicle (0.9% saline) or the superoxide dismutase mimetic 4- hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) and were administered intravenous infusions of d-glucose to achieve target blood glucose concentrations of 350 and 600 mg/dl (moderate and severe hyperglycemia, respectively). Endothelial function and ROS generation were assessed by coronary blood flow responses to acetylcholine (10, 30, and 100 ng/kg) and dihydroethidium fluorescence of myocardial biopsies, respectively. Indexes of wall shear stress were calculated with conventional fluid dynamics theory. Hyperglycemia produced dose-related endothelial dysfunction, increases in ROS production, and reductions in oscillatory shear stress that were normalized by tempol. The results suggest a direct association between hyperglycemia-induced ROS production, endothelial dysfunction, and decreases in oscillatory shear stress in vivo.     

Numerical 3D-simulation of pulsatile wall shear stress in an arterial T-bifurcation model

The structure of pulsatile blood flow and wall shear stress in a 90° T-bifurcation model is analysed numerically. The nonlinear Navier-Stokes equations for time-dependent incompressible Newtonian fluid flow are approximated using a newly developed pressure correction, finite element method. The wall shear stress is calculated from the finite element velocity field. The investigation shows viscous flow phenomena such as flow separation and stagnation and the distribution of high and low wall shear stress during the pulse cycle. Furthermore, the effect of a sharp corner the bifurcation edge on the wall shear stress is analysed. Detailed local flow investigation is required to examine fluid dynamic contribution to the development of arterial diseases such as atherosclerosis and thrombosis.     

Numerical simulation of wall shear stress conditions and platelet localization in realistic end-to-side arterial anastomoses

Research studies over the last three decades have established that hemodynamic interactions with the vascular surface as well as surgical injury are inciting mechanisms capable of eliciting distal anastomotic intimal hyperplasia (IH) and ultimate bypass graft failure. While abnormal wall shear stress (WSS) conditions have been widely shown to affect vascular biology and arterial wall self-regulation, the near-wall localization of critical blood particles by convection and diffusion may also play a significant role in IH development. It is hypothesized that locations of elevated platelet interactions with reactive or activated vascular surfaces, due to injury or endothelial dysfunction, are highly susceptible to IH initialization and progression. In an effort to assess the potential role of platelet-wall interactions, experimentally validated particle-hemodynamic simulations have been conducted for two commonly implemented end-to-side anastomotic configurations, with and without proximal outflow. Specifically, sites of significant particle interactions with the vascular surface have been identified by a novel near-wall residence time (NWRT) model for platelets, which includes shear stress-based factors for platelet activation as well as endothelial cell expression of thrombogenic and anti-thrombogenic compounds. Results indicate that the composite NWRT model for platelet-wall interactions effectively captures a reported shift in significant IH formation from the arterial floor of a relatively high-angle (30 deg) graft with no proximal outflow to the graft hood of a low-angle graft (10 deg) with 20% proximal outflow. In contrast, other WSS-based hemodynamic parameters did not identify the observed system-dependent shift in IH formation. However, large variations in WSS-vector magnitude and direction, as encapsulated by the WSS-gradient and WSS-angle-gradient parameters, were consistently observed along the IH-prone suture-line region. Of the multiple hemodynamic factors capable of eliciting a hyperplastic response at the cellular level, results of this study indicate the potential significance of platelet-wall interactions coinciding with regions of low WSS in the development of IH.     

Twenty-fold difference in hemodynamic wall shear stress between murine and human aortas

Endothelial cells regulate vascular tone and mural remodelling in a shear-dependent manner that is commonly assumed to keep wall shear stress constant across arteries and species. Allometric arguments show that aortic flow velocity is constant across species, a deduction that is consistent with much experimental data, but the same arguments also show that the shear stress experienced by aortic endothelium will depend inversely on body mass to the 3/8th power, and hence will be 20-fold higher in mice than in men. This conclusion is robust and has important implications for the study of shear-dependent vascular biology and pathology.     

Acute laminar shear stress reversibly increases human glomerular endothelial cell permeability via activation of endothelial nitric oxide synthase

Laminar shear stress is a key determinant of systemic vascular behavior, including through activation of endothelial nitric oxide synthase (eNOS), but little is known of its role in the glomerulus. We confirmed eNOS expression by glomerular endothelial cells (GEnC) in tissue sections and examined effects of acute exposure (up to 24 h) to physiologically relevant levels of laminar shear stress (10-20 dyn/cm(2)) in conditionally immortalized human GEnC. Laminar shear stress caused an orientation of GEnC and stress fibers parallel to the direction of flow and induced Akt and eNOS phosphorylation along with NO production. Inhibition of the phophatidylinositol (PI)3-kinase/Akt pathway attenuated laminar shear stress-induced eNOS phosphorylation and NO production. Laminar shear stress of 10 dyn/cm(2) had a dramatic effect on GEnC permeability, reversibly decreasing the electrical resistance across GEnC monolayers. Finally, the laminar shear stress-induced reduction in electrical resistance was attenuated by the NOS inhibitors l-N(G)-monomethyl arginine (l-NMMA) and l-N(G)-nitroarginine methyl ester (l-NAME) and also by inhibition of the PI3-kinase/Akt pathway. Hence we have shown for GEnC in vitro that acute permeability responses to laminar shear stress are dependent on NO, produced via activation of the PI3-kinase/Akt pathway and increased eNOS phosphorylation. These results suggest the importance of laminar shear stress and NO in regulating the contribution of GEnC to the permeability properties of the glomerular capillary wall.     

Maximal wall shear stress in arterial stenoses: application to the internal carotid arteries

Maximal wall shear stress (MWSS) in the convergent part of a stenosis is calculated by the interactive boundary-layer theory. A dimensional analysis of the problem shows that MWSS depends only on a few measurable parameters. A simple relationship between MWSS and these parameters is obtained, validated, and used to calculate the magnitude of MWSS in a carotid stenosis, as a function of the patency of the circle of Willis and the stenotic pattern. This demonstrates the huge effect of collateral pathways. Elevated MWSS are observed even in moderate stenoses, provided they are associated with a contralateral occlusion, a large anterior, and narrow posterior communicating arteries, suggesting a potential risk of embolus release in this configuration.     

Measurement of wall motion and wall shear in a compliant arterial cast

Initial measurements of the time-varying wall shear rate at two sites in a compliant cast of a human aortic bifurcation are presented. The shear rates were derived from flow velocities measured by laser Doppler velocimetry (LDV) near the moving walls of the cast. To derive these shear rate values, the distance from the velocimeter sampling volume to the cast wall must be known. The time variation of this distance was obtained from LDV measurements of the velocity of the wall itself.     

Advances in endothelial shear stress proteomics

The vascular endothelium lining the luminal surface of all blood vessels is constantly exposed to shear stress exerted by the flowing blood. Blood flow with high laminar shear stress confers protection by activation of antiatherogenic, antithrombotic and anti-inflammatory proteins, whereas low or oscillatory shear stress may promote endothelial dysfunction, thereby contributing to cardiovascular disease. Despite the usefulness of proteomic techniques in medical research, however, there are relatively few reports on proteome analysis of cultured vascular endothelial cells employing conditions that mimic in vivo shear stress attributes. This review focuses on the proteome studies that have utilized cultured endothelial cells to identify molecular mediators of shear stress and the roles they play in the regulation of endothelial function, and their ensuing effect on vascular function in general. It provides an overview on current strategies in shear stress-related proteomics and the key proteins mediating its effects which have been characterized so far.     

颈动脉血管壁切应力的分析

动脉中管壁的脉动低切应力在动脉粥样硬化形成中起始动和主要的决定作用。本文比较了几种计算血管壁切应力的方法,认为采用有约束的弹性管模型计算获得的动脉壁切应力更适合于临床应用。根据检测得到的正常人和动脉硬化性脑血管病患者的颈动脉血流速度、血管管径等数据,计算两者的颈动脉壁面切应力。研究发现动脉硬化性脑血管病患者的壁面切应力比正常人显著减小。这表明,颈动脉的壁面切应力可以作为动脉硬化性脑血管疾病的早期诊断的重要参考指标。     

Relative contribution of wall shear stress and injury in experimental intimal thickening at PTFE end-to-side arterial anastomoses

BACKGROUND: Intimal hyperplastic thickening (IHT) is a frequent cause of prosthetic bypass graft failure. Induction and progression of IHT is thought to involve a number of mechanisms related to variation in the flow field, injury and the prosthetic nature of the conduit. This study was designed to examine the relative contribution of wall shear stress and injury to the induction of IHT at defined regions of experimental end-to-side prosthetic anastomoses. METHODS AND RESULTS: The distribution of IHT was determined at the distal end-to-side anastomosis of seven canine Iliofemoral PTFE grafts after 12 weeks of implantation. An upscaled transparent model was constructed using the in vivo anastomotic geometry, and wall shear stress was determined at 24 axial locations from laser Doppler anemometry measurements of the near wall velocity under conditions of pulsatile flow similar to that present in vivo. The distribution of IHT at the end-to-side PTFE graft was determined using computer assisted morphometry. IHT involving the native artery ranged from 0.0+/-0.1 mm to 0.05+/-0.03 mm. A greater amount of IHT was found on the graft hood (PTFE) and ranged from 0.09+/-0.06 to 0.24+/-0.06 mm. Nonlinear multivariable logistic analysis was used to model IHT as a function of the reciprocal of wall shear stress, distance from the suture line, and vascular conduit type (i.e. PTFE versus host artery). Vascular conduit type and distance from the suture line independently contributed to IHT. An inverse correlation between wall shear stress and IHT was found only for those regions located on the juxta-anastomotic PTFE graft. CONCLUSIONS: The data are consistent with a model of intimal thickening in which the intimal hyperplastic pannus migrating from the suture line was enhanced by reduced levels of wall shear stress at the PTFE graft/host artery interface. Such hemodynamic modulation of injury induced IHT was absent at the neighboring artery wall.     

Longitudinal movements and resulting shear strain of the arterial wall

There has been little interest in the longitudinal movement of the arterial wall. It has been assumed that this movement is negligible compared with the diameter change. Using a new high-resolution noninvasive ultrasonic method, we measured longitudinal movements and diameter change of the common carotid artery of 10 healthy humans. During the cardiac cycle, a distinct bidirectional longitudinal movement of the intima-media complex could be observed in all the subjects. An antegrade longitudinal movement, i.e., in the direction of blood flow, in early systole [0.39 mm (SD 0.26)] was followed by a retrograde longitudinal movement, i.e., in the direction opposite blood flow [-0.52 mm (SD 0.27)], later in systole and a second antegrade longitudinal movement [0.41 mm (SD 0.33)] in diastole. The corresponding diameter change was 0.65 mm (SD 0.19). The adventitial region showed the same basic pattern of longitudinal movement; however, the magnitude of the movements was smaller than that of the intima-media complex, thereby introducing shear strain and, thus, shear stress within the wall [maximum shear strain between the intima-media complex and the adventitial region was 0.36 rad (SD 0.26). These phenomena have not previously been described. Measurements were also performed on the abdominal aorta (n = 3) and brachial (n = 3) and popliteal (n = 3) arteries. Our new information seems to be of fundamental importance for further study and evaluation of vascular biology and hemodynamics and, thus, for study of atherosclerosis and vascular diseases.     

Effects of arterial compliance and non-Newtonian rheology on correlations between intimal thickness and wall shear.

A minimally diseased (mean intimal thickness = 56 microns) human aortic bifurcation was replicated in rigid and compliant flow-through casts. Both casts were perfused with physiological flow waves having the same Reynolds and unsteadiness numbers; the pulse pressure in the compliant cast produced radial strains similar to those expected from post-mortem measurements of the compliance of the original tissue. The compliant cast was perfused with a Newtonian fluid and one whose rheology was closer to that of blood. Wall shear rate histories were estimated from near-wall velocities obtained by laser Doppler velocimetry at identical sites in both casts. Intimal thickness was measured at corresponding sites in the original vessel and linear regressions were performed between these thicknesses and several normalized shear rate measures obtained from the histories. The correlations showed a positive slope--that is, the intima was thicker at sites exposed to higher shear rates--consistent with earlier results for relatively healthy vessels, but their significance was often poor. There was no significant effect of either model compliance or fluid rheology on the slopes of the correlations of intimal thickness against any normalized shear rate measure.     

Cell-free layer and wall shear stress variation in microvessels

In this study, we simulated multiple red blood cells flowing through straight microvessels with the immersed-boundary lattice-Boltzmann model to examine the shear stress variation on the microvessel surface and its relation to the properties of cell-free layer. Significant variation in shear stress has been observed due to the irregular configuration of blood cells flowing near the microvessel wall. A low shear stress is typically found at locations where there is a cell flowing close to the wall, and a large shear stress at locations with a relatively wide gap between cell and wall. This relationship between the shear stress magnitude and the distance between cell and wall has been attributed to the reverse pressure difference developed between the front and rear sides of a cell flowing near the vessel wall. We further studied the effects of several hemodynamic factors on the variation of shear stress, including the cell deformability, the flow rate, and the aggregation among red blood cells. These simulations show that the shear stress variation is less profound in situations with wider cell-free layers, since the reverse pressure difference around the edge cells is less evident, and the influence of this pressure difference on wall shear stress becomes weaker. This study also demonstrates the complexity of the flow field in the gap between cell and wall. More precise experimental techniques are required accurately measure such shear stress variation in microcirculation.     

Effects of arterial wall stress on vasomotion

Smooth muscle and endothelial cells in the arterial wall are exposed to mechanical stress. Indeed blood flow induces intraluminal pressure variations and shear stress. An increase in pressure may induce a vessel contraction, a phenomenon known as the myogenic response. Many muscular vessels present vasomotion, i.e., rhythmic diameter oscillations caused by synchronous cytosolic calcium oscillations of the smooth muscle cells. Vasomotion has been shown to be modulated by pressure changes. To get a better understanding of the effect of stress and in particular pressure on vasomotion, we propose a model of a blood vessel describing the calcium dynamics in a coupled population of smooth muscle cells and endothelial cells and the consequent vessel diameter variations. We show that a rise in pressure increases the calcium concentration. This may either induce or abolish vasomotion, or increase its frequency depending on the initial conditions. In our model the myogenic response is less pronounced for large arteries than for small arteries and occurs at higher values of pressure if the wall thickness is increased. Our results are in agreement with experimental observations concerning a broad range of vessels.     

Unsteady wall shear stress in a distensible tube

An asymptotic expression of the wall shear stress (WSS) in an elastic tube is deduced for small values of the Womersley parameter. In the case of a rigid tube this asymptotic expression is shown to compare better with the exact solution than Poiseuille's or Lambossy's approximations. Its integration in a one-dimensional model of the internal carotid artery blood flow predicts more marked systolic and less marked diastolic WSS than those predicted by the commonly used Poiseuille's approximation.     

A mechanical model for morphological response of endothelial cells under combined wall shear stress and cyclic stretch loadings

The shape and morphology of endothelial cells (ECs) lining the blood vessels are a good indicator for atheroprone and atheroprotected sites. ECs of blood vessels experience both wall shear stress (WSS) and cyclic stretch (CS). These mechanical stimuli influence the shape and morphology of ECs. A few models have been proposed for predicting the morphology of ECs under WSS or CS. In the present study, a mathematical cell population model is developed to simulate the morphology of ECs under combined WSS and CS conditions. The model considers the cytoskeletal filaments, cell–cell interactions, and cell–extracellular matrix interactions. In addition, the reorientation and polymerization of microfilaments are implemented in the model. The simulations are performed for different conditions: without mechanical stimuli, under pure WSS, under pure CS, and under combined WSS and CS. The results are represented as shape and morphology of ECs, shape index, and angle of orientation. The model is validated qualitatively and quantitatively with several experimental studies, and good agreement with experimental studies is achieved. To the best of our knowledge, it is the first model for predicting the morphology of ECs under combined WSS and CS condition. The model can be used to indicate the atheroprone regions of a patient’s artery.     

The relationship between wall shear stress distributions and intimal thickening in the human abdominal aorta

Purpose

The goal of this work was to determine wall shear stress (WSS) patterns in the human abdominal aorta and to compare these patterns to measurements of intimal thickness (IT) from autopsy samples.

Methods

The WSS was experimentally measured using the laser photochromic dye tracer technique in an anatomically faithful in vitro model based on CT scans of the abdominal aorta in a healthy 35-year-old subject. IT was quantified as a function of circumferential and axial position using light microscopy in ten human autopsy specimens.

Results

The histomorphometric analysis suggests that IT increases with age and that the distribution of intimal thickening changes with age. The lowest WSS in the flow model was found on the posterior wall inferior to the inferior mesenteric artery, and coincided with the region of most prominent IT in the autopsy samples. Local geometrical features in the flow model, such as the expansion at the inferior mesenteric artery (common in younger individuals), strongly influenced WSS patterns. The WSS was found to correlate negatively with IT (r² = 0.3099; P = 0.0047).

Conclusion

Low WSS in the abdominal aorta is co-localized with IT and may be related to atherogenesis. Also, rates of IT in the abdominal aorta are possibly influenced by age-related geometrical changes.