Concentration Polarization Of Low-density Lipoproteins Research Articles

The counterbalance of endothelial glycocalyx and high wall shear stress to low-density lipoprotein concentration polarization in mouse ear skin arterioles

Background and aimsAtherosclerosis preferentially occurs at regions in arterial branching, curvature, and stenosis, which may be explained by the geometric predilection of low-density lipoprotein (LDL) concentration polarization that has been investigated in major arteries in previous studies. Whether this also happens in arterioles remains unknown. MethodsHerein, a radially non-uniform distribution of LDL particles and a heterogeneous endothelial glycocalyx layer in the mouse ear arterioles, as shown by fluorescein isothiocyanate labeled wheat germ agglutinin (WGA-FITC), were successfully observed by a non-invasive two-photon laser-scanning microscopy (TPLSM) technique. The stagnant film theory was applied as the fitting function to evaluate LDL concentration polarization in arterioles. ResultsThe concentration polarization rate (CPR, the ratio of the number of polarized cases to that of total cases) in the inner walls of curved and branched arterioles was 22% and 31% higher than the outer counterparts, respectively. Results from the binary logistic regression and multiple linear regression analysis showed that endothelial glycocalyx thickness increases CPR and the thickness of the concentration polarization layer (CPL). Flow field computation indicates no obvious disturbances or vortex in modeled arterioles with different geometries and the mean wall shear stress is about 7.7–9.0 Pa. ConclusionsThese findings suggest a geometric predilection of LDL concentration polarization in arterioles for the first time, and the existence of an endothelial glycocalyx, acting together with a relatively high wall shear stress in arterioles, may explain to some extent why atherosclerosis rarely occurs in these regions.

Transfer of Low-Density Lipoproteins in Coronary Artery Bifurcation Lesions with Stenosed Side Branch: Numerical Study.

Evidence from clinical data suggests that the stenotic side branch (SB) is one of the key predictors for SB occlusion-based adverse events. In this study, we hypothesized that coronary bifurcations with stenotic SB might lead to severe concentration polarization of atherogenic lipids, such as the low-density lipoproteins (LDL), motivating the adverse events in the clinic. To confirm this hypothesis, this work numerically investigated the transport of LDL in different bifurcation lesions based on the Medina classification with various location and stenosis severities. The results showed that the coronary bifurcations with stenotic SB might be suffering more serious concentration polarization of LDL on the luminal surface of the SB due to higher level of LDL concentrations. Moreover, compared to the other bifurcation lesion types, the type (1,0,1) had the highest luminal surface LDL concentration along the SB and the highest degree of risk to enhance the process of atherosclerosis. In addition, this study also showed that the luminal surface LDL concentration increased with elevated stenosis severity. The type (1,0,1) with the severe stenosis (75% diameter reduction) had the highest concentration at the SB. In conclusion, these results suggested that both location of lesions and stenosis severities had great influence on the distribution of LDL on the luminal surface of the SB. Therefore, the estimation of disease severity and the interventional therapy should be carried out not only according to the stenosis severities in clinic. Moreover, compared to the other bifurcation lesion types, the type (1,0,1), rather than the type (1,1,1) as usually considered, had the highest luminal surface LDL concentration along the SB and the highest degree of risk to enhance the process of atherosclerosis.

Numerical simulation of low-density lipoprotein mass transport in human arterial stenosis - Calculation of the filtration velocity.

Accumulation of cholesterol and other atherogenic lipids such as low-density lipoprotein (LDL) in artery wall causes reduction of vessel diameter and artery stenosis. The study of the mass transfer of these large molecules in the wall with considering effective factors on lumen flow and different physiological factors is the subject considered nowadays. In this paper, results of two dimensional and axi-symmetric simulations of three different models of the artery with 60% stenosis under pulsatile blood flow are presented. Filtration velocity of LDL mass transport in the permeable artery wall and shear stress of blood flow are investigated using ADINA software Three different flow models are considered. In the first and second models, the filtration velocity considered as a given parameter and constant in arterial wall boundary, while in third model arterial wall considered as porous wall, the filtration velocity is calculated from pressure difference as an input parameter of the model. The results show that filtration velocity is strongly depend on geometry and it is not constant along the wall, contrary to simplified models. The results of concentration variations in lumen and wall illustrate the increase in near wall LDL concentration or concentration polarization.

Analysis of flow and LDL concentration polarization in siphon of internal carotid artery: Non-Newtonian effects

Carotid siphon is known as one of the risky sites among the human intracranial arteries, which is prone to formation of atherosclerotic lesions. Indeed, scientists believe that accumulation of low density lipoprotein (LDL) inside the lumen is the major cause of atherosclerosis. To this aim, three types of internal carotid artery (ICA) siphon have been constructed to examine variations of hemodynamic parameters in different regions of the arteries. Providing real physiological conditions, blood considered as non-Newtonian fluid and real velocity and pressure waveforms have been employed as flow boundary conditions. Moreover, to have a better estimation of risky sites, the accumulation of LDL particles has been considered, which has been usually ignored in previous relevant studies. Governing equations have been discretized and solved via open source OpenFOAM software. A new solver has been built to meet essential parameters related to the flow and mass transfer phenomena. In contrast to the common belief regarding negligible effect of blood non-Newtonian behavior inside large arteries, current study suggests that the non-Newtonian blood behavior is notable, especially on the velocity field of the U-type model. In addition, it is concluded that neglecting non-Newtonian effects underestimates the LDL accumulation up to 3% in the U-type model at the inner side of both its bends. However, in the V and C type models, non-Newtonian effects become relatively small. Results also emphasize that the outer part of the second bend at the downstream is also at risk similar to the inner part of the carotid bends. Furthermore, from findings it can be implied that the risky sites strongly depend on the ICA shape since the extension of the risky sites are relatively larger for the V-type model, while the LDL concentrations are higher for the C-type model.

Enhanced accumulation of LDLs within the venous graft wall induced by elevated filtration rate may account for its accelerated atherogenesis

ObjectiveTo test the hypothesis that the venous graft when implanted in an arterial bypass might endure a significantly elevated water filtration rate, leading to fast infiltration/accumulation of low-density lipoproteins (LDLs) within the graft wall and hence the accelerated atherogenesis. MethodsWe measured filtration rates of the swine femoral artery and lateral saphenous vein under venous and arterial hemodynamic conditions in vitro. Based on the measured filtration rates, we numerically simulated LDL transport in an arterial bypass model with a venous graft. Moreover, in order to validate the theoretical prediction, we measured DiI-LDLs uptake by both arteries and veins under arterial condition. ResultsThe experimental results showed that when subjected to arterial hemodynamic condition, the filtration rate of the venous wall was increased sharply, and significantly higher than that of the artery. Moreover, different from the hydraulic conductivity of artery, the venous one would increase with increasing pressure. The numerical results showed that for the venous graft, both luminal surface LDL concentration and LDL accumulation within the vessel wall were significantly higher than those for the host artery. In addition, the experiment, which was used to confirm theoretical prediction, showed that the amount of DiI-LDLs uptake by the venous wall was much higher compared with arterial wall. ConclusionThe present study suggests that the accelerated atherogenesis of the venous graft is attributable to its elevated filtration rate that may lead to both aggravated concentration polarization of LDLs and enhanced convective transport of LDLs into the graft wall.

In vitro and in vivo investigations on the effects of low-density lipoprotein concentration polarization and haemodynamics on atherosclerotic localization in rabbit and zebrafish

Atherosclerosis (AS) commonly occurs in the regions of the arterial tree with haemodynamic peculiarities, including local flow field disturbances, and formation of swirling flow and vortices. The aim of our study was to confirm low-density lipoprotein (LDL) concentration polarization in the vascular system in vitro and in vivo, and investigate the effects of LDL concentration polarization and flow field alterations on atherosclerotic localization. Red fluorescent LDL was injected into optically transparent Flk1: GFP zebrafish embryos, and the LDL distribution in the vascular lumen was investigated in vivo using laser scanning confocal microscopy. LDL concentration at the vascular luminal surface was found to be higher than that in the bulk. The flow field conditions in blood vessel segments were simulated and measured, and obvious flow field disturbances were found in the regions of vascular geometry change. The LDL concentration at the luminal surface of bifurcation was significantly higher than that in the straight segment, possibly owing to the atherogenic effect of disturbed flow. Additionally, a stenosis model of rabbit carotid arteries was generated. Atherosclerotic plaques were found to have occurred in the stenosis group and were more severe in the stenosis group on a high-fat diet. Our findings provide the first ever definite proof that LDL concentration polarization occurs in the vascular system in vivo. Both lipoprotein concentration polarization and flow field changes are involved in the infiltration/accumulation of atherogenic lipids within the location of arterial luminal surface and promote the development of AS.

Upregulation of SDF-1 is Associated with Atherosclerosis Lesions Induced by LDL Concentration Polarization

Previous numerical simulations on low-density lipoprotein (LDL) concentration polarization in the arterial system indicated that LDL concentration polarization might play an important role in the genesis and development of atherosclerosis. To date, no in vivo experiments have examined this question directly, and the molecular mechanisms are unknown. In this study, ten rabbits were treated with gel-silica loop to develop a defined local stenosis in the straight segment of the left carotid artery. Both numerical simulation and experiment measurements showed that the concentration of LDL was about 35% higher at the blood/arterial wall interface than in the lumen on the distal side of the stenosis. Atherosclerotic lesions with abundant lipid deposits were observed and stromal derived factor-1 (SDF-1) was detected at the distal end of the stenosis, while the straight segment was plaque-free. In vitro studies demonstrated that LDL-induced SDF-1 expression in endothelial cells and increased monocyte adhesion to endothelial cells in a dose-dependent manner. The adhesion was suppressed when endothelial cells were pretreated with SDF-1 antibody. These results suggested LDL concentration polarization contributed to the localization of atherosclerosis and to the expression of SDF-1. In turn, SDF-1 facilitated plaque formation.

Compositional or charge density modification of the endothelial glycocalyx accelerates flow-dependent concentration polarization of low-density lipoproteins

We hypothesized that diminished endothelial glycocalyx (GCX) at atherosclerotic lesion-prone sites accelerates flow-dependent concentration polarization of low-density lipoproteins (LDLs) at the luminal surface, and in turn contributes to vulnerability of these sites to atherosclerosis. A parallel plate flow chamber was applied to expose cultured endothelial monolayers to three different levels of shear stress (3, 12, 20 dyn/cm(2)). Heparinase III (Hep.III) was employed to degrade heparan sulfate proteoglycans selectively and 3-(N-morpholino) propanesulfonic acid-buffered physiological salt solutions (MOPS-PSS) were used at either normal ionic strength (Normal-MOPS), low ionic strength (LO-MOPS) or high ionic strength (HI-MOPS) to modify the effective charge density of the endothelial GCX. Water filtration velocity (V(w)) across the endothelial monolayer, the luminal concentration of LDLs (C(w)) and the uptake of LDLs by endothelial cells were measured and compared among the following five groups of cells: (1) Control; (2) Hep.III treatment; (3) LO-MOPS; (4) Normal-MOPS; and (5) HI-MOPS. The results obtained substantiated the aforementioned hypothesis and demonstrated that compositional or charge density modification of the endothelial GCX facilitated water filtration across the endothelium, enhanced the accumulation of LDLs on the luminal surface and increased the uptake of LDLs by endothelial cells, therefore contributing to atherogenesis.

3,3′-Dioctadecylindocarbocyanine-low-density lipoprotein uptake and flow patterns in the rabbit aorta–iliac bifurcation under three perfusion flow conditions

The aim of this study was to elucidate which of the following two factors plays a more important role in the localization of atherogenesis: the barrier function of the arterial endothelium modulated by wall shear stress or flow-dependent low-density lipoprotein (LDL) concentration at the blood/wall interface. To determine this, the rabbit aorto-iliac bifurcation was perfused with 3,3'-dioctadecylindocarbocyanine (DiI)-LDL solution under three different flow conditions: (i) forward flow (perfused in the in vivo flow direction); (ii) backward flow (perfused in a reversed flow direction); and (iii) static group (no flow). The results showed that there was a peak in the curve of DiI-LDL uptake distribution along the lateral wall of the bifurcation for all three groups, which was located in the branching areas where the endothelial cells were round and polygonal with no preferred orientation. Nevertheless, the peak of the forward flow group was much sharper than those of the other two groups. The overall DiI-LDL uptake was the highest for the static group. The present experimental study supports the concept that both the barrier function of the endothelium modulated by wall shear stress and the mass transport phenomenon of LDL concentration polarization are involved in the infiltration/accumulation of atherogenic lipids within the arterial wall. Nevertheless, the latter might play a larger role in the localization of atherogenesis.

A numerical study on the flow of blood and the transport of LDL in the human aorta: the physiological significance of the helical flow in the aortic arch

It has been proposed that a mass transfer phenomenon called concentration polarization of low-density lipoproteins (LDLs) may occur in the arterial system and is likely involved in the localization of atherogenesis. To test the hypothesis that concentration polarization of LDL may be suppressed by the helical flow pattern in the human aorta, hence sparing the ascending aorta from atherosclerosis, the effects of aortic torsion, branching, curvature, and taper on blood flow and LDL transport in the lumen were simulated numerically under steady-state flow conditions using four aorta models constructed based on in vivo MRI slices. The results showed that it was the aortic torsion that induced the helical flow in the aortic arch, stabilizing the flow of blood in the aorta, and compensated the adverse effects of the aortic curvature on blood flow and LDL transport. The helical flow reduced the luminal surface LDL concentration in the aortic arch and probably played a role in suppressing severe polarization of LDL at the entrances of the three branches on the arch, hence, protecting them from atherogenesis. The taper of the aorta was another important feature of the aorta that further stabilized the flow of blood and delayed the attenuation of the helical flow, making it move beyond the arch and into the beginning part of the descending aorta. The results therefore may account for why the ascending aorta and the arch are relatively free of atherosclerosis.

The Effect of a Spatially Heterogeneous Transmural Water Flux on Concentration Polarization of Low Density Lipoprotein in Arteries

Uptake of low density lipoprotein (LDL) by the arterial wall is likely to play a key role in atherogenesis. A particular process that may cause vascular scale heterogeneity in the rate of transendothelial LDL transport is the formation of a flow-dependent LDL concentration polarization layer on the luminal surface of the arterial endothelium. In this study, the effect of a spatially heterogeneous transmural water flux (that traverses the endothelium only via interendothelial cell clefts) on such concentration polarization is investigated numerically. Unlike in previous investigations, realistic intercellular cleft dimensions are used here and several values of LDL diffusivity are considered. Particular attention is paid to the spatially averaged LDL concentration adjacent to different regions of the endothelial surface, as such measures may be relevant to the rate of transendothelial LDL transport. It is demonstrated in principle that a heterogeneous transmural water flux can act to enhance such measures, and cause them to develop a shear dependence (in addition to that caused by vascular scale flow features, affecting the overall degree of LDL concentration polarization). However, it is shown that this enhancement and additional shear dependence are likely to be negligible for a physiologically realistic transmural flux velocity of 0.0439 μm s−1 and an LDL diffusivity (in blood plasma) of 28.67 μm2 s−1. Hence, the results imply that vascular scale studies of LDL concentration polarization are justified in ignoring the effect of a spatially heterogeneous transmural water flux.

Effect of LDL concentration polarization on the uptake of LDL by human endothelial cells and smooth muscle cells co-cultured

To substantiate our hypothesis that concentration polarization of low-density lipoprotein (LDL) plays an important role in the localization of atherogenesis, we investigated the effects of wall shear stress and water filtration rate (or perfusion pressure) on the luminal surface LDL concentration (c(w)) and the LDL uptake by human vascular endothelial cells and smooth muscle cells co-cultured on a permeable membrane using a parallel-plate flow chamber technique and a flow cytometry method. The results indicated that the uptake of fluorescent labeled LDL (DiI-LDL) by the co-cultured cells was positively correlated with c(w) in a non-linear fashion. When c(w) was low, the uptake increased very sharply with increasing c(w). Then the increase became gradual and the uptake was seemingly leveled out when c(w) reached beyond 160 microg/ml. The present study therefore has provided further experimental evidence that concentration polarization may occur in the arterial system and have a positive correlation with the uptake of LDLs by the arterial wall, which gives support to our hypothesis regarding the localization of atherogenesis.

Theoretical prediction of low-density lipoproteins concentration at the luminal surface of an artery with a multiple bend.

To elucidate the mechanisms of localization of atherosclerotic lesions in man, the effects of various physical and hemodynamic factors on transport of atherogenic low-density lipoproteins (LDL) from flowing blood to the wall of an artery with a multiple bend were studied theoretically by means of a computer simulation under the conditions of a steady flow. It was found that due to a semipermeable nature of an arterial wall to plasma, flow-dependent concentration polarization of LDL occurred at the luminal surface of the vessel, creating a region of high LDL concentration distal to the apex of the inner wall of each bend where the flow was locally disturbed by the formation of secondary and recirculation flows and where wall shear stresses were low. The highest surface concentration of LDL occurred distal to the acute second bend where atherosclerotic intimal thickening developed. At a Re0=500, the values calculated using estimated diffusivities of LDL in whole blood and plasma were respectively 35.1% and 15.6% higher than that in the bulk flow. The results are consistent with our hypothesis that the localization of atherosclerotic lesions results from the flow-dependent concentration polarization of LDL which creates locally a hypercholesterolemic environment even in normocholesterolemic subjects, thus augmenting the uptake of LDL by vascular endothelial cells existing at such sites.

Coupled Computational Analysis of Arterial LDL Transport -- Effects of Hypertension

Hypertension, a risk factor for atherosclerosis, increases the uptake of low density lipoproteins (LDL) by the arterial wall. Our objective in this work was to use computational modeling to identify physical factors that could be partially responsible for this effect. Fluid flow and mass transfer patterns in the lumen and wall of an arterial model were computed in a coupled manner, replicating as closely as possible previous experimental studies in which LDL uptake into the artery wall was measured in straight, excised arterial segments. Under conditions of both flow and no-flow, simulations predicted an increase in concentration polarization of LDL at the artery wall when arterial pressure was increased from 120 to 160 mmHg. However, this led to only a slight increase in mean LDL concentration within the arterial wall. However, if the permeability of the endothelium to LDL was allowed to vary with intra-arterial pressure, then the simulations predicted that the uptake of LDL would be enhanced 1.9-2.6 fold at higher pressure. The magnitude of this increase was consistent with experimental data. We conclude that the concentration polarization effects, enhanced by elevated intra-arterial pressure, cannot explain the increase in LDL uptake seen under hypertensive conditions. Instead, the data are most consistent with a pressure-linked increase in endothelial permeability to LDL.

Bioengineering. The Effect of Creating a Moderate Stenosis on the Localization of Intimal Thickening in the Common Carotid Artery of the Rabbit Fed on a Cholesterol-Rich Diet.

The effect of a locally disturbed flow on intimal thickening was studied by creating a moderate axisymmetric stenosis (mean diameter reduction: 26%) in common carotid arteries of the rabbit and feeding a cholesterol-rich diet. In eight of nine specimens obtained from four rabbits, intimal thickening occurred at the distal side of the stenosis, mainly in a restricted region which extended from the apex of the stenosis to the distal end, the point of the maximum thickness locating approximately a half of the vessel diameter downstream of the apex of the stenosis. The result was compared with the distributions of wall shear stress and surface concentration of low-density lipoproteins (LDL) which were calculated using a theoretical model of blood flow and LDL transport through the stenosed artery. It was found that the site of intimal thickening well corresponded to the region where wall shear stress was relatively low and surface concentration of LDL was locally elevated. These results suggest that blood flow plays an important role in the localized pathogenesis and development of intimal thickening by locally augmenting concentration polarization of LDL at a blood/endothelium boundary.

Experimental Demonstration of Flow-Dependent Concentration Polarization of Plasma Proteins at a Blood/Endothelium Boundary by Optically Measuring the Concentration Profile of Flowing Microspheres through a Straight Tube with a Semipermeable Wall.

It is we11 accepted that hemodynamics plays an important role in atherogenesis in man. However, the precise mechanisms have not been elucidated yet. Recently, Karino et al. hypothesized that flow-dependent concentration polarization of low-density lipoproteins (LDL) may occur at a blood / endothelium boundary, leading to a high risk of atherogenesis in regions of low wall shear rate where the concentration of LDL builds up. In this study, we attempted to experimentally confirm their predictions by optically measuring the concentration profile of polystyrene latex microspheres in a suspension flowing through a dialysis tube. It was found that the surface concentration of microsphere certainly increases with decreasing the flow rate and it occurs even under the condition of a very low water filtration velocity encountered in normal arteries in vivo, giving a strong support to the hypothesis proposed by Karino et al.