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

Abstract

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.

Zebrafish models of dyslipidemia: relevance to atherosclerosis and angiogenesis

“…Furthermore, the LDL concentration at the artery bifurcations, where lipid deposits tend to accumulate, was significantly elevated compared to the linear areas of the vasculature. Consistent with our findings, the injected DiI-LDL accumulated in the caudal vein 3 days after injection [28]. …”

“…Xie et al injected a red fluorescent DiI-LDL into flk1:EGFP embryos and recorded the hemodynamics of the injected LDL using a laser scanning confocal microscope [28]. The authors found that the concentration of LDL was increased at the vascular wall compared to the center of the lumen, suggesting a polarized LDL distribution.…”

Rear actomyosin contractility-driven directional cell migration in three-dimensional matrices: a mechano-chemical coupling mechanism

“…In previous works, we demonstrated the important contribution to cell migration and adhesion by cytoskeletal reorganization associated with focal adhesions assembly when the cells overexpressed Id1 [14], stimulated by various concentrations of oxLDLs (oxidized low-density lipoprotein) at static conditions [15 -17], placed on surfaces with different degrees of wettability [18,19] or LDL treatment under shear stress [20,21]. It is well established that cells use actin polymerization coupled with integrin-mediated adhesion to generate lamellipodial protrusions at the cell front to migrate on two-dimensional substrates [2].…”

Endothelial biocompatibility and accumulation of SPION under flow conditions

“…We therefore investigated if nanoparticle accumulation is spontaneously increased in the non-uniform shear stress region in vitro, as described for the spontaneous in vivo accumulation of LDL particles in these regions [14]. For this purpose, we seeded the endothelial cells in the bifurcating flow-through cell culture slides, which simulate the non-uniform shear stress gradient at arterial bifurcations [12].…”