Permeability change of arterial endothelium is an age-dependent function of lesion size in apolipoprotein E-null mice

Abstract

The remodeling process of the arterial wall in atherosclerosis involves intimal thickening, which can be related to the barrier functions of the endothelial cell layer (ECL) and internal elastic lamina (IEL) using horseradish peroxidase (HRP) as a tracer. To evaluate the ECL and IEL permeabilities ( PECL and PIEL, respectively) and intimal transport parameters, e.g., apparent HRP velocity ( VI) and diffusivity, we compared simulations with a mathematical model to experimental data. In this study, we injected HRP into the vein of apolipoprotein E-null mice and measured HRP concentration profiles in lesioned areas of aortas. Lesion size was characterized by lower, middle, and upper ranges of the intimal/medial thickness (δI/δM): 0 < δI/δM ≤ 0.5, 0.5 < δI/δM ≤ 1.0, and δI/δM > 1.0. The PECL (in micrometers per minute) of 5-mo-old mice in the middle range (0.98 ± 0.14) was significantly greater than that in the lower range (0.21 ± 0.03) but not significantly different from mice in the upper range (0.99 ± 0.55). The PECL of 12-mo-old mice increased significantly with the relative intimal thickness: 0.27 ± 0.04 in the lower range, 1.12 ± 0.15 in the middle range, and 1.74 ± 0.24 in the upper range. In both age groups, VI (in micrometers per minute) increased significantly from lower to upper ranges of intimal thickness. However, PIEL did not change significantly with relative intimal thickness and age. In the upper range of intimal thickness, PECL and VI were significantly greater in 12-mo-old mice than in 5-mo-old mice. These data indicate an interaction between lesion growth and aging that leads to progressive loss in the integrity of the endothelial barrier function. Furthermore, the IEL is not a significant barrier between the intima and tunica media in the atherosclerotic process.