Quantifying barriers to macromolecular transport in the arterial wall

Atherosclerosis is characterized by the abnormal accumulation of blood-borne macromolecules, viz., low density lipoprotein (LDL) in the arterial intima, which is bounded by the endothelial cell layer (ECL) and internal elastic lamina (IEL). Quantifying the ECL and IEL transport barriers is essential to determine the basis for macromolecule accumulation in the intima. Mathematical models based on dynamic mass balances describe macromolecular transport and concentration distributions across the arterial wall. In the normal arterial wall, ECL is the major barrier for macromolecular transport.; To determine if decreased IEL permeability precedes lesion development, HRP was injected in C57BL/6J WT mice and ApoE-null mice at 3 and 5 months of age. Optimal estimates of ECL and IEL permeabilities in lesion free areas of the thoracic and abdominal aortas were found that minimize the differences between model simulated and measured HRP concentration distributions. IEL permeabilities of the thoracic and abdominal aortas decreased between 3 to 5 months of age in ApoE-null mice, which contributes to macromolecule accumulation in the intima. Optimal estimates of the IEL permeability were obtained of the greater and lesser curvature of the aortic arch. The IEL permeability in the lesser curvature of the aortic arch was significantly decreased in comparison to that in the greater curvature. These data suggest that atherogenesis involves the pathological remodeling of the IEL, not the endothelium prior to lesion development.; In advanced atherosclerotic lesions, vascular remodeling exacerbates the disease progression and is believed to be associated with change in the integrity of the ECL. Arterial tissue samples were organized into subgroups according to the thickness ratio of intima to media (TR) from ApoE-null mice at 5 months and 1 year. At both ages, the ECL permeability of lesion areas with TR≥0.5 was approximately twice that compared to lesion areas with TR<0.5. Whereas the IEL permeability in 5-month old was inversely related to TR, it was independent of TR in 1-year old mice. These data support the concept that atherosclerosis involves continuous pathological remodeling of the ECL and IEL and that lesion growth is associated with progressive changes in the barrier functions of distinct layers.