Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries.

Abstract

We asked if the arterial sites most prone to early lesions in cholesterol-fed rabbits have higher permeabilities to low density lipoprotein (LDL) in normolipidemic rabbits or if these sites become more permeable shortly after the onset of cholesterol feeding. We also considered whether the focal increases in the concentration of LDL within the arterial wall in lesion-susceptible sites before fatty streak formation can be explained by increased arterial permeability to LDL or by other mechanisms such as decreased rates of LDL efflux or degradation. 125I-tyramine cellobiose-labeled LDL was injected 1 hour before death to determine the initial rate of LDL entry into lesion-prone and lesion-resistant sites of aorta as a measure of permeability. This was studied in normal rabbits and in rabbits fed cholesterol for 4, 8, or 16 days. Combining this permeability data with the tracer data described in the accompanying article, we fit a kinetic model to calculate the mass and mean residence time of intact LDL within the artery and the fractional rates of LDL degradation and efflux from the artery. In normal rabbits, the permeability of lesion-susceptible branch sites of the abdominal aorta was about four times that of the lesion-resistant, nonbranched areas. However, the permeability of the aortic arch, a susceptible site, was similar to that of the lesion-resistant descending thoracic aorta. Permeability to LDL did not increase in any aortic site during the 16 days of cholesterol feeding, even in sites with the largest increases in arterial LDL concentrations. Plasma LDL cholesterol concentration increased substantially and total LDL cholesterol delivery into the artery increased many fold. Since there was no differential change in permeability between susceptible and resistant sites, the increased entry of LDL did not explain the selective increases in arterial LDL concentration in susceptible sites. Kinetic analysis indicated that the fractional rate of degradation of the arterial LDL pool was lower in lesion-prone sites than in lesion-resistant sites in all animals. Fractional rates of efflux of arterial LDL decreased in lesion-susceptible branch sites of the abdominal aorta and were low in the lesion-susceptible aortic arch. These results suggest that the focal increases in LDL concentration observed in all lesion-susceptible sites of cholesterol-fed rabbits before fatty streak formation are due to localized differences in LDL retention and diminished fractional rates of LDL degradation, not to selectively increased permeability.(ABSTRACT TRUNCATED AT 400 WORDS)