Atherosclerotic lesions are composed of a complex mixture of cell types that are engorged with lipid and enveloped in extracellular matrix elements. This manifestation probably results from imbalances in the cellular processing of cholesterol-delivering lipoproteins, changes in extracellular matrix deposition, and growth factor elaboration. One receptor class that could modulate these processes is LDL receptor-related protein/alpha(2)-macroglobulin receptors (LRP/alpha(2)-MR). Consequently, the presence of LRP/alpha(2)-MR was determined on a temporal basis in lesions of distinct morphologies that were developed in cholesterol-fed New Zealand and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. The two strains of rabbits developed similar degrees of hypercholesterolemia in response to 0.5% wt/wt cholesterol in their diet. Lipoprotein-cholesterol distribution was also similar in the two strains. Aortic intimal areas covered by grossly discernible atherosclerotic lesions were extensive and not statistically different between the strains. Despite the similarities in the extent of hypercholesterolemia, lipoprotein distribution, and extent of atherosclerosis, the cellularity of the lesions formed was different in the two groups. Atherosclerotic lesions in cholesterol-fed New Zealand rabbits were uniformly rich in macrophages and deficient in smooth muscle cells, as determined by immunocytochemical staining with the cell-specific monoclonal antibodies RAM-11 and HHF-35. In contrast, atherosclerotic lesions formed in cholesterol-fed heterozygous WHHL rabbits covered a spectrum ranging from macrophage-rich lesions to those predominantly composed of disaggregated smooth muscle cells that were embedded in dense layers of extracellular matrix. Immunocytochemical detection of LRP/ alpha(2)-MR with the monoclonal antibody 5A6B6 demonstrated that the protein was strongly localized to macrophages of atherosclerotic lesions. The expression of LRP/alpha(2)-MR mRNA was determined by nuclease protection assay. Relative abundance of LRP/alpha(2)-MR mRNA in aortic tissue increased modestly during cholesterol feeding. Given the diverse ligand specificity of LRP/alpha(2)-MR, its presence within atherosclerotic tissue may contribute to the evolution of lesion morphology.
