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We tested the hypotheses that vascular cell adhesion molecule-1 (VCAM-1) expression on endothelium at lesion-prone sites in the rabbit aorta correlates with exposure to plasma cholesterol and that macrophage accumulation is associated with endothelial cells expressing VCAM-1. After rabbits were fed 0.25% cholesterol for 2 weeks, VCAM-1 expression was selectively increased at the distal and lateral portions of the major abdominal branches. In the arch and the celiac, superior mesenteric, and renal artery branches, VCAM-1 expression was positively correlated with the plasma cholesterol integrated over the duration of the experiments. After 2 weeks of cholesterol feeding, more macrophages were present around distal and lateral portions of the intercostal arteries and major abdominal branches relative to nonbranch regions. In the arch and around the intercostals and major abdominal branches, macrophage densities were positively correlated with the integrated plasma cholesterol. VCAM-1 and macrophage levels were correlated in lesion-prone regions. In normocholesterolemic rabbits, 23+/-4% (mean+/-SEM) of the macrophages were directly associated with VCAM-1-positive endothelium. After 2 weeks of 0.25% cholesterol feeding, the association increased to 37+/-4% (P<0.015). Associations were highest around the lateral and distal regions of the major abdominal branches. These results suggest that (1) VCAM-1 expression and intimal macrophage densities are influenced by plasma cholesterol and regional factors such as arterial fluid dynamics and (2) VCAM-1 plays a significant role in the localization of macrophages.

Macrophages play an important role in atherogenesis and have been reported within the intima at lesion-prone sites in normocholesterolemic animals as well as infants and children. The objective of this study was to determine the spatial distribution of intimal white blood cells (WBC) in the normal rabbit aorta and the association of intimal WBC with replicating endothelial cells and sites of increased 125I-LDL permeability. Intimal WBC and macrophages were identified en face on whole aortic tissue and on Häutchen preparations based on their morphology, ingestion of exogenous horseradish peroxidase, non-specific esterase activity, and labeling with a monoclonal antibody for rabbit macrophages (RAM11). WBC were primarily located in the lesion-prone flow divider regions of the large abdominal branch arteries. Using [3H]thymidine autoradiography to determine cell proliferation, 4.4% of the WBC and 0.12% of the endothelial cells were labeled on the Häutchen preparations. The distribution of replicating endothelial cells was not localized to the arterial orifices and was not correlated with the distribution of intimal WBC. Intimal WBC were, however, spatially correlated with the distribution of 125I-LDL permeable sites about the celiac artery orifice and were directly associated with 31% of the LDL permeable spots. Moreover, mitotic endothelial cells accounted for only 8% of the total number of LDL permeable sites. The presence of intimal WBC at lesion-prone sites in the normocholesterolemic rabbit suggests that these cells may be important in the initiation of atherosclerotic lesions.

En face autoradiography of the endothelium was used to quantify the distribution, area, and permeability of sites with enhanced permeability to 125I-low-density lipoprotein (125I-LDL) around the intercostal and celiac arteries and at the iliac bifurcation of normal rabbit aortas. The density of such sites was highest in the upper thoracic aorta and around the celiac and superior mesenteric branches and was lowest in the lower abdominal aorta. Permeable sites occurred more frequently distal to the intercostal branch orifices and both lateral and distal to the orifice at the celiac branch. At the intercostal branch orifices, these sites were larger, with a lower permeability and higher frequency than those away from the branch. At the celiac flow divider, sites of elevated autoradiographic grain density were more permeable and larger than at other locations in the abdominal aorta. Mean regional permeabilities were obtained by weighted area averages of low- and high-permeability sites. Mean regional permeabilities around the intercostal branches were 1.5 times higher than values away from the intercostal branches. Within 0.25 and 1 mm away from the celiac flow divider, mean regional permeability was 3.1 and 1.3 times higher, respectively, than those away from the flow divider. Few sites of elevated permeability were found distal to the aortoiliac bifurcation, and the permeabilities at the medial and lateral walls of the iliac arteries were not different. Mitotic cells were associated with 13 +/- 8% of all sites with elevated permeability to 125I-LDL. The frequency of mitotic endothelial cells was not increased at branch sites, suggesting that mechanisms other than cell replication were responsible for increased LDL permeability in the rabbit. These results suggest that the permeability and frequency of occurrence of sites with elevated permeability around the celiac and intercostal branches may influence the distribution and severity of early lesions in rabbits fed a hypercholesterolemic diet.