Development of atherosclerotic plaque with endothelial disruption in Watanabe heritable hyperlipidemic rabbit aortas

To better understand the morphogenesis of atherosclerotic plaque, we evalua ted temporal distribution of leukocytes, macrophages, foam cells, vascular smooth muscle cells, and subendothelial lipid in Watanabe heritable hyperli pedimic (WHHL) rabbit aortas. Aortas of WHHL (n = 20) and New Zealand White (NZW, controls; n = 8) rabbits were perfusion fixed at 1, 3, 6, and 12 mon ths of age. At initial gross evaluation of lipid distribution, we identifie d aortic areas at high risk for lesion development. ln WHHL rabbits, the li pid-positive portion of high-risk areas increased from 3% at 1 month to 50% at 12 months; during the same period, adherent cell count increased from < 1 leukocyte and monocyte/mm(2) to 25 leukocytes, 44 monocytes, and 10 foam cells/mm(2). Controls showed no increase over time in lipid-positive areas or cellular adherence to the endothelium. One-month-old WHHL rabbit aortas had scattered lipid-positive cells in the intima (primarily branch points) . Immunostaining of these areas did not show rabbit macrophages (RAM antibo dy) but were actin positive. Occasionally, platelets and monocytes adhered to the endothelial surface. By age 3 months, well-defined fatty streaks/ath erosclerotic plaques had RAM-positive cells within foam cell core, along co re margins, and in focal clusters in the fibrous cap and subendothelium. By age 12 months, isolated RAM-positive cells were on the endothelial surface , and surface morphology showed endothelial cell disruption foci containing clusters of macrophages and foam cells. Our results indicate that lipid ac cumulation (extra- and intracellular) is important in the early development of atherosclerotic lesions; a corresponding, slower accumulation of adhere nt cells on the lesion surface promotes lipid conversion from fatty streak to plaque. (C) 2001 Elsevier Science Inc. All rights reserved.