Differential accumulation of intimal monocyte-macrophages relative to lipoproteins and lipofuscin corresponds to hemodynamic forces on cardiac valves in mice

Abstract

We have studied the distribution of monocyte-macrophages, lipids, and lipoproteins in sections of aorta and aortic valves from mice fed an atherogenic diet. By immunocytochemical analysis with Mac-1 and F4/80 antibodies, apolipoprotein B antibody, and oil red O staining, three discrete regions were identified: 1) the aortic wall of the sinus of Valsalva, which contained deposits of lipid that colocalized with lipoproteins and monocyte-macrophages; 2) the sides of the aortic valve leaflets facing the ventricle, which did not contain lipids or lipoproteins but which were lined with macrophages that colocalized with lipofuscin; and 3) the sides of the leaflets facing the aorta, which did not contain lipids, lipoproteins, monocyte-macrophages, or lipofuscin deposits. This pattern of distribution resembles the expected distribution of mechanical forces, especially those of systolic blood flow, which in the three areas are predominantly 1) low-shear disturbed flow, 2) high-shear laminar flow, and 3) low-shear laminar flow, respectively. These findings suggest that lesions in the mouse closely resemble early atherosclerotic lesions in humans and other primates with respect to monocyte-macrophage and lipoprotein accumulation. The results also strikingly demonstrate that the accumulation of monocyte-macrophages and lipoproteins can occur independently, with spatial differences corresponding to the distribution of hemodynamic forces.