Pathology of atheromatous lesions in inbred and genetically engineered mice. Genetic determination of arterial calcification.

Abstract

We report comprehensive pathological studies of atheromatous lesions in various inbred mouse strains fed a high-fat, high-cholesterol diet and in two genetically engineered strains that develop spontaneous lesions on a low-fat chow diet. Coronary and aortic lesions were studied with respect to anatomic locations, lesion severity, calcification, and lipofuscin deposition. Surprisingly, the genetic determinants for coronary fatty lesion formation differed in part from those for aortic lesion development. This suggests the existence of genetic factors acting locally as well as systemically in lesion development. We used immunohistochemical analyses to determine the cellular and molecular compositions of the lesions. The aortic lesions contained monocyte/macrophages, lipid, apolipoprotein B, serum amyloid A proteins, and immuno-globulin M and showed expression of vascular cell adhesion molecule-1 and tumor necrosis factor-a, all absent in normal arteries. In certain strains, advanced lesions developed in T he mouse is being increasingly used as a model for the study of atherosclerosis and its risk factors. 1 The model has two unique advantages among mammals. First, the mouse is the most useful mammal for genetic studies. In particular, many inbred strains exhibiting genetic variations relevant to lipoprotein metabolism and atherosclerosis have been identified. 213 Also, a complete linkage map including many highly polymorphic markers has been constructed in the mouse, making genetic analysis feasible for even multigenic traits. 114 Second, techniques for genetic modification in vivo, including construction of transgenic and gene-targeted animals, are much more advanced in the mouse than any other mammal. Such genetic modification has proved particularly useful for analysis of interactions between lipoprotein metabolism and atherosclerosis. 1536 Methods for the quantitative pathological analysis of diet-induced atherosclerosis in the mouse model have been developed. 37 Although these methods have revealed dif-which smooth muscle cells were commonly observed. The lesions in mice targeted for a null mutation in the apolipopro-tein E gene were much larger, more widely dispersed, and more fibrous, cellular, and calcified in nature than the lesions in laboratory inbred strains. When apolipoprotein A-II trans-genic mice were maintained on a low-fat chow diet, the lesions in these mice were relatively small and located in the very proximal regions of the aorta. There were clear differences in the occurrence of arterial wall calcification among genetically distinct inbred mouse strains, indicating for the first time a genetic component in this clinically significant trait. Analysis of a genetic cross indicated a complex pattern of calcification inheritance with incomplete penetrance. (Arterioscler Thromb. 1994;14:1480-1497.) Key Words • apolipoproteins • adhesion molecules • atherosclerosis • calcification • genetics ferences in susceptibility to diet-induced atherosclerosis of the aorta in a variety of inbred strains, there...

osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification

“…Genetic studies looking at engineered and inbred strains of mice indicate that aortic calcification is likely regulated by two or more genetic components (Qiao et al 1994). Matrix GLA protein (MGP), an extracellular matrix mineral binding protein, has been implicated as one possible genetic determinant of arterial calcification.…”

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

“…After 4 weeks, the heart tissue was collected as described (8). Methods for determining arterial calcification, aortic aneurysms, and atherosclerotic lesions, were described (35,36). For further information, see SI Methods.…”

The emergence of mouse models of atherosclerosis and their relevance to clinical research

“…ApoE is an important ligand for the uptake of lipoproteins by many receptors in the LDL receptor gene family, and deficiency of apoE leads to the accumulation of cholesterol ester [19,41,43]. However, plaque rupture and thrombosis is not seen in this model.…”

“…C57BL/6J mice fed the diet for 14 weeks or 9 months had lesions covering only 1 or 8% of the descending aorta, respectively [16]. When the aortic root lesions of mice fed the Paigen diet for 15-22 weeks were studied histologically, they were found to be similar to human early fatty streaks, consisting of primarily macrophage foam cells, without evidence, or with only minimal, intimal smooth muscle cells and fibrous cap formation [17][18][19]. In addition, aortic root calcification was sometimes observed to be associated with these fatty lesions [19].…”

“…The lesions of the apoE-deficient mouse also contain the same types of cells seen in human lesions: macrophages, T-cells, and smooth muscle cells [41,[44][45][46]. In contrast to diet-induced atherosclerosis in mice in which lesions are largely limited to the aortic root, lesions in apoE-deficient mice form throughout the arterial tree with similar sites of predilection -as seen in human atherosclerosis -at the aortic root, lesser curvature of the arch, proximal coronary arteries, and at branch points [19,39,40,41,47,48]. Lesion size and progression in apoE-deficient mice are diet-dependent, similar to the diet-dependence of atherosclerotic heart disease observed in human epidemiological studies, such as the Honolulu Heart Study which compares ethnic Japanese in Japan and Hawaii [49].…”