Rapid development of vein graft atheroma in ApoE-deficient mice.
Several animal models manifesting lesions resembling neointimal hyperplasia of human vein grafts have been developed, but no spontaneous atheromatous lesions in their vein grafts have been observed. We developed and here characterize a new animal model of vein graft atheroma, a maturated atherosclerotic plaque, in apoE-deficient mice. The lesion displayed classical complex morphological features and heterogeneous cellular compositions and consisted of a fibrous cap, infiltrated mononuclear cells, foam cells, cholesterol crystal structure, necrotic core with calcification, and neovasculature. Cell component analysis revealed smooth muscle cells (SMCs) localized in the cap region, macrophages which made up a large portion of the lesions, and CD4+ T cells scattered under the cap. Importantly, apoptotic/necrotic cells determined by TUNEL assay in vein grafts into apoE-/- mice were significantly higher than wild-type mice, although a similar number of proliferating cell nuclear antigen-positive cells in both types of lesions was found. Interestingly, vascular SMCs cultivated from aortas of apoE-deficient mice showed a high rate of spontaneous apoptosis/necrosis and a higher rate of cell death stimulated by a nitric oxide donor, sodium nitroprusside, H(2)O(2), and oxidized low density lipoprotein (LDL), although no difference in proliferation of both SMCs incubated with platelet-derived growth factor, angiotensin II, LDL, and oxidized LDL was seen. Thus, the pathogenic mechanisms of vein graft atheroma involve increased intimal cell death initiated by biomechanical stress and amplified by hypercholesterolemia, which leads to continuous recruitment of blood mononuclear cells to constitute atheromatous lesions. This mouse model resembling human vein graft disease has many advantages over other animal models.
Institute for General and Experimental Pathology, University of Innsbruck Medical School, Innsbruck, Austria.
H
H
Dietrich
Y
Y
Hu
Y
Y
Zou
U
U
Huemer
B
B
Metzler
C
C
Li
M
M
Mayr
Q
Q
Xu
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000473:pathology*; D016923:Cell Death; D004195:Disease Models, Animal; D005838:Genotype; D006083:Graft Occlusion, Vascular / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology; D013997:Time Factors; D014684:Venae Cavae / Q000637:transplantation*
D001057:Apolipoproteins E