Advanced Atherosclerotic Lesions in the Innominate Artery of the ApoE Knockout Mouse

Abstract—Most previous studies of atherosclerosis in hyperlipidemic mouse models have focused their investigations on lesions within the aorta or aortic sinus in young animals. None of these studies has demonstrated clinically significant advanced lesions. We previously mapped the distribution of lesions throughout the arterial tree of apolipoprotein E knockout (apoE−/−) mice between the ages of 24 and 60 weeks. We found that the innominate artery, a small vessel connecting the aortic arch to the right subclavian and right carotid artery, exhibits a highly consistent rate of lesion progression and develops a narrowed vessel characterized by atrophic media and perivascular inflammation. The present study reports the characteristics of advanced lesions in the innominate artery of apoE−/− mice aged 42 to 60 weeks. In animals aged 42 to 54 weeks, there is a very high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap. By 60 weeks of age, the lesions are characterized by the presence of collagen-rich fibrofatty nodules often flanked by lateral xanthomas. The processes underlying these changes in the innominate artery of older apoE−/− mice could well be a model for the critical processes leading to the breakdown and healing of the human atherosclerotic plaque.

[1]  M A Konerding,et al.  Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. , 1999, Circulation.

[2]  N. Maeda,et al.  Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis* , 1997, The Journal of Biological Chemistry.

[3]  T. Drake,et al.  Pathology of atheromatous lesions in inbred and genetically engineered mice. Genetic determination of arterial calcification. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[4]  Stephen G. Young,et al.  A mouse model of human familial hypercholesterolemia: Markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet , 1998, Nature Medicine.

[5]  Movat Hz.  Demonstration of all connective tissue elements in a single section; pentachrome stains. , 1955 .

[6]  R. Hammer,et al.  Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a). , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[7]  K. Jan,et al.  Role of dying endothelial cells in transendothelial macromolecular transport. , 1990, Arteriosclerosis.

[8]  S. Schwartz,et al.  Hypertension and atherosclerosis. Cause and effect, or two effects with one unknown cause? , 1991, Circulation.

[9]  R. Virmani,et al.  Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[10]  S. Young,et al.  Genetically modified mice for the study of apolipoprotein B. , 1998, Journal of lipid research.

[11]  M. Linton,et al.  Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo. , 1999, The Journal of clinical investigation.

[12]  P. Libby,et al.  Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice. , 1998, The Journal of clinical investigation.

[13]  R. Krauss,et al.  Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI , 1991, Nature.

[14]  K. Ley,et al.  Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. , 1999, Circulation research.

[15]  B. Rollins,et al.  MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. , 1999, The Journal of clinical investigation.

[16]  P. Libby,et al.  Hyperlipidemia and atherosclerotic lesion development in LDL receptor-deficient mice fed defined semipurified diets with and without cholate. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[17]  A. Tall,et al.  A Mouse Model with Features of Familial Combined Hyperlipidemia , 1997, Science.

[18]  A. Henney,et al.  Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Michael Ginsberg,et al.  Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Yukiko Kurihara,et al.  A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection , 1997, Nature.

[21]  R. Hynes,et al.  The combined role of P- and E-selectins in atherosclerosis. , 1998, The Journal of clinical investigation.

[22]  P. Denéfle,et al.  Protection Against Atherogenesis in Mice Mediated by Human Apolipoprotein A-IV , 1996, Science.

[23]  T. Mayadas,et al.  Absence of P-selectin delays fatty streak formation in mice. , 1997, The Journal of clinical investigation.

[24]  N. Maeda,et al.  Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[25]  J. Qiao,et al.  Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. , 1993, Science.

[26]  S M Schwartz,et al.  Peripheral vascular stenosis in apolipoprotein E-deficient mice. Potential roles of lipid deposition, medial atrophy, and adventitial inflammation. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[27]  I. Charo,et al.  Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis , 1998, Nature.

[28]  S. Schwartz,et al.  Sequential injury of the rabbit abdominal aorta induces intramural coagulation and luminal narrowing independent of intimal mass: extrinsic pathway inhibition eliminates luminal narrowing. , 1998, Circulation research.

[29]  M. Karnovsky,et al.  A formaldehyde-glutaraldehyde fixative of high osmolality for use in electron-microscopy , 1965 .

[30]  K. Marotti,et al.  Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein , 1993, Nature.

[31]  R. F. Hoyt,et al.  Targeted Disruption of the Mouse Lecithin:Cholesterol Acyltransferase (LCAT) Gene , 1997, The Journal of Biological Chemistry.

[32]  S. Ylä-Herttuala,et al.  Characterization of atherosclerotic lesions in apo E3-leiden transgenic mice. , 1998, Atherosclerosis.

[33]  P. Thorén,et al.  Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[35]  J. Douglas,et al.  Endothelial cell origin and migration in embryonic heart and cranial blood vessel development , 1991, The Anatomical record.

[36]  S M Schwartz,et al.  Studies on aortic intima. I. Structure and permeability of rat thoracic aortic intima. , 1972, The American journal of pathology.

[37]  P. Libby,et al.  Molecular Determinants of Atherosclerotic Plaque Vulnerability a , 1997, Annals of the New York Academy of Sciences.

[38]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[39]  P. Libby,et al.  Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. , 1998, Molecular cell.

[40]  N. Maeda,et al.  Aortic atherosclerotic plaque injury in apolipoprotein E deficient mice. , 1998, Atherosclerosis.

[41]  W. Roberts,et al.  Morphometric analysis of the composition of coronary arterial plaques in isolated unstable angina pectoris with pain at rest. , 1990, The American journal of cardiology.