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

Abstract

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 Ϫ/Ϫ ) 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 Ϫ/Ϫ 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 Ϫ/Ϫ mice could well be a model for the critical processes leading to the breakdown and healing of the human atherosclerotic plaque. Key Words: atherosclerosis Ⅲ apoE knockout mice Ⅲ hemorrhage Ⅲ fibrosis G enetically modified hyperlipidemic mice have helped to delineate the processes regulating fatty streak formation. The fatty streak, a xanthoma formed in the intima of hyperlipidemic animals and often called the early atherosclerotic lesion, is composed of fat-filled macrophages focally situated in the arterial intima. 1 These mouse models have demonstrated that formation of the intimal xanthoma can be accelerated or retarded by a variety of different manipulations, including the following: alterations of apolipoprotein production and/or structure, changes in lipoprotein lipid composition, and additions or deletions of lipoprotein receptors. [2][3][4][5][6][7][8][9][10][11][12][13][14] Furthermore, transgenic and knockout mouse models, which interfere with monocyte adherence and chemotaxis [15][16][17][18][19][20] or macrophage differentiation and foam cell development, [21][22][23] in most cases inhibit formation of these xanthomata, whereas models that increase macrophage involvement stimulate the formation of xanthomata. 4 See page 2503In spite of this success in modeling early lesion formation, there has been limited use of these mice in modeling the progression of lesions to more complex advanced stages, as occur in humans. Murine lesions that are usually described as "advanced" typically contain an imperfectly formed fibrous cap overlying a central fatty mass that has undergone extensive necrosis. Even in the rare cases in which mouse lesions have progressed to occlusion, the morphology suggests obstruction of the lumen by formation of a very large xanthoma, 24 a pattern rarely seen in humans. 1 Thus, whereas mous...

Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

“…Thus, because normal diet-fed apoE Ϫ/Ϫ mice do not develop unstable coronary plaques or suffer from spontaneous atherothrombotic events, despite their severe atherosclerosis, the convincing negative result of the present study is not surprising. More complex plaques have been reported in the innominate artery of aged fat-fed apoE Ϫ/Ϫ mice, with evidence of intra-plaque hemorrhage and atherothrombosis (57,58). These lesions merit further investigation in the human CRP transgenic model, especially in view of the report that arterial thrombosis is increased after vascular injury in human CRP transgenic mice (59).…”

Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress

“…Intraplaque hemorrhages are considered prominent markers of plaque instability. 11,18,23,24 Without angiotensin II stimulation, the more extensive lesions that developed in the lowered shear stress regions showed small intraplaque hemorrhages close to the internal elastic lamina in 28% of the treated animals. Hemorrhages were never observed in the lesions in oscillatory shear stress regions.…”

Using Mice to Dissect Genetic Factors in Atherosclerosis

“…As yet, robust mouse models for lesion rupture and thrombosis have not been developed, but recent observations by several laboratories suggest that apoE-null or LDL receptor (LDLR)-null mice can develop lesions that share many of the features of advanced human lesions and that might be capable of rupture. [15][16][17][18] Molecular studies have also suggested potential mechanisms that could contribute to unstable plaque formation in mice. 19 -21 The first linkage studies of atherosclerosis susceptibility in mice were carried out with RI strains derived from susceptible strains, such as C57BL/6J, and resistant strains, such as C3H/HeJ, BALB/cJ, and A/J.…”