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...

Abstract-We hypothesized that short-term exposure to angiotensin II (Ang II) could result in structural and functional changes in the kidney that would favor sodium retention and the development of sustained hypertension. To test this hypothesis, rats were exposed to pressor doses (435 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) of Ang II for 2 weeks. The infusion of Ang II was associated with acute hypertension, renal dysfunction, proteinuria, and focal tubulointerstitial and vascular damage. At sites of the tubulointerstitial damage, there was a reduction in peritubular capillary endothelial cell staining. By use of immunostaining, we found focal loss of endothelial nitric oxide synthase (eNOS) in the peritubular capillaries at sites of injury and a generalized reduction in eNOS in collecting ducts, thin loops of Henle, and vascular bundles in the medulla. When the Ang II infusion ended, the rats became normotensive and renal function returned toward normal. However, exposure of the rats to high salt diet (4% NaCl) resulted in the redevelopment of hypertension after 3 to 4 weeks. Rats maintained on a high salt diet with no prior exposure to Ang II and rats placed on low salt diet (0.1% NaCl) after exposure to Ang II remained normotensive. Thus, we report a new model of salt-sensitive hypertension induced by transient exposure to pressor doses of Ang II. The mechanism may relate to microvascular injury with peritubular capillary loss coupled with functional changes, such as a loss in intrarenal nitric oxide formation, that could alter the ability of the kidney to excrete a salt load. (Hypertension. 1999;33:1013-1019.)

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Very low-density lipoprotein (VLDL) and LDL plasma levels are associated with cardiovascular mortality. Whereas VLDL/LDL lowering causes regression of early atherosclerotic lesions, less is known about the effects of aggressive lipid lowering on regression of advanced complex lesions. We therefore investigated the effect of VLDL/LDL lowering on pre-existing lesions in LDL receptor-deficient mice. Mice fed a highfat diet for 16 weeks developed advanced lesions with fibrous caps, necrotic cores, and cholesterol clefts in the brachiocephalic artery. After an additional 14 weeks on a low-fat diet, plasma cholesterol levels decreased from 21. Dyslipidemia is a central risk factor for cardiovascular disease and is the primary target for prevention of cardiovascular mortality.1 Modification of low-density lipoproteins (LDL) is considered a key contributor to cardiovascular disease in the general population.2 Furthermore, levels of VLDL/triglycerides are often elevated in patients with type 2 diabetes or the metabolic syndrome, 3 and increased level of triglycerides is considered a risk factor for atherosclerotic heart disease in patients with and without diabetes. 4,5 The great majority of acute clinical cardiovascular events, myocardial infarction and stroke, are believed to be caused by unstable atherosclerotic lesions.6,7 Studies of human atherosclerotic lesions have indicated that most clinically relevant lesions are composed of necrotic cores covered by thin fibrous caps containing macrophage-rich re-

A systematic analysis of the distribution of advanced atherosclerotic lesions was undertaken in chow-fed, 9-month-old apolipoprotein (apo) E-deficient mice to identify sites amenable for study of mechanisms of formation of stenotic lesions. The arterial tree was dissected intact and included medium-sized arteries in the extremities as well as arteries of the head and neck. The most reproducible lesions were seen in the ascending aorta and in the carotid, femoral, and popliteal arteries. Casting of the vascular tree provided additional verification of the presence of lumen narrowing in the external branches of the carotid artery. Consistent with what has been observed in human atherosclerotic arteries, there was dilation in response to lesion growth and no correlation between lesion mass and lumen loss in the mouse arteries. This adaptation was especially true in the ascending aorta, where normal lumen size was maintained at atherosclerotic sites. In contrast, the external carotid arteries were stenotic in 9 of 12 animals. Here too, however, loss of lumen did not correlate with lesion mass but did correlate with adventitial inflammation and medial atrophy. Lumen narrowing also occurred most frequently at sites where extracellular cholesterol clefts were a prominent part of the lesion. These data suggest that the stenotic process in advanced atherosclerotic vessels may depend on death of medial smooth muscle cells, possibly in response to inflammatory changes in the plaque or adventitia.

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