© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Advanced Atherosclerotic Lesions in the Innominate Artery of the ApoE Knockout Mouse
From the Departments of Pathology (M.E.R., P.P., S.M.S.) and Pathobiology (M.E.R.), University of Washington, Seattle; the Armed Forces Institute of Pathology (R.V.), Washington, DC; and Berlex Biosciences (K.K., G.R.), Richmond, Calif.
Correspondence to Dr Michael E. Rosenfeld, Department of Pathobiology, Box 353410, University of Washington, Seattle, WA 98195. E-mail ssmjm{at}u.washington.edu
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Abstract |
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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.
Key Words: atherosclerosis • apoE knockout mice • hemorrhage • fibrosis
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Introduction |
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Genetically 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 chemotaxis15 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
In 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 mouse models have helped to explain xanthoma formation and progression to a fibrous cap lesion, these models have provided little confirmatory information about the proposed mechanisms involved in the progression to an unstable plaque and ultimately to rupture and healing of the fibrous cap lesion.25 26 The failure to see more advanced disease in mice could be due to the choice of model or, more simply, to the anatomic locations and age of animals used in previous studies. In a recent systematic study of the distribution of lesions in the apoE mouse, we found that the innominate artery, a small vessel connecting the aortic arch to the right subclavian and right carotid artery, showed a highly consistent rate of progression, not only in the initial xanthoma but also in the development of a narrowed vessel characterized by atrophic media and perivascular inflammation.27
In an effort to extend our previous observations, we have
continued to look at this site in animals of an older age. In animals
aged 
42 weeks, we now report that this site shows loss of continuity
of the fibrous cap, rupture of xanthomas located at the shoulders of
the atherosclerotic lesions, and intraplaque hemorrhage.
Moreover, these events occur consistently at this site. These
events either precede or are simultaneous with the fibrotic
conversion of the necrotic core to a fibrofatty nodule, a process
reminiscent of the formation of scar tissue during wound healing.
Although the appearance of these changes in the mouse is not identical
to changes seen in advanced human lesions, we suggest that the
processes underlying these changes could well be a model for some of
the critical processes leading to the breakdown and healing of the
human atherosclerotic plaque.
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Methods |
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Preparation of Animals
Eighty-four male apoE knockout (apoE-/-) mice on a C57Bl/6 background (Jackson Labs) were randomly divided into 7 groups of 12 mice. They were fed a rodent chow diet (Harlan Teklad) and water ad libitum. At 20 weeks of age, half of each group had either a placebo or a 17ß-estradiol pellet implanted subcutaneously (17ß-estradiol, 0.25 mg/pellet, 90-day release, catalogue No. NE 121 IRA, Innovative Research of America). One group of mice was euthanized at 24 weeks, and another group was euthanized every 6 weeks thereafter up to 60 weeks of age. We have observed that the presence of 17ß-estradiol does not alter the composition of lesions in the innominate artery (authors’ unpublished data, 2000). Thus, representative examples of changes in lesion composition with age shown in the present study include tissue obtained from control and 17ß-estradiol–treated animals (Figures 1
, 4, and 6).
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Blood was obtained from each animal at the time of death for
analysis of serum cholesterol and
triglyceride levels. There were no differences in plasma
cholesterol levels in the control and
17ß-estradiol–treated animals (data not shown). Plasma
triglycerides were significantly elevated in the
17ß-estradiol–treated animals (data not shown). The animals were
perfusion-fixed at a pressure equal to the cardiac output of the heart
of a mouse via the left ventricle (24-g 
-in Becton Dickinson
Angiocath intravenous catheter). The animals were
perfused first with lactated Ringer’s solution for 20 seconds and then
10% buffered formalin (catalogue No. UN-2209, Histology Reagent Co)
for 4 minutes. After perfusion fixation, the whole animal was stored in
10% buffered formalin until the arterial tree could be
removed.
Preparation of Tissue
The central arterial tree was dissected
intact with the use of a dissecting microscope. The tree included the
external carotids and branches, the proximal internal carotids, the
proximal right subclavian artery, the heart, the thoracic and abdominal
aortas, the renal arteries with attached kidneys, and the iliac,
femoral, and popliteal arteries. The adventitia was dissected from the
arterial wall to facilitate mapping of the lesions before
removal of the arterial tree from the animal. Eleven sites
were chosen for further investigation of the size and composition of
atherosclerotic lesions. These sites included the distal and proximal
right and left carotid arteries, the innominate artery, the ascending
aorta, the aorta at the level of the diaphragm, the right and left
iliac arteries, and the popliteal arteries. These sites were cut from
the rest of the arterial tree and were processed and
embedded in paraffin. Each of the paraffin blocks was serially
sectioned (5-µm sections), and the sections at the point of maximum
lesion thickness were stained with a modified Movat’s
pentachrome
stain.28
An additional group of 6 animals aged 58 to 60 weeks were euthanized for analysis of lesion composition by transmission electron microscopy. The animals were perfusion-fixed with 4% paraformaldehyde as described above and immersion-fixed with modified Karnovsky’s fixative.29 The innominate artery, left distal carotid arteries, and abdominal aorta were embedded in plastic (Epon 12) and processed for transmission electron microscopic evaluation by using standard techniques.
Immunostaining for 
-actin and fibrinogen
was conducted by use of a standard immunoperoxidase protocol. A primary
rat anti-mouse -actin antibody (1A4, DAKO Corp) was applied at a
dilution of 1:400, and a goat anti-mouse fibrinogen antibody (YN6
MFB67S, Accurate Chemical and Scientific Corp) was applied at a
dilution of 1:2000 for 1 hour at room temperature to determine the
location of smooth muscle cells and fibrinogen, respectively, in the
tissue sections. The sections were incubated with biotin-labeled
secondary antibodies followed by avidin-labeled horseradish peroxidase
and diaminobenzidine according to the supplier’s
recommendations (Vector
Laboratories).
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Results |
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Atherosclerotic Lesions in Innominate Arteries of Mice Aged 60 Weeks
Figure 1
shows a typical lesion in the innominate artery of
an apoE-/- mouse aged 60 weeks as seen
with a light microscope. One important feature is the disappearance of
the fibrous cap and necrotic core. The fibrous cap and underlying
necrotic zones (typical of early lesions) are replaced by an extensive
acellular collagenous mass, a fibrotic nodule with
cholesterol clefts that extends to the lumen. Another
characteristic feature of lesions in these older animals is
xanthomatous masses situated adjacent to the principal lesion. These
accumulations of macrophages often have necrotic zones
consisting of lipid and/or necrotic macrophage-derived foam
cells located laterally to the acellular core and immediately beneath
the endothelium
(Figure 2). As described by others, we also noted areas
within the plaque showing chondroplastic
conversion.30 By
electron microscopy, these chondroplastic regions typically contain
smooth muscle–like cells (cells with large amounts of fibrillar
cytoplasm) surrounded by dense collagen (Figures I and II, which may be
accessed online at http://atvb.ahajournals.org).
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The most dramatic feature of these lesions is the presence
of the large fibrofatty nodules. As noted, in some cases, these largely
acellular masses extend completely from the lumen into the media
(Figure 1 and Figure III, which may be accessed online at
http://atvb.ahajournals.org). These hyalinized masses, which replace
the necrotic core, consist largely of cholesterol clefts
embedded in a matrix composed of dense collagen (resembling the
collagen seen in the chondroplastic regions shown in Figure II, which
may be accessed online at http://atvb.ahajournals.org), hyaluronic acid
(personal communication, Dr Thomas Wight, 2000;
immunocytochemical staining data not shown), and accumulations of
necrotic cell debris (resembling the content of
macrophage-derived foam cells).
Another interesting feature of these fibrofatty masses is the appearance of the overlying endothelium. Although these vessels were fixed at physiological pressure and flow rates,31 the endothelium was often disrupted, usually appeared apoptotic or necrotic, and in some cases was totally absent (Figures IV to VI, which may be accessed online at http://atvb.ahajournals.org).3 32 33 There were also cases in which macrophages within lateral xanthomas erupted through the overlying endothelium (Figure VII, which may be accessed online at http://atvb.ahajournals.org). Conspicuously absent from these sections, however, were thrombosis or adherent platelets on denuded surfaces or exposed macrophages.
Atherosclerotic Lesions in Innominate Arteries
of Mice Aged 42 to 54 Weeks
The fibrofatty nodule forming the central mass of
60-week lesions usually appears as a necrotic fatty mass containing
cholesterol clefts and necrotic debris in mice aged 42 to
54 weeks
(Figure 3). This necrotic zone presumably develops during
this 7-month period via the death of macrophages (data not
shown) and begins to convert to a fibrofatty nodule, as suggested by
the intermediate stages seen in many of the younger animals
(Figure 3). This necrotic zone resembles the
"atheroma" or fatty core of the classic lesion
described by Virchow (Virmani et
al1 ). Therefore, we
assume that the fibrofatty nodule represents the healed end
stage of coalesced lateral necrotic zones derived from the original
xanthomas
(Figure 4).
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In contrast to the 60-week-old animals, in the 42- to
54-week-old animals the endothelial cells and smooth
muscle cells are still frequently observable above the necrotic zones
(Figure VIII, which may be accessed online at
http://atvb.ahajournals.org). Thus, in a majority of animals, the
fibrous cap still exists but is thin, fragmented, and missing in many
areas
(Figures 3 and 4). An additional characteristic of these
advanced lesions in the 42- to 54-week group is extensive erosion of
the underlying media that involves replacement of the media by
macrophages and other plaque components. On occasion, the
medial erosion is so severe that the plaque components are contained
only by the adventitia (Figures IX and X, which may be accessed online
at http://atvb.ahajournals.org).
Intraplaque Hemorrhage
We were surprised to see evidence of intraplaque
hemorrhage (defined as masses of red blood cells free in the
plaque matrix or filling the necrotic core) in a significant
percentage of the lesions in the animals aged 30 to 60 weeks
(percentages of 12 animals per time point exhibiting intraplaque
hemorrhage in the innominate artery were as follows: 30 weeks,
17%; 36 weeks, 66%; 42 weeks, 66%; 48 weeks, 42%; 54 weeks, 75%;
and 60 weeks, 33%). The extent of hemorrhage and the
associated changes in the blood vessel wall were remarkably
variable. In some instances, the hemorrhage was quite
widespread, and the vessel was nearly occluded, as shown in
Figure 5. In other cases, the hemorrhage was more
focal and appeared to arise from the lateral xanthomata
(Figure 6), although associated fissures or ruptures were not
evident. Electron microscopy (not shown) revealed red blood cells in
various stages of degradation, surrounded by macrophages
containing phagocytized red blood cell debris. Some of these cells were
very flattened, resembling a
pseudoendothelium.34
Electron microscopy did not reveal evidence of well-formed fibrin,
although in all of the younger animals, the lesions contained
significant amounts of immunoreactive fibrinogen (Figure XII,
which may be accessed online at http://atvb.ahajournals.org). Although
immunoreactivity for fibrinogen cannot distinguish the formation of
fibrin from other mechanisms of accumulation of fibrinogen, the
concentration of fibrinogen epitopes at this sight suggests that
intramural clotting may have occurred in some of the animals aged 42 to
54 weeks.
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Discussion |
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To date, xanthomatous and larger lesions within the aorta and aortic sinus have been well characterized.35 36 37 These lesions, which are analogous to the early fibrous cap atheromas in humans,1 have provided the bases of comparison for the effects of crossbreeding other transgenic or knockout mice with apoE-/- mice, as well as for pharmacological interventions with use of this mouse model. The limited characterization of advanced lesions in these mice in previous studies is likely the result of a failure to look at sites other than the aorta or aortic sinus and of not allowing sufficient time for critical processes to have an impact on altering the xanthomas.
Our effort to analyze lesions at different sites in the older animals required that we carefully delineate the criteria for advanced lesions. This was in part motivated by our recent simplified description of the advanced human lesion seen in patients undergoing sudden death.1 The present study uses these human criteria to provide additional characterization of the advanced lesions in the innominate artery of the older mice and demonstrates that changes occurring in human advanced disease are also seen in advanced disease in the mouse.
The key changes for progression to a more clinically significant state are as described below.
Loss of Lumen Caliber
We have already described this feature in the external
carotid artery of apoE-/-
mice.27 In humans,
although narrowing does not correlate with lesion mass, it does
correlate with the formation of highly fibrotic
lesions.1 In this
regard, we do not yet know whether scarring in the mouse lesions is
correlated with narrowing.
Atrophy of the Fibrous Cap
Loss of the fibrous cap correlates with plaque rupture
in human lesions.1
Similarly, thinning and loss of the fibrous cap occurs as lesions
advance in the mice.
Intramural Hemorrhage
Up to 75% of all animals aged 30 to 60 weeks showed
intraplaque hemorrhage. The disruption appeared to occur
predominantly within the lateral xanthoma
(Figure 6) and is consistent with similar plaque
rupture along the lateral margins in humans. However, another possible
source of red blood cells within the plaques is the presence of
intraplaque microvessels. This possibility is supported by the
immunocytochemical detection of microvessels in the
apoE-/- mice as reported by Moulton et
al.38 Despite studies
with electron microscopy (data not shown), we have not seen such
vessels in our studies, suggesting that Moulton et al either mistook
flattened CD-31–positive macrophages for
endothelial cells, that the endothelium
has been lost at this stage of lesion development, or that plaque
vessels form only in aortic lesions.
Thrombosis and Coagulation Within the Plaque or
at Its Surface
Occlusive thrombi within the lumen as well as
intraplaque thrombi are hallmarks of advanced human lesions. Although
immunocytochemistry could detect fibrinogen (Figure XII, which may be
accessed online at http://atvb.ahajournals.org), neither platelet
aggregates nor fibrin clots were observed in any of the mice by use of
either light microscopy or the electron
microscope.
Layering, ie, Formation of a Layered Lesion
Implying Multiple Events
Layered lesions could be seen as early as 42 weeks and
in many of the 60-week-old animals. Such layered lesions may be the
result of confluence of lateral lesions with the central mass
(Figures 3 and 4).
Fibrous Scarring
Fibrous scarring was seen universally in the innominate
arteries from these mice by 60 weeks of age
(Figures 1 and 2 and Figure II, which may be accessed online
at http://atvb.ahajournals.org).
The most worrisome difference between the pathology in the
mouse and the pathology of human disease is the absence of fibrin
formation either within the lesion or within the lumen. The presence of
red blood cells within the plaque is definitive evidence that
hemorrhage occurs and that it occurs frequently in these
animals. The reasons for a failure of fibrin to form despite the
presence of fibrinogen are not known. However, if fibrin is being
formed, it must be removed rapidly by
fibrinolysis.39
The failure of the mouse lesions to stimulate thrombosis may be the
reason that we do not see a complete loss of lumen more frequently,
inasmuch as highly occlusive lesions were only occasionally observed
(Figure 5). However, the absence of thrombosis in the older
apoE mice is not indicative of a lack of thrombotic potential, because
thrombi do form in these mice after mechanical
injury.40
Obviously, there are many other reasons that the pathology of a lesion in a tiny 0.3-mm mouse vessel would be different from the pathology of lesions in a 3-mm human coronary artery. Nonetheless, the 3 changes in the mouse most reminiscent of changes likely to explain plaque rupture in a human vessel are (1) the formation of an acellular necrotic core, (2) the erosion of that mass through to the lumen with its exposure to the lumen, and (3) the appearance of intraplaque hemorrhage. Our data suggest that transient hemorrhagic events occur in the mouse at the stage in which the central mass of the lesion is necrotic.
We suggest that the fibrofatty nodules (shown in
Figures 1, 2, and 4) may be the result of healing after 1
episode of hemorrhage. Lesions of this sort (fibrocalcific
nodules) are seen in 
5% of cases of sudden death in humans. The
fibrocalcific nodule, like the nodule we describe in the mouse, can
extend completely to the surface. Intriguingly, this lesion in humans
is correlated with a loss of lumen
caliber.41 Whether
similar processes account for the loss of lumen in the mouse remains an
open question.
In summary, the present study demonstrates that processes analogous to changes occurring in advanced human disease are also seen in advanced disease in the innominate artery of older apoE-/- mice. These processes should now be considered as important parameters for future evaluations of the effects of the addition of transgenes or of pharmacological interventions in the apoE-/- mouse.
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Acknowledgments |
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This study was supported by an unrestricted gift from Berlex Biosciences Inc and National Institutes of Health grants R01 HL-98033 and R01 HL-26405. The authors would like to acknowledge the technical assistance of Baby Martin-McNulty, Jerry Ricks, Sharlene Moore, and Renee Collman.
Received July 6, 2000; accepted October 10, 2000.
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H. R. Davis Jr, D. S. Compton, L. Hoos, and G. Tetzloff Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Inhibits the Development of Atherosclerosis in ApoE Knockout Mice Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2032 - 2038. [Abstract] [Full Text] [PDF]
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L. V. d'Uscio, L. A. Smith, and Z. S. Katusic Hypercholesterolemia Impairs Endothelium-Dependent Relaxations in Common Carotid Arteries of Apolipoprotein E-Deficient Mice Stroke, November 1, 2001; 32(11): 2658 - 2664. [Abstract] [Full Text] [PDF]
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S. M. Schwartz, T. S. Hatsukami, and C. Yuan Molecular Markers, Fibrous Cap Rupture, and the Vulnerable Plaque: New Experimental Opportunities Circ. Res., September 14, 2001; 89(6): 471 - 473. [Full Text] [PDF]
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J. Zhou, J. Moller, C. C. Danielsen, J. Bentzon, H. B. Ravn, R. C. Austin, and E. Falk Dietary Supplementation With Methionine and Homocysteine Promotes Early Atherosclerosis but Not Plaque Rupture in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1470 - 1476. [Abstract] [Full Text] [PDF]
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C. A. Reardon, L. Blachowicz, T. White, V. Cabana, Y. Wang, J. Lukens, J. Bluestone, and G. S. Getz Effect of Immune Deficiency on Lipoproteins and Atherosclerosis in Male Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 1011 - 1016. [Abstract] [Full Text] [PDF]
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G. S. Getz Mouse Model of Unstable Atherosclerotic Plaque? Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2503 - 2505. [Full Text] [PDF]
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A. Braun, B. L. Trigatti, M. J. Post, K. Sato, M. Simons, J. M. Edelberg, R. D. Rosenberg, M. Schrenzel, and M. Krieger Loss of SR-BI Expression Leads to the Early Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions, Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E-Deficient Mice Circ. Res., February 22, 2002; 90(3): 270 - 276. [Abstract] [Full Text] [PDF]
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J. Silence, D. Collen, and H.R. Lijnen Reduced Atherosclerotic Plaque but Enhanced Aneurysm Formation in Mice With Inactivation of the Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Gene Circ. Res., May 3, 2002; 90(8): 897 - 903. [Abstract] [Full Text] [PDF]
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