doi: 10.1161/hq0801.093669
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Compensatory Enlargement and Stenosis Develop in ApoE-/- and ApoE*3-Leiden Transgenic Mice
From the Departments of Pathology (E.L., S.H., M.J.A.P.D.) and Cardiology (E.D.d.M.), University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
Correspondence to M.J.A.P. Daemen, MD, PhD, Department of Pathology, P. Debeyelaan 25, PO Box 5800, 6202 AZ, Maastricht, Netherlands. E-mail MDA{at}LPAT.AZM.NL
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Abstract |
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Abstract—— Atherosclerotic mouse models develop little ischemic organ damage and no infarctions, despite the presence of large atherosclerotic lesions. Therefore, we hypothesize that luminal changes do not follow atherosclerotic lesion development. Because a phenomenon that may explain the discrepancy between luminal changes and lesion size is vascular remodeling, we measured parameters of vascular remodeling in the carotid arteries (CAs), thoracic aorta (TA), and abdominal aorta (AA) of apolipoprotein E (apoE)–deficient (apoE-/-) and apoE*3-Leiden mice, 2 well-known mouse models of atherosclerosis. Atherosclerotic lesions were classified (American Heart Association [AHA] types II through V), and plaque thickness, compensatory enlargement versus constrictive remodeling, lumen diameter, stenosis, and media thickness were measured relative to the nondiseased arterial wall. In CAs, plaque thickness increased during atherogenesis. CAs showed compensatory enlargement (apoE-/- 55%, apoE*3-Leiden 38%). Regression analysis revealed a positive correlation between plaque and lumen area (for apoE-/-, R=0.95; for apoE*3-Leiden, R=0.90). Medial thinning and elastolysis were also observed. During atherogenesis, lumen diameter decreased (apoE-/- -69%, apoE*3-Leiden -40%), and stenosis >70% developed. TA and AA showed similar features, but neither developed a progressive decrease in lumen diameter or stenosis >70%. In CAs, TA, and AA of apoE-/- and apoE*3-Leiden mice, atherogenesis is associated with compensatory enlargement, medial thinning, and elastolysis. A progressive decrease in lumen diameter and stenoses >70% occur only in CAs. Vascular remodeling is more prominent in apoE-/- mice.
Key Words: remodeling • animal models • atherosclerosis pathophysiology
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Introduction |
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For a long time, the arterial system was considered to be a rigid tube that showed a decrease in lumen diameter in response to a growing plaque mass.1 However, in 1987, Glagov et al,2 and many others thereafter,3–6 showed that coronary arteries (CAs) developed compensatory enlargement in response to plaque growth. Later, it was shown that besides compensatory enlargement, constrictive remodeling may develop.7 The mode of remodeling (compensatory versus constrictive) may vary strongly over the length of 1 artery and between different arteries.8 Clinically, constrictive remodeling is associated with ischemic organ complications.9
Although enlargement and constrictive remodeling have extensively been reported in different animal models after balloon angioplasty, such as the baboon,10,11 the rat, the rabbit12 and the pig,13 an animal model of de novo atherosclerosis that shows constrictive remodeling with significant stenosis and ischemic organ complications is still lacking.9 Hypercholesterolemic macaque monkeys, rabbits, and pigs all show arterial compensatory enlargement, whereas high-grade stenosis or a decrease in lumen diameter is hardly ever observed.10,11
Also, apoE-deficient (apoE-/-) mice, the most frequently used atherosclerotic mouse model, show compensatory enlargement, and when they are fed an extremely high cholesterol diet or infused with angiotensin II, they even demonstrate aneurysm formation.14–17 Some apoE-/- mice do develop significant stenosis in the external CA but without evidence of ischemia.15
We hypothesize that parameters of vascular remodeling change during lesion progression in differently sized arteries of atherosclerotic mouse models. Therefore, we investigated these parameters at all stages of atherosclerosis in 3 differently sized vessels in 2 different hypercholesterolemic mouse models: the apoE-/- mouse18 and the apoE*3-Leiden transgenic mouse.19–21 Our data indicate that both mouse strains show compensatory enlargement, medial thinning, and elastolysis in the CAs, the thoracic aorta (TA), and the abdominal aorta (AA). Interestingly, the CAs showed a decrease in lumen diameter and stenosis >70%, especially in type IV and V lesions. However, constrictive remodeling and ischemic organ damage did not develop.
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Methods |
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Mice
In the present study, data were obtained from apoE-/- mice (n=14 males) and apoE*3-Leiden mice (n=45, 23 male and 22 female mice). Both strains are on a C57BL/6 background. Mice were fed an atherogenic diet containing 15% cocoa butter, 0.5% cholate, 1% cholesterol, 40.5% sucrose, 10% corn starch, 1% corn oil, and 4.7% cellulose (Hope Farms)22 for 4 to 12 months. For validation purposes (see Results), wild-type (C57BL/6) mice on a normal chow (n=6) or the atherogenic diet (n=6) were used.
Tissue Handling
After the experimental period, mice were euthanized, and tissue was processed. In summary, blood (0.5 to 1 mL) was collected from the caval vein for the assessment of the lipid profile, and the arterial tree was perfused under standardized pressure (100 mm Hg) with 0.9% NaCl (3 minutes) and 10% phosphate-buffered formalin (pH 7.4, 3 minutes), with both containing 0.1 mg/mL nitroprusside through a catheter inserted into the left ventricular apex. The entire arterial tree was excised and formalin-fixed for 24 hours. Both CAs, the TA, and AA were embedded in paraffin in the axial dimension to obtain a complete overview of plaque distribution. Subsequently, 4-µm sections were cut, and 5 sections (16 µm apart) of the CAs, TA, and AA were stained with hematoxylin and eosin (HE) and classified from II to V according to the AHA classification.23 This multiple section approach, combined with analysis in the axial dimension, enabled us to obtain proper reference values and a reliable view on vascular remodeling processes in atherosclerosis.
Morphometry
For morphometry, 5 sections of CA, TA, and AA, consecutive to the HE-stained sections, were stained with Lawson (a modified elastica von Gieson stain). Morphometric parameters were determined by using a microscope coupled to a computerized morphometry system (Quantimet 570, Leica).
Parameters were measured at the center of the lesion as well as at the nondiseased part of the same vessel (100 µm proximal and distal to the atherosclerotic plaque). These measurements were taken as reference values (Figure 1a).
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Plaque thickness at the center of the lesion, plaque area, lumen area, and the area between the 2 innermost elastic laminae were measured as described in Figure 1a and 1b. Compensatory enlargement/constrictive remodeling was defined as the relative increase/decrease of the distance between the 2 innermost elastic laminae compared with reference values. Relative lumen diameter was defined as the distance between the 2 innermost elastic laminae minus plaque thickness compared with reference values. Media thinning/thickening was defined as the relative decrease/increase of the media underlying the plaque (distance between the innermost and outermost elastic laminae) compared with reference values. The amount of medial elastolysis was defined as the number of elastin breaks in the media underlying the atherosclerotic lesion. The percentage stenosis was defined as plaque thickness divided by the distance between the 2 innermost elastic laminae. Poststenotic dilatation was defined as the difference of the distance between both innermost elastic laminae of the reference value sites distal and proximal from the atherosclerotic lesion.
Lipid Profile
Plasma cholesterol and plasma triglyceride levels were determined in duplicate by using a colorimetric assay (CHOD-PAP 1442341 and GPO-PAP 701912, respectively, La Roche).
Statistical Analysis
Values are given as mean±SEM. Relative increases and decreases were obtained by dividing the value of the center of the lesion by the mean of both reference values. Arteries in which it was impossible to obtain proper reference values and arteries containing 2 opposite lesions in 1 segment were discarded. Differences during lesion progression were tested by a 1-way ANOVA. For the analysis of differences between the same lesion types between both mouse models, a Mann-Whitney U test was used. Regression analysis was performed to test the correlation between plaque area, lumen area, and the area between both innermost elastic laminae. To test whether vascular remodeling was an age-dependent effect, reference values as well as plaque values of mice of the different diet groups (4, 6, 9, and 12 months) were compared by a 2-way ANOVA. The level of statistical significance was considered to be P<0.05.
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Results |
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General
Mean body weight did not differ between the mouse strains. Survival rates were 92% for apoE-/- mice, 96% for apoE*3-Leiden mice, and 100% for C57BL/6 mice. Histological analysis of heart, brain, lungs, kidneys, and liver (HE-stained sections) revealed no ischemic damage. In 1 apoE-/- mouse, an apical myocardial infarction caused by an occlusion of the left anterior descending coronary artery was observed, and in 1 apoE*3-Leiden mouse, cerebral infarction was observed. Cholesterol and triglyceride levels were elevated in apoE*3-Leiden mice compared with apoE-/- mice (cholesterol levels 34.0±0.6 versus 24.0±1.2 mmol/L, respectively; triglyceride levels 2.0±0.2 versus 0.9±0.1 mmol/L, respectively). In C57BL/6 mice, these levels were low (on normal chow, cholesterol 0.6±0.3 mmol/L, triglycerides 0.1±0.0 mmol/L; on an atherogenic diet, cholesterol 0.9±0.4 mmol/L and triglycerides 0.1±0.0 mmol/L).
For validation of the measurements, reference values of apoE-/- and apoE*3-Leiden mice were compared with remodeling parameters obtained from nondiseased arteries of C57BL/6 mice on a normal chow diet or an atherogenic diet. No significant differences were found between reference values of arteries of atherosclerotic and nondiseased mice. Also, remodeling parameters between C57BL/6 mice on normal chow and the atherogenic diet were not different. To investigate whether remodeling was an age-dependent effect, reference values and plaque values of the individual AHA lesion types of mice of the different diet groups (4-, 6-, 9-, and 12-month diet) were compared. Age-dependent remodeling and sex differences were not observed.
In total, 367 atherosclerotic lesions (1835 sections) of 3 differently sized arteries were analyzed (for apoE-/-, n=37 CA lesions, n=43 TA lesions, and n=99 AA lesions; for apoE*3-Leiden, n=98 CA lesions, n=40 TA lesions, and n=50 AA lesions). The TA had the largest diameter (apoE-/-, 689±21 µm; apoE*3-Leiden, 629±19 µm), followed by the AA (apoE-/-, 479±13 µm; apoE*3-Leiden, 541±17 µm) and the CA (apoE-/-, 285±9 µm, apoE*3-Leiden, 289±7 µm).
Vascular Remodeling
Carotid Arteries
Plaque thickness increased during the progression from type II to type V lesions (apoE-/-, 804±89%; apoE*3-Leiden, 547±113%; Figures 2a and 3a through 3e and Table). Compared with apoE*3-Leiden mice, the increase in plaque thickness was significantly higher in apoE-/- mice, especially the thickness of type IV and V lesions (Figure 2a and Table).
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P<0.05). To evaluate the progression of remodeling parameters during atherogenesis within a mouse strain, a 1-way ANOVA was performed (
P<0.05).
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The increase in plaque thickness was associated with the development of compensatory enlargement. Compensatory enlargement (from type II to type V lesions) was 55% in apoE-/- mice and 38% in apoE*3-Leiden mice (Figure 2b and Table). In apoE-/- mice, compensatory enlargement was more prominent than that in apoE*3-Leiden mice. Statistically significant differences between both mouse strains were observed in type IV and V lesions (Figure 2b and Table). Regression analysis revealed a high correlation between plaque area and compensatory enlargement (apoE-/- mice, R=0.95; apoE*3-Leiden mice, R=0.90; Figures 2c and 2d).
Despite the development of compensatory enlargement, lumen diameter decreased, and stenosis >70% developed (Figure 2e and 2f, Figure 3d and 3e, and Table). The decrease of lumen diameter was more prominent in apoE-/- mice compared with apoE*3-Leiden mice (for apoE-/-, type II lesions -19±3%, type V lesions -88±9%; for apoE*3-Leiden, type II lesions -23±2%, type V lesions -63±5%; Figure 2e). These data indicate that during lesion progression, compensatory enlargement of the arteries in response to plaque development at some point is no longer adequate. At that point, plaque load does not follow compensatory enlargement, and significant stenoses, associated with a decrease in lumen diameter, develop (Figure 2). Stenoses >70% were observed in advanced type IV and V lesions, predominantly in apoE-/- mice (type IV lesions, 90±4% for apoE-/- versus 71±4% for apoE*3-Leiden; type V lesions, 91±5% versus 73±4%, respectively; Figures 2f and 3c through 3e and Table). Significant poststenotic dilatation was not observed. Regression analysis revealed no correlation between plaque area and lumen area (apoE-/-, R=0.21; apoE*3-Leiden, R=0.56). Constrictive remodeling (defined as negative compensatory enlargement) did not occur (Figure 2b and Table).
Also, the media underlying the plaque changed. First of all, in both mouse models, the media hypertrophied in early lesions (type II lesions, 64±17% for apoE-/- and 31±11% for apoE*3-Leiden) and atrophied in type V lesions (-29±7% for apoE-/- and -17±6% for apoE*3-Leiden;Figures 2g and 4a through 4c). Second, medial elastin breaks were observed. Interestingly, the number of medial elastin breaks and the distribution pattern differed between both mouse models (Figures 2h and 4b through 4c and Table). The mean number of elastin breaks was 4.1±0.6 in apoE-/- mice, whereas it was only 1.9±0.2 in apoE*3-Leiden mice compared with 1.1±0.3 and 0.6±0.4, respectively, in the nondiseased parts (Figure 2h). Furthermore, in apoE-/- mice, breaks were distributed equally throughout the lesion, whereas in apoE*3-Leiden mice, breaks were confined to the innermost elastic laminae (37.8% in apoE-/- versus 70.7% in apoE*3-Leiden; Figure 2h).
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TA and AA
Although an increase in plaque thickness, compensatory enlargement, and a positive correlation between plaque area and compensatory enlargement (for TA, R=0.74 for apoE-/- and R=0.84 for apoE*3-Leiden; for AA, R=0.78 and R=0.94, respectively) were also observed in TA and AA, a progressive decrease in lumen diameter and stenosis >70% did not occur (Table). No significant differences between apoE-/- and apoE*3-Leiden mice were found. In TA and AA, regression analysis revealed no negative correlation between plaque area and lumen diameter (for TA, R=0.32 for apoE-/- and R=0.57 for apoE*3-Leiden; for AA, R=0.42 and R=0.56, respectively). Also, in TA and AA, medial changes were observed in both mouse models. In apoE-/- mice, progressive medial thinning occurred (for TA, -28±9% in type V; for AA, -18±3% in type V), whereas in apoE*3-Leiden mice, the media hypertrophied in all lesion types (for TA, 46±10%; for AA, 30±12% [both in type V]; Table). The pattern of elastolysis equaled that in the CA (Table).
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Discussion |
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The present study is the first to provide data on parameters of vascular remodeling in 3 differently sized arteries of 2 hypercholesterolemic mouse models, in all atherosclerotic lesion types. The main findings are that (1) both mouse models develop compensatory enlargement, correlated with plaque area; (2) only CAs are able to develop a progressive decrease in lumen diameter and stenosis >70%; (3) medial hypertrophy is a feature of early atherosclerosis, whereas medial thinning with elastin breaks are observed in advanced lesions; and (4) the development of constrictive remodeling is lacking.
Vascular remodeling is an adaptive process that occurs as a response to chronic changes in hemodynamic conditions.2,3 When a human atherosclerotic plaque develops, compensatory enlargement and poststenotic dilatation occur as an attempt to maintain preexisting flow and shear stress.2,4–6,24 In the early stages of atherosclerosis, even overcompensation of the lumen was observed.2,5,25 When atherosclerotic lesions progress, the capacity of the arterial wall to compensate for the increase in plaque thickness decreases. At this stage, compensatory enlargement is inadequate,4,9,26 and a correlation between plaque area and lumen loss can be found.2 Additionally, constrictive remodeling, with a decrease in lumen diameter, has been reported.8,27
Consistent with data found in humans and in atherosclerotic animal models,12,14–16,28 we demonstrate compensatory enlargement in advanced atherosclerotic lesions of apoE-/- and apoE*3-Leiden mice. However, overcompensation of the lumen in early lesions was not observed in either of the 2 mouse models. As in other animal models of de novo atherosclerosis, apoE-/- and apoE*3-Leiden mice failed to develop constrictive remodeling. However, in contrast to other atherosclerotic animal models, both mouse models did develop significant stenosis in the common CAs but not in the TA or AA. These data are consistent with the data of Seo et al,15 who observed significant stenosis in peripheral vessels (popliteal and external CAs) of 9 of 12 apoE-/- mice. The difference in remodeling that we observed between the differently sized arteries may be due to the smaller vessel diameter of the CA. In the CA, vessel diameter is twice as small, whereas maximal plaque thickness is equal to that in the TA or AA. This suggests that the vessel undergoes stenosis twice as fast in the CA compared with the TA or AA. A reason for this phenomenon might be the different structural composition and function of the CA, which is a musculoelastic vessel with a relative thin media, and the TA or AA, which is a thick-walled conduit vessel.
Paradoxically, poststenotic dilation in the CAs in mouse models of atherosclerosis is lacking despite the development of compensatory enlargement. Some of the explanations for this apparent paradox might be the different hemodynamic situation in the mouse vascular system29 and the different composition of mouse atherosclerotic lesions compared with human atherosclerosis. In mice, lesions are predominantly composed of macrophage-derived foam cells, and the relative amount of vascular smooth muscle cells and calcification is reduced compared with that in human plaques. Furthermore, endothelial function in mice might be compromised proximal as well as distal from the atherosclerotic lesion.
Until now, the mechanisms of vascular remodeling are poorly understood. Postulated mechanisms are changes in shear stress, shear stressed–induced NO production, endothelial dysfunction, hypertension, and the activation of matrix-degrading proteins.9
During atherogenesis, shear stress changes, and as a response, the arterial endothelium adapts by inducing the chronic expression of vasodilatory substances, such as NO.30,31 Consequently, the artery dilates and thereby compensates for the initial lumen loss. On the other hand, atherosclerosis induces endothelial dysfunction, causing an impaired endothelium-dependent relaxation, which contributes to inadequate vasodilation and inadequate compensatory enlargement.32–34 In addition, it has been reported that a decreased blood flow causes constrictive remodeling.24,30 These features also apply, albeit to a lesser extent, in apoE-/- mice. Although apoE-/- mice develop compensatory enlargement, they show a diminished vasodilatation response to acetylcholine and to NO.16,35–37 The severity of endothelial dysfunction in apoE-/- mice varies in the different studies and seems to be positively correlated with age and atherogenicity of the diet.16,35–38 Furthermore, the mouse hyperdynamic circulation may result in a continuous release of vasodilatory factors that could prevent the development of constrictive remodeling.29
In humans, hypertension is also correlated with an increase in arterial diameter and could thereby contribute to compensatory enlargement.39 However, vice versa, the stiffness of a chronic dilated artery could facilitate the manifestation and maintenance of systolic hypertension.39 Interestingly, hypertension and increased arterial wall stiffness were also observed in apoE-/- mice, possibly contributing to dilation of the arteries.35,38
Another mechanism responsible for remodeling is the involution of the support structure of the arterial wall.9,40,41 During atherogenesis, collagen and elastin are degraded. This often results in an atrophic elastolytic media and a decreased collagen content of the adventitia. As a response, the artery enlarges, often resulting in aneurysm formation.40,42 ApoE-/- mice after being fed a severe atherogenic diet or after 1 month of angiotensin II infusion develop medial elastolysis with aneurysm formation.14,17 Degradation of collagen and elastin is mediated by plasmin-dependent activation of matrix metalloproteinases (MMPs), especially MMP-3, MMP-9, MMP-12, and MMP-13, which are produced by infiltrating macrophages.14 The importance of macrophages in mouse atherosclerotic lesion development was confirmed in 1 of our previous studies.21 Because macrophages produce MMP-3, MMP-9, MMP-12, and MMP-13,14 macrophages may play a key role in mouse vascular remodeling. Other observations supporting the important role of MMPs in aneurysm formation are that administration of an MMP inhibitor in rats and targeted disruption of MMP-9 in mice suppress the development of experimental abdominal aortic aneuryms.43,44 Also, in the present study, medial elastolysis was observed in apoE-/- and apoE*3-Leiden mice. In apoE-/- mice, the level of elastolysis was elevated compared with the level in apoE*3-Leiden mice, and elastin breaks were found throughout the media, whereas in apoE*3-Leiden mice, elastolysis was confined to the innermost elastic laminae. This might explain the more prominent vascular remodeling in apoE-/- compared with apoE*3-Leiden mice.
Whether elastin degradation in the media is the cause of the development of compensatory enlargement or the consequence is still not clear. In favor of a causative role of elastin degradation are the recently published results of a study showing that administration of a serine elastase inhibitor completely reverses fatal pulmonary remodeling in rats.45 In the present study, an increased amount of elastin breaks was already present in initial lesions, before significant compensatory enlargement develops, also indicating a causative role for media degeneration in the development of compensatory enlargement. The results of an elastin inhibitor in atherosclerosis are yet to be determined.
In conclusion, apoE-/- mice and apoE*3-Leiden mice are appropriate small animal models for studying vascular remodeling, especially in the CA. For the investigation of the regulation of remodeling, apoE-/- mice are more appropriate, because in this model, compensatory enlargement, stenosis, medial atrophy, and elastolysis are most prominent. However, direct extrapolation to the human condition should be performed with caution, because some human features of vascular remodeling (such as poststenotic dilation and constrictive remodeling) are not observed in apoE-/- or apoE*3-Leiden mice.
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Acknowledgments |
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This project was sponsored by the Wynand Pon Foundation, Leusden, the Netherlands
Received February 11, 2001; accepted March 15, 2001.
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