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(Circulation. 1997;95:1293-1300.)
© 1997 American Heart Association, Inc.
Articles |
Collagen Content Is Significantly Lower in Restenotic Versus Nonrestenotic Vessels After Balloon Angioplasty in the Atherosclerotic Rabbit Model
the Division of Cardiology (W.D.C., D.T.C., J.W.C., D.P.F.), Department of Medicine, University of Southern California School of Medicine, Los Angeles; The Heart Institute (P.W.), The Hospital of the Good Samaritan, Los Angeles, Calif; and The Children's Hospital (B.H.), Department of Surgery, Los Angeles, Calif.
Correspondence to William D. Coats, Jr, PhD, Division of Cardiology AHC 117, 1355 San Pablo St, Los Angeles, CA 90033. E-mail coats{at}hsc.usc.edu
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Abstract |
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Background It is recognized that restenosis is primarily due to alterations in geometric remodeling of the extracellular matrix rather than intimal hyperplasia. Prior studies have shown that angioplasty stimulates an increase in both synthesis and degradation of collagen in the atherosclerotic vessel. However, differences in collagen content and metabolism between restenotic and nonrestenotic vessels have not been examined.
Methods and Results Four weeks after angioplasty in an atherosclerotic rabbit model, collagen content in restenotic and nonrestenotic vessels was measured both biochemically by hydroxyproline quantitation and histologically by a digital subtraction method with the use of circularly polarized images of picrosirius red–stained sections. Collagenase and gelatinase activity also were measured in the same restenotic and nonrestenotic vessels by use of a radiosubstrate assay. Collagen content was found to be significantly lower in restenotic vessels than in nonrestenotic vessels both biochemically (127.0±32.6 versus 212.6±84.3 µg/mg tissue; n=11 vessels; P<.05) and histologically (67.3±7.9% versus 76.3±11.8% area fraction; n=20 sections from 6 vessels; P=.05). There was a significant inverse correlation between biochemically determined collagen content and gelatinase activity (P=.02) and a significant correlation between histologically determined lumen area and percent collagen content (P=.0071).
Conclusions Collagen content is significantly decreased in restenotic versus nonrestenotic vessels after angioplasty in the atherosclerotic rabbit model. The increased collagen content in nonrestenotic vessels was associated with preserved lumen area and may play a role in geometric remodeling after angioplasty.
Key Words: angioplasty • restenosis • collagen • remodeling
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Introduction |
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Changes in collagen content, subtype composition, and biosynthesis after angioplasty have been investigated in several different animal models. Studies from our laboratory and others indicated that there was a significant increase in collagen content and biosynthesis 4 weeks after angioplasty,1 2 3 and there was no apparent difference in collagen I and III subtypes versus nondilated, control vessels of the same luminal area, with type I being the predominant collagen subtype (85% to 90%).1 Collagen was shown to make up >50% of vascular protein content by 30 days after angioplasty in an atherosclerotic rabbit model.2 In a study by Strauss et al,3 angioplasty induced a 4-fold to 10-fold increase in collagen, elastin, and glycoprotein synthesis. At 1, 2, and 4 weeks after injury, the increased synthesis was accompanied by a significant increase in collagen content that coincided with the increase in cross-sectional area. These latter two studies suggested that extracellular matrix accumulation after vascular injury is a major factor in the development of the restenotic lesion.
Collectively, these results suggest that changes in vascular wall collagen metabolism (synthesis and degradation) after angioplasty may be important in the pathophysiology of restenosis. However, these previous studies examined changes in collagen content, subtype, and biosynthesis after angioplasty irrespective of the presence or absence of restenosis. The purpose of the present study was to investigate differences in collagen content and degradation between restenotic and nonrestenotic vessels in an atherosclerotic rabbit model after angioplasty.
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Methods |
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Materials
All chemicals (reagents, etc) were purchased from Sigma Chemical Co unless otherwise noted. Ketamine, xylazine, lidocaine, and dual-acting penicillin (Ambi-pen) were purchased from Western Medical and Nembutal (sodium pentobarbital) from The James Brudnick Co. DMEM (sterile, endotoxin free) and PennStrep were purchased from Gibco.
Atherosclerotic Rabbit Model of Restenosis
Twenty male New Zealand White rabbits weighing 2.5 to 3 kg were purchased from Irish Farms (Norco, Calif). After angioplasty and 4-week post–follow-up angiography, as described below, animals were randomized to biochemical or histological analyses until a total of three restenotic and three nonrestenotic vessels were obtained for histological analyses. Thereafter, all animals were placed into the restenotic and nonrestenotic groups used for biochemical analyses. The vessels obtained for biochemical analyses were bisected at the point of maximal stenosis, and half the vessel was used for determination of collagen content and the other half for determination of matrix metalloproteinase (MMP) activity. The details of iliac artery dissection and segmentation and the biochemical and histological analyses are described below. Prior studies1 4 5 6 7 8 9 10 had shown that these numbers of animals would be sufficient to detect statistical significance between groups.
Treatment of the rabbits was subject to the policies of the University of Southern California Institutional Animal Care and Use Committee and the NIH Guide for the Care and Use of Laboratory Animals governing animal care and standard euthanasia techniques. The animals were housed in the University of Southern California Vivaria and quarantined for 7 days before use. Atherosclerosis was developed in both iliac arteries as described previously.4 5 6 7 8 9 10 All animals underwent primary iliac artery deendothelialization by use of a 3F Fogarty balloon catheter and were then placed on an atherogenic diet consisting of standard rabbit chow supplemented with 0.5% cholesterol and 6% peanut oil (ICN Biomedicals). In this model, 
50% of the balloon-injured iliac arteries develop significant (
50%) stenoses.
Angiography was performed 6 to 7 weeks after initiation of atherogenesis by use of a 4F Swan-Ganz catheter (Baxter Health Care, Edwards Division) introduced into the right carotid artery. Rabbits with iliac arteries having significant angiographic stenosis (>50% occlusion) underwent balloon angioplasty as described previously4 5 6 7 8 9 10 with the use of a 2.5-mm Mills intraoperative coronary angioplasty catheter (SCIMED Life Systems, Inc) or similar angioplasty catheter. The balloon was inflated three times to 5 atm for a 30-second interval during each inflation at the site of maximal stenosis. Thirty minutes after angioplasty, a repeat angiogram was performed to assess whether a successful dilation had occurred. The animals were allowed to recover and were returned to their cages.
At the time the animals were killed, repeat angiography was performed as described above. Follow-up angiography was performed 4 weeks after angioplasty. Image acquisition was accomplished with 0.5-in super VHS 12-in laser disc tape and 12-in laser disc recorders, and analysis was performed by use of a cine MAC 2000 (Angiographic Devices Corp). The degree of stenosis preangioplasty, postangioplasty, and 4 weeks after angioplasty was measured by use of a validated computerized edge-detection system. The percent narrowing was calculated by comparing the minimal lumen diameter (MLD) to a proximal reference segment with the use of a 1-cm reference grid to correct for magnification differences. Restenosis was defined by use of binary definitions of 50% stenosis and a minimal lumen area 
0.5 mm2 at follow-up angiography 4 weeks after angioplasty. These are the standards used in the definition of clinical restenosis. The animals were euthanatized with an overdose of sodium pentobarbital (120 mg/kg), and the iliac arteries were removed immediately for biochemical analyses or the vasculature was perfusion fixed at mean arterial pressure with 10% phosphate-buffered formalin (Fisher Scientific) for histological analyses. All analyses were performed by investigators who were blinded to vessel MLD.
Iliac Artery Dissection
The procedures for iliac artery dissection before biochemical analyses were essentially those described by Coats and Brecher11 for the dissection and incubation of the descending thoracic aorta. After review of the angiograms to guide sampling at the point of MLD, a 2-cm segment of the dilated iliac artery was removed by careful dissection. The segment was immediately placed in ice-cold, sterile (endotoxin-free) normal saline (0.9% NaCl, pH 7.4, Baxter Health Care Corp) for subsequent dissection and segmentation. The adhering periadventitial tissue was rapidly removed, and the arteries were bisected at the midpoint and cut into two segments 5 mm in length. Two rings on each side of the midpoint of the MLD were then either snap-frozen in liquid nitrogen for biochemical analyses of collagen content or placed in incubation medium for determination of interstitial type I collagenase and gelatinase activity according to established methods described below.
Determination of Total Collagen Content
Hydroxyproline Assay and Calculation of Collagen Content
Hydroxyproline content was determined with the use of a modification of the method of Grant12 as described in detail by Coats et al,1 and collagen content was calculated as described in detail by Coats et al.1
Determination of Interstitial (MMP-1) and Basal Membrane (MMP-2) Collagenase Activity
Iliac Ring Incubation
Iliac arterial rings 5 mm in length were prepared from rabbits 4 weeks after the final angiography, as previously described.11 Incubation of the iliac rings was performed in 50-mL sterile Falcon tubes containing rings suspended in 10 mL DMEM, which was preequilibrated by warming to 37°C and perfusing 95% air/5% CO2 through the medium until a pH of 7.5 was achieved. The medium was supplemented with 100 U-µg/mL PennStrep (100 U penicillin and 100 µg streptomycin per milliliter). The atmosphere above the medium was replaced with 95% air and 5% CO2, and the tubes were tightly capped to maintain equilibrium. The rings were then incubated for 24 hours at 37°C with constant shaking under these conditions. Ten milliliters of DMEM supplemented with 100 U-µg/mL PennStrep was incubated under the same conditions, and the medium was used as a control.
Radioactive Substrate Assay
Collagenase activity was measured in the media of incubated iliac rings obtained after the final angiography because previous studies have shown that these collagenolytic enzymes are secreted from the cell essentially on synthesis.13 14 Iliac rings were incubated for 24 hours, and aliquots of the incubation media were concentrated to a volume equivalent to 20 µg wet tissue weight per microliter of incubation media to normalize the samples to the wet tissue weight of the rings. Gelatinase activity was measured according to previously described methods.13 14 Interstitial type I collagenase activity was measured similarly with the use of a [3H]-collagen bovine type I substrate according to the methods described below. Briefly, 30 µL of normalized and concentrated incubation medium or control medium was activated in the presence of para-aminophenylmercuric acetate (1 mmol) for 35 minutes at 22°C, then added to 50 µL of a solution containing labeled substrate (20 000 cpm of [3H]-collagen bovine type I collagen or denatured [3H]-bovine type I collagen [radiolabeled gelatin]). The final reaction mixture contained Tris-HCl (50 mmol, pH 7.5), NaCl (150 mmol), CaCl2 (5 mmol), and Brij (0.1%). The reaction was stopped after 35 minutes at 37°C by the addition of EDTA, albumin, and trichloroacetic acid added to a final concentration of 12.5%. After standing at 4°C for 30 minutes, the reaction was centrifuged at 5000g for 10 minutes at 4°C, and aliquots of the supernatant were dissolved in 4.5 mL of Liquiscint scintillation cocktail (National Diagnostics) for subsequent measurement of radioactivity. Data are expressed as counts per minute of liberated [3H].
Histological Analyses
Tissue Preparation
After review of the angiograms to guide sampling at the point of MLD, a 2-cm segment of the perfusion-fixed artery including the lesion was dissected free of adhering periadventitial tissue and cut into five cross-sectional segments that were paraffin embedded. Five-micrometer sections were removed from the block at 600 µm depth and stained with picrosirius red. Thus, each lesion was sampled at five sites within the angiographically determined MLD. Picrosirius red staining used in conjunction with polarized light microscopy is specific for the detection and identification of collagen and has been shown to be superior to that achieved with trichrome staining.15
Morphometric Quantification of Lumen Area and Collagen Content
Measurements were made only on sections that were complete. Sections that were incomplete due to processing or sectioning were not included in the data because analysis of less than a whole cross section would lead to erroneous results. Histological quantification of collagen content and lumen area in at least three representative sections from each of the six iliac arteries harvested 4 weeks after angioplasty (three nonrestenotic, three restenotic) was done according to previously published methods.15 16 Twenty complete sections were obtained and examined on a Nikon Optiphot-pol microscope with the use of circularly polarized light. The analyzer (upper polarizing filter) was rotated so that its transmission axis was aligned at 45° to the fast axis of a quarter plate above it. The polarizer (lower polarizing filter) was replaced by a circular polarizer (Meadowlark Optics) aligned so that the field of view was dark. Images were observed on a monochrome, solid-state, charge-coupled–device video camera (4800 series, Cohu, Inc) mounted on the vertical tube of the microscope along with a x1 relay lens. The images were digitized by a video frame grabber (Truevision, Inc) displayed on a high-resolution monitor (PVM 1342Q Trinitron, Sony Corp) and analyzed by use of the Java video analysis software package (Jandel Scientific). Digital planimetry of tissue sections was performed with the computer-assisted morphometric program. The luminal area and the total tissue area (excluding the tunica adventitia) were measured directly, and the total vessel area was calculated as the sum of the two. It should be noted that lumen area and total vessel area varied along each arterial segment.
Picrosirius red–stained collagen fibers appear bright when viewed with polarized light; however, other vascular elements, such as elastin and smooth muscle cells, appear dark. This optical property of the tissue was exploited to assess collagen content. Collagen content in the nonadventitial tissue was calculated by use of a digital subtraction method similar to that previously described by Whittaker et al.15 Briefly, to eliminate everything except collagen from the vessel image, a blue-filtered, monochrome, bright-field image of the picrosirius red–stained sections was subtracted from a circularly polarized image. This produced an image composed of bright collagen fibers on a black background. A histogram of the brightness of each pixel in the image was plotted. All of the noncollagenous area was removed by the subtraction and had a gray-scale level of zero, using a scale from 0 (black) to 255 (white). Thus, any pixel with a gray-scale level >0 represented collagen. The collagen content in each section was expressed as the area fraction (percent) of pixels with a gray scale >0. The organization of collagen fibers in the polarized color image was qualitatively and quantitatively examined according to previously published methods.17
Statistical Analyses
All values are expressed as mean±SD. An unpaired Student's t test was used to determine the statistical significance of differences in lumen diameters, areas, percent stenoses, collagen content, and metalloproteinase activity between the restenotic and nonrestenotic groups. The F test was performed for equality of variances and, if significant, an unpaired t test for unequal variances was used. Linear regression analysis was used to evaluate the relation between histologically determined percent collagen content and lumen area and between biochemically determined collagen content and gelatinase activity. A value of P.05 was considered statistically significant.
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Results |
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Angiography
The 20 rabbits developed 18 significant lesions at the time of initial angiography, 17 of which underwent successful angioplasty. Ten lesions were not restenotic, and 7 were restenotic at the time of follow-up angiography 4 weeks after angioplasty. Quantitative angiography was performed to ensure that the nonrestenotic and restenotic groups were comparable in MLD and reference lumen diameter at the time of angioplasty as well as in the immediate angiographic result of angioplasty. There was no significant difference in MLD before or immediately after angioplasty between the two groups (Table
). The reference diameter was also similar for both groups at those time points as well as at the 4-week follow-up angiography. The nonrestenotic and restenotic MLDs, areas, and percent stenosis significantly differed, by definition, at the 4-week follow-up study. The nonrestenotic stenoses had a significantly larger MLD (1.46±0.31 versus 0.75±0.21 mm; n=17; P=.032) and calculated minimal lumen area (1.74±0.71 versus 0.45±0.24 mm2; n=17; P<.007) and were significantly less stenotic (13.5±11.1% versus 84.1±14.6%; n=17; P<.0001) than the restenotic group.
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Collagen Content and Collagenase Activity
Collagen content (µg/mg tissue) in restenotic lesions was significantly lower than in nonrestenotic lesions (127.0±32.6 versus 212.6±84.3; n=11; P<.05) at the 4-week follow-up angiography, as shown in Fig 1. There was no difference in type I collagenase activity at this time point, and the enzymatic activity was similar to that in control incubation mediums, suggesting that very little type I collagenase activity was present in the vessels 4 weeks after angioplasty. Gelatinase activity also was not different between restenotic and nonrestenotic segments (913.3±118.4 versus 888.3±64.2 cpm; P=.66), but there was a significant inverse correlation between gelatinase activity and collagen content (P=.02), as shown in Fig 2.
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Histology
The percent collagen content was significantly lower in the restenotic segments with morphometrically measured lumen areas 0.5 mm2 than in the nonrestenotic segments (67.3±7.9% versus 76.3±11.8% of tissue area; n=20; P=.05). There also was a significant correlation between lumen area and percent collagen content at 4 weeks after angioplasty, as shown in Fig 3 (P=.0071). In addition, the nonrestenotic group had a significantly greater total vessel area than did the restenotic group (3.05±0.17 versus 2.68±0.37 mm2; n=20; P=.01), whereas there was no difference in the intima+media area between the groups. The data indicate that the same degree of hyperplasia existed in each group and that the lack of restenosis was due to compensatory enlargement of the total vessel area.
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Representative sections of the circularly polarized images from restenotic and nonrestenotic vessels are shown in Fig 4. Vessels with preserved lumen area contained a large number of yellow-orange (hence, thick18 ) circumferentially aligned, densely packed collagen fibers. In contrast, the color of the collagen fibers was more green (hence, thin18 ) and the organization of collagen fibers far less coherent in restenotic vessels. These fibers were often relatively loosely packed and were sometimes aligned radially in the vessel wall (Fig 4). High-magnification views of hematoxylin and eosin–stained sections showed increased cellularity among the loose fibers in the restenotic vessels compared with the nonrestenotic vessel (Fig 5A and 5B). Serial sections of the same vessels stained with picrosirius red and viewed with circularly polarized light at the same magnification show details of the difference in collagen-fiber alignment between restenotic and nonrestenotic vessels (Fig 5C and 5D). This difference in alignment is quantitatively illustrated in Fig 5E. The histograms show that the collagen fibers from the restenotic vessel (left histogram) are not as aligned as those from the nonrestenotic vessel (right histogram). Furthermore, some of the fibers in the restenotic vessel were radially aligned (90° to the tangent), as were nearly all fibers in sectors of restenotic vessels not shown.
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Discussion |
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These studies are the first to provide quantitative data comparing collagen content and metalloproteinase activity after angioplasty in restenotic and nonrestenotic vessels. We and others1 2 3 have previously shown that total collagen content is increased after angioplasty injury. However, despite an increase in total collagen content after angioplasty, restenotic vessels contained less collagen than nonrestenotic vessels as determined by both biochemical and histological analyses in an atherosclerotic rabbit model of restenosis. In addition, there was a positive correlation between percent collagen content and luminal area. These observations are counterintuitive to many of the early paradigms of restenosis, which attributed arterial renarrowing to accumulation of extracellular matrix containing collagen and proteoglycans in association with migrating, hyperplastic, synthetic smooth muscle cells.19 20 21 However, efforts to prevent restenosis through alterations in thrombosis, inflammation, and smooth muscle cell function have been largely unrewarding in numerous clinical trials.22 Recent studies23 suggest that this may be due to the importance of late healing events that involve extracellular matrix deposition, degradation secondary to metalloproteinase activation, and reorganization with final conversion of the smooth muscle cell back to the quiescent phenotype, reendothelialization, and favorable geometric remodeling (late compensatory enlargement).
Arterial remodeling is well described in de novo atherosclerosis.24 25 26 27 28 Studies from our laboratory16 29 were the first to demonstrate that abnormal geometric remodeling of a vessel was the primary determinant of restenosis in the atherosclerotic rabbit model used in the present study. We showed the enlargement of the total vessel area (favorable remodeling) could prevent restenosis, irrespective of the degree of intimal hyperplasia. In nearly all concurrent and subsequent animal studies using a variety of models, similar findings have been documented.23 30 31 32 33 34 35 36 In light of the findings in the present study that the collagen content of nonrestenotic vessels is higher than that of restenotic vessels and that the percent collagen content is positively correlated with luminal area in this model, and given our current and previous observations that restenosis in this model is due to lack of favorable remodeling,16 it is reasonable to strongly suspect that collagen plays an important role in remodeling. However, the mechanisms of remodeling are poorly understood,37 38 and a causal relationship between late compensatory enlargement and collagen content has not been established.39 40 41 42
Although the decrease in collagen content in restenotic vessels may be due to a decrease in collagen biosynthesis and accumulation, it is more likely that it is a result of an increase in degradation, because absolute collagen biosynthetic rates have been shown to remain above control levels as long as 12 weeks after angioplasty.3 Collagen is degraded by a family of 10 enzymes known as MMPs.43 MMP-1 and MMP-2 appear to be most important in the vessel wall. Increased activity of these enzymes has been shown to be present in atherosclerotic lesions, abdominal aortic aneurysms, and restenotic tissue.44 45 46 47 48 49 In the present study, there was no difference in type I collagenase activity between restenotic and nonrestenotic vessels at 4 weeks after angioplasty, and enzymatic activity was similar to that in control incubation mediums, suggesting that very little type I collagenase activity was present at this time point. These results are consistent with previous studies50 51 that demonstrated very low, sometimes nearly undetectable MMP-1 activity (eg, 1±1% of the normal artery) in human atherosclerotic and restenotic tissue. Gelatinase activity also was not significantly different between restenotic and nonrestenotic segments, although there was a significant inverse correlation between gelatinase activity and collagen content (P=.02). The latter data suggest that there may be increased collagen degradation after angioplasty in restenotic versus nonrestenotic arteries.
Finally, collagen organization may also be an important step in late wound healing and geometric remodeling.52 53 54 Fibroblasts are known to contract and reorganize collagen fibers into a more compact space, leading to final scar formation. Smooth muscle cells have been shown, in our laboratory and in others,55 56 to also organize and compact collagen. In the present study, picrosirius red–stained sections revealed that collagen fibers were less organized in restenotic vessels than were those seen in the nonrestenotic vessels. These qualitative observations were supported by quantitative measurement of fiber orientation. Whether this reorganization of collagen plays an important pathophysiological role in restenosis remains to be determined. The observation that collagen fibers are less organized in restenotic vessels in a model in which restenosis is entirely due to a lack of compensatory enlargement suggests that collagen organization, in addition to content, also plays a role in remodeling.
Study Limitations
The present study has several limitations. First, this model uses iliac, not coronary, arteries and the histology of the restenotic lesions has several differences from that in humans, such that the pathophysiology may differ.6 57 58 On the other hand, the advantage of the model is that unlike other restenosis models, angioplasty is performed on hemodynamically significant stenoses containing a large amount of plaque volume. The presence of intimal and medial disruption in a severely diseased artery after angioplasty in this model may better mimic the flow and shear-stress conditions seen after coronary angioplasty in humans.15
Second, there was a lack of statistically significant differences between gelatinolytic activity in restenotic and nonrestenotic vessels, and there was no detectable type I collagenolytic activity 4 weeks after angioplasty. This finding may be due to the fact that analyses were performed 4 weeks after angioplasty, at which time the metalloproteinase activity induced by vascular injury may have subsided. In a previous study from our laboratory, collagen content in this model was initially lower in the dilated vessels versus age-matched, nondilated control vessels 1 week after angioplasty (212.4±64.2 versus 320.7±53.9 µg/mg tissue), which may indicate early upregulation of metalloproteinase activity after angioplasty (W.D.C., PhD, et al, unpublished data, 1995). On the other hand, we have shown in this model that collagen content was higher 4 weeks after angioplasty than in age-matched, nondilated vessels,1 suggesting that collagenolytic activity after angioplasty was either transient and had declined before the follow-up measurement, collagen biosynthesis exceeded degradation, or both.
Less initial collagen content in vessels likely to restenose or relatively less collagen biosynthesis in the restenotic group might also be an explanation for our findings. However, we found no relationship between lumen area and collagen content immediately after angioplasty (W.D.C., PhD, et al, unpublished data, 1995).
Because postprocedural lumen diameter may be one of the most important predictors of coronary restenosis, the observed difference in MLD (0.3 mm) between restenotic and nonrestenotic groups in the present study could be of concern. However, the loss index59 (calculated as the ratio of the change in immediate gain in MLD divided by the change between the postprocedural MLD and the follow-up MLD) was -0.92 for the restenotic group and -18.0 for the nonrestenotic group. Thus, the difference in the loss index is too great for the postprocedural MLD to be the major determinant of restenosis in the present study group.
Finally, the present study did not examine adventitial collagen organization and content. The adventitia has been shown to be involved in the vascular repair process after medial injury in some animal models,32 and therefore, it may influence remodeling and restenosis. Gross inspection showed similar collagen organization, content, and fiber thickness among the restenotic and nonrestenotic groups in the present study, as illustrated in Fig 4
, but detailed analysis may be warranted in future studies.
Received September 3, 1996; accepted October 27, 1996.
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