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Cardiovascular Research 2002 55(4):864-869; doi:10.1016/S0008-6363(02)00467-4
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Matrix metalloproteinase inhibition reduces adventitial thickening and collagen accumulation following balloon dilation

Marion J Sierevogela,b,*, Evelyn Velemaa, Freek J van der Meera, Manon Oude Nijhuisa, Mirjam Smeetsa,b, Dominique P.V de Kleijna,b, Cornelius Borsta and Gerard Pasterkampa,b

aExperimental Cardiology Laboratory, University Medical Center, Utrecht, The Netherlands
bInteruniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands

m.sierevogel{at}hli.azu.nl

* Corresponding author. Tel.: +31-30-250-7155; fax: +31-30-252-2693

Received 21 January 2002; accepted 15 April 2002


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Constrictive arterial remodeling following balloon angioplasty has been related to adventitial collagen accumulation and subsequent thickening and can be prevented by matrix metalloproteinase (MMP) inhibition. Following balloon dilation, we examined the effect of MMP inhibition on collagen turnover and the relationship between adventitial area and degree of constrictive remodeling. Methods: In 12 non-atherosclerotic landrace pigs, balloon dilation was performed in 39 peripheral arteries with and without MMP inhibition. Follow up with intravascular ultrasound was performed at 42 days. Collagen content was quantified using polarized light and digital image microscopy. Procollagen expression was determined using immunochemistry and Western blotting. Results: In the MMP inhibitor group, constrictive remodeling was inhibited at 42 days follow up. In control and MMP inhibitor groups, a positive relation was observed between adventitial thickness and degree of constrictive remodeling (P<0.001). Adventitial thickening and adventitial collagen content were reduced in the MMP inhibitor group (P = 0.002 and P = 0.001, respectively). Procollagen immunostaining, but not protein analysis on Western blotting, was decreased in the MMP inhibitor group. Conclusion: MMP inhibition impaired adventitial thickening by reduction of collagen content 42 days after balloon dilation. This might explain its inhibitory effect on constrictive remodeling.

KEYWORDS Angioplasty; Enzyme (kinetics); Remodeling; Arteries; Extracellular matrix


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Constrictive arterial remodeling is the major determinant of restenosis following balloon angioplasty. Earlier proposed explanations for constrictive remodeling are based on adventitial changes following arterial injury [1–3]. Hypercellularity of the adventitia, myofibroblast formation and fibrosis have been observed together with subsequent thickening of the adventitia [2]. Lafont et al. [4] demonstrated that the ratio of adventitial area to the area of intima+media at the lesion site correlated with chronic constriction. Moreover, enhanced collagen breakdown and synthesis are important features in arterial remodeling in the first weeks following balloon angioplasty [5–8], which results in an increase of collagen at the site of injury. Bakker et al. [9] suggested that constrictive remodeling follows chronic vasoconstriction by reposition and cross-linking of fresh collagen in the arterial wall.

Matrix metalloproteinases (MMPs) play important roles in physiological as well as pathological processes including collagen turnover [6], restenosis [6,10,11], and heart failure [12,13]. Their activities increase after balloon angioplasty [7,14]. Previously, we demonstrated that oral MMP inhibition significantly inhibits constrictive arterial remodeling following balloon dilation in favor of both neutral — and expansive remodeling [10]. With intravascular ultrasound (IVUS), we showed that only a short duration (14–28 days) of MMP inhibition is sufficient to block the constrictive remodeling response at 42 days follow up [11].

The mechanisms underlying inhibition of constrictive remodeling by MMP inhibition are unknown. Differences in collagen accumulation might explain the altered remodeling response. In the present study, we determined the effect of MMP inhibition on collagen turnover by assessing collagen content, density and procollagen expression in MMP inhibited and non-inhibited porcine vessels that were obtained after balloon dilation. Furthermore, we assessed the relationship between adventitial area and the degree of constrictive remodeling at 42 days following balloon dilation for both the control and the MMP inhibitor group.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Animal model
Twelve non-atherosclerotic landrace pigs with an average weight of 20 kg were studied. Balloon dilation was performed in femoral and internal iliac arteries. Animals were treated with a MMP inhibitor or served as controls. Arteries (n = 39) were harvested at 42 days (seven control, five MMP inhibitor pigs) follow up. The investigation was approved by the ethical committee on Animal Experimentation of the University Medical Center Utrecht and conforms with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.2 MMP-inhibition
The oral non-specific synthetic MMP inhibitor Marimastat (BB-2516) was supplied by British Biotech Pharmaceuticals Limited, Oxford, U.K. This drug inhibits in the nanomolar range all known classes of MMPs. Marimastat was administered for 0 (control) or 42 days, 10 mg/kg twice a day, starting 1 day prior to the intervention. An unpublished dosimetry study in landrace pigs in our lab established that a dose of 10 mg/kg Marimastat twice a day would give exposure of 100–200 ng/ml plasma, a concentration that had previously been effective in animal models of cancer. In a previous study [10], 1–10 ng/ml functional Marimastat was detected in vessel extracts of Marimastat treated animals.

2.3 Intervention
Balloon dilation was performed as described previously [10,11]. In short, the arterial tree was accessed through a carotid approach. For balloon dilation, a standard peripheral balloon catheter (Cordis, Opta 5, length 2–4 cm, diameter 4–6 mm) was used. In the femoral arteries, balloon dilation was performed approximately 1 cm distal to the lateral femoral circumflex. In the internal iliac arteries, the mid-segments were balloon dilated. With a balloon/artery ratio of approximately 1.2, the balloon was inflated three times for 1 min at a pressure of 6–10 atm. A continuous infusion of nitroglycerin (20 µg/min) was given to prevent arterial spasm. To assess arterial remodeling, intravascular ultrasound (IVUS) was performed before intervention, immediately after intervention and at follow up, using a 4.1 F, 30 MHz ultrasound catheter with an axial resolution of 0.1 mm (Princeps®, DuMed/EndoSonics, Rijswijk, The Netherlands). Fluoroscopy was performed during IVUS in order to document the location of the images relative to an anatomic landmark for adequate matching. After angiography and IVUS at follow up, the animals were euthanisized by an overdose of pentobarbital. Vessels were harvested, snapfrozen in liquid nitrogen and stored at –80 °C until further analysis.

2.4 IVUS-analysis
The IVUS images were analyzed at regular intervals (every 0.5 cm). In each IVUS image, lumen area (LA) and vessel area (VA) were measured as before [10,11]. Anatomic landmarks were used to match the imaged locations at different time-points. Untreated segments (proximal parts of external iliac arteries, parts proximal and distal to the dilated segments of the femoral arteries, parts distal to the dilated segments of the internal iliac arteries) were used for correction of growth of all areas at 42 days follow up as follows: mean {pi}r2 pre intervention/mean {pi}r2 termination. The radius (r) was determined angiographically. The provided value was multiplied with the LA and VA measurements determined at termination. Within the balloon dilated segment, the location with the smallest LA at follow up was clearly identified and selected for further calculations.

Definitions:

• Loss in VA, being a measure of remodeling=VA post intervention–VA follow up.
• Remodeling Index (RI)=VA follow up/VA post intervention. A value of >1 indicates expansive remodeling. A value of <1 indicates constrictive remodeling.

2.5 Histomorphometry and quantification of collagen content
Quantification of total collagen content and collagen density was performed in intima, media and adventitia using picro Sirius red staining and digital image microscopy with circularly polarized light as described by Smeets et al. [15]. In short, a picro Sirius red image was converted into a grey value image. Regions of interest (ROI) were drawn to select the different arterial layers. The total amount of grey values in each layer was determined for total collagen content. Collagen density was calculated by dividing the collagen content in each layer by the cross-sectional area of this layer.

Per dilated segment, two cross sections were selected at fixed locations (proximally and distally) and analysed by observers who were blinded for the different groups.

Measurements of the two cross-sections were averaged for each artery. In addition, non-dilated femoral artery segments, approximately 2 cm distally of the treated area, were analysed.

Definitions:

• Injury score (IS), based on rupture of the internal (IEL) and external (EEL) elastic lamina:
{checkmark}0: intimal hyperplasia absent; both IEL and EEL intact
{checkmark}1: intimal hyperplasia present, both IEL and EEL intact;
{checkmark}2: IEL ruptured, EEL intact;
{checkmark}3: both IEL and EEL ruptured.

• Adventitial area index=adventitial areahistomorphometry at follow up/vessel areaIVUS at follow up.

2.6 Quantification of procollagen
2.6.1 Immunohistochemistry
To determine the area of procollagen producing cells, a mouse anti-sheep procollagen I NH2-terminal monoclonal antibody SP1.D8 (1:10, Developmental Studies Hybridoma Bank) was used. Sections (8 µm) were fixed in acetone containing 0.03% hydrogen peroxide and preincubated with 10% normal goat serum in 1% PBSA for 30 min at room temperature (RT). Subsequently, the sections were incubated with SP1.D8 diluted in 0.1% PBSA for 1 h at RT and washed three times in PBS. Incubation with the secondary antibody goat anti-mouse peroxidase (1/250, DAKO A/S Denmark) in 1% PBSA containing 5% normal swine serum was for 1 h at RT. Visualization of the sections was performed with diaminobenzidine (DAB). Negative controls were carried out with IgG1 isotype or by omitting the primary antibody. At the site of maximal injury, the sections were analyzed quantitatively by light microscopy using Sis-analysis 2.1 software. Sections were carefully studied and color thresholds were set and adjusted until the computerized detection met the visual interpretation of positive staining. For all cross-sections, the intima, media and adventitia were analyzed separately. The degree of procollagen staining was expressed in percentage of unit of intima/adventitial/medial area.

2.6.2 Western blotting
To quantify procollagen, protein was isolated using TriPureTM Isolation Reagent (Boehringer Mannheim). Same amounts of proteins (5 µg) were separated on a 6% SDS–PAGE and subsequently blotted onto Hybond-ECL. To block the non-specific binding sites, the membrane was put overnight at 4 °C in PBS containing 0.1% Tween 20 (Merck) and 5% protifar (Nutricia) (PBSTB). The blot was incubated for 1 h with SP1-D8 (1:100 in PBSTB) followed by goat–anti-mouse (DAKO A/S Denmark). Detection was performed using Chemiluminescence Reagent Plus (Renaissance®, NEN) and exposure to X-Omat Blue XB-1 films (Kodak).

2.7 Statistics
Data are presented as mean±standard error of the mean. SPSS 9.0 was used for all statistical calculations. The independent t-test with post hoc Bonferroni correction was used to compare normally distributed data among groups. A Mann–Whitney test was used to compare groups when data were not normally distributed. A Pearson's linear regression analysis was performed to study the relation between adventitial area and the degree of constrictive remodeling. P<0.05 was considered to be statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Gain in weight did not differ among groups: 11.3±0.6 in the control group versus 10.4±1.0 in the MMP inhibitor group at 42 days follow up (P = 0.65). The growth correction factor was also not different among groups: 0.81 in the control group versus 0.82 in the MMP inhibitor group.

At 42 days following balloon dilation, constrictive remodeling was observed in control vessels but not in the MMP inhibitor treated vessels: VA loss 3.07±0.93 mm2 versus –0.47±0.74 mm2 (P = 0.005).

In both the control and the MMP inhibitor group, an inverse relation was observed between adventitial area index and the remodeling index at follow up (Fig. 1, p≤0.005). Note the smaller averaged adventitial area index in the MMP inhibitor group: mean adventitial area index 0.21±0.03 versus 0.39±0.04 in the control group (P = 0.001).


Figure 1
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  		Fig. 1 Adventitial area index versus remodeling index at 42 days follow up. Control group (square markers): y = 0.68X+1.08, r = 0.56, P = 0.005. MMP inhibitor group (plus markers): y = –1.32X+1.30, r = 0.77, P = 0.001. Adventitial area index=adventitial area at follow up/vessel area at follow up. Remodeling index=vessel area at follow up/vessel area post-intervention.

 
Fig. 2 shows the relation between the degree of injury and adventitial area for control and MMP inhibitor groups at 42 days follow up. In both groups, adventitial area increased with increasing injury score. A smaller adventitial area was observed in the MMP inhibitor group irrespective of injury score.


Figure 2
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  		Fig. 2 Adventitial area in the different injury categories at 42 days follow up for control (solid bars) and MMP inhibitor group (striped bars). * P = 0.01 and 0.05 compared to control.

 
Fig. 3 demonstrates total adventitial collagen content, as well as its two determinants, adventitial collagen density and adventitial area for both the control and the MMP inhibitor pigs at follow up. In the control group, an increase in collagen content and adventitial area was observed in the dilated segments compared with the non-dilated segments (total adventitial collagen content: 210±30 grey values * 106, adventitial area 2.9±03 mm2, collagen density 69.4±4.1 grey values/µm2 in non-dilated segments) (total collagen P<0.0001, adventitial area P = 0.001). In the MMP inhibitor group, however, total collagen at 42 days follow up was lower due to a smaller adventitial area (P = 0.001 and P = 0.002, respectively). Table 1 depicts the medial and intimal collagen content, density and area for the different groups. At 42 days, density did not differ among groups irrespective of the arterial layer. However, total collagen differed between control and MMP inhibitor group in the intimal layer (P = 0.04).


Figure 3
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  		Fig. 3 Total adventitial collagen content, adventitial area and adventitial collagen density for both the control (C) and the MMP inhibitor pigs (M).

 

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  		Table 1 Medial and intimal total collagen content (total), density and area for the different groups at 42 days follow up

 
In all layers of both control and MMP inhibitor groups, the area of procollagen expressing cells was increased following balloon dilation at 42 days (media 0.3±0.1 versus 6.0±1.3% and adventitia 0.7±0.2 versus 2.5±0.4% in non-dilated arterial segments and control dilated arterial segments, respectively). MMP inhibition resulted in less procollagen stained cells in the media (3.7±1.3%, P = 0.09) and the adventitia (1.9±0.6%, P = 0.048). MMP inhibition did not influence procollagen staining in the intimal layer (5.2±1.4 versus 4.6±0.8% in the control group, P = 0.82). At protein level, no differences were observed in procollagen expression in the MMP inhibitor group compared to the control group (0.7±0.2 versus 0.9±0.3 ODu * mm2 in the control group). Differences in protein content were also not observed using Western blot analysis in another, smaller group of pigs terminated at 2, 7, and 14 days (n = 2 for MMP inhibitor and control groups) (data not shown).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The principal findings of the present study are (1) in both the control and the MMP inhibitor group, a positive relation between adventitial area and the degree of constrictive remodeling was evident at 42 days follow up; (2) after MMP inhibition, total adventitial collagen content and adventitial area were significantly reduced at follow up; (3) the reduction in collagen content could not be explained by a reduction in collagen density or altered procollagen expression at protein level.

The adventitia is the first layer to respond to injury and is assumed to play an essential role in constrictive arterial remodeling following balloon angioplasty [1–3]. Three to 7 days after injury, the adventitial layer becomes hypercellular due to the proliferation of fibroblasts [2]. Between 7 and 14 days, the adventitial fibroblasts change into myofibroblasts, followed by accumulation of collagen containing scar tissue within the adventitia [2]. These changes are accompanied by thickening of the adventitial layer. In the present study, constrictive remodeling was observed in the control group at 42 days following balloon angioplasty. In the MMP inhibitor group, however, constrictive remodeling was significantly reduced (82%) at 42 days follow up. In both control and MMP inhibitor groups, the adventitial area index was inversely related with the remodeling index. However, adventitial area at 42 days was smaller in the MMP inhibitor group, which might explain the inhibitory effect on constrictive remodeling. This reduction in adventitial area could not be explained by less severe injury, since adventitial area in the MMP inhibitor group appeared smaller compared to the control group for all injury score categories. In addition to the smaller adventitial area in the MMP inhibitor group at 42 days follow up, a lower total adventitial collagen content was observed. Although the area of procollagen producing cells was reduced in the MMP inhibitor group, on a protein level, altered procollagen expression did not differ among groups. Enhanced breakdown might be an alternative explanation for the altered collagen content by MMP inhibition. However, this is very unlikely since MMP inhibitors are known to inhibit collagen breakdown [16,17]. Yet, it seems that MMPs are involved in collagen production or cross-linking apart from its role in collagen breakdown. This hypothesis is supported by the study by Strauss et al. [6] that showed that MMP inhibition reduces collagen content in the injured rabbit vessel wall. Uzel et al. [18] demonstrated in mouse embryo fibroblasts cultures, that members of the metalloproteinase family (bone morphogenetic protein 1-related) process pro-lysyl oxidase and control lysyl oxidase activation. Lysyl oxidase catalyzes the final enzymatic step required for collagen and elastin cross-linking in extracellular matrix biosynthesis. Changes in the process of cross-linking of collagen molecules are associated with defects in the biomechanical stability of the extracellular matrix and might result in enhanced breakdown of the adventitia which is the layer containing most collagen in the vessel wall.

4.1 Limitations
One must keep in mind that MMPs play an important role in several other processes besides collagen turnover, like amplification of the initial signaling coagulation pathway, and in the absorption and utilization of dietary proteins. It is unknown how these actions affect the injury response and other systems of the body.

The comparison between histology and IVUS is limited by the fact that the vessels were not pressure-fixed after sacrifice, whereas the IVUS measurements were performed at arterial blood pressure. Post mortem shrinkage of the pathology specimens, in part by preservation and staining techniques, may confound these observations, but might expected to be similar among groups.

Animals were terminated at 6 weeks after intervention. This duration of follow up merits careful consideration. It was assumed that this time frame reflects the 6 months follow up in humans. We cannot exclude that the remodeling response continues after 6 weeks which could affect the observations of this study.

In conclusion, constrictive arterial remodeling following balloon angioplasty was positively related with adventitial growth. MMP inhibition significantly reduced total adventitial collagen content at 42 days follow up due to a significant reduction in adventitial area, which might explain the inhibitory effect of MMP inhibition on constrictive arterial remodeling.

Time for primary review 18 days.


   Acknowledgements
 
This study was supported by grants from the Sorbo Foundation, the Netherlands Heart Foundation (99209) and the Netherlands Organization for Scientific Research (NWO 902-16-239 and 902-16-222).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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