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Cardiovascular Research 2005 65(3):737-742; doi:10.1016/j.cardiores.2004.10.034
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Copyright © 2004, European Society of Cardiology

Tenascin-C is an essential factor for neointimal hyperplasia after aortotomy in mice

Kiyohito Yamamotoa, Koji Onodaa,*, Yasuhiro Sawadaa, Kazuya Fujinagaa, Kyoko Imanaka-Yoshidab, Hideto Shimpoa, Toshimichi Yoshidab and Isao Yadaa

aDepartment of Thoracic and Cardiovascular Surgery, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
bDepartment of Pathology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

* Corresponding author. Department of Thoracic and Cardiovascular Surgery, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. Tel.: +81 59 232 1111; fax: +81 59 231 2845. Email address: k-onoda{at}clin.medic.mieu.ac.jp

Received 16 July 2004; revised 2 October 2004; accepted 18 October 2004


   Abstract
Top
 Abstract
1. Materials and methods
 2. Statistical analysis
 3. Results
 4. Discussion
 References
 
Objective: Neointimal hyperplasia at the arterial anastomotic site is a critical problem during cardiovascular surgery. It has been suggested that tenascin-C (TN-C), an extracellular matrix (ECM) glycoprotein, might play an important role in neointimal hyperplasia. In this study, the direct contribution of tenascin-C to neointimal hyperplasia after aortotomy was examined using tenascin-C-deficient (TNKO) mice.

Methods and results: A simple aortotomy model was constructed in mice. In wild-type (WT) mice, neointimal hyperplasia was observed at the suture sites at days 14 and 28. Immunohistochemical staining showed strong expression of tenascin-C in both neointima and media around the suture line at day 14. At day 28, tenascin-C staining was detected in neointima, but not in media. In tenascin-C-deficient mice, much less neointimal hyperplasia was seen compared to that in wild-type mice, and the mean neointima/media area ratio decreased to 52.8% and 34.3% at days 14 and 28, respectively. The proliferating cell nuclear antigen indices in wild-type mice were twice those in tenascin-C-deficient mice at day 14. There were fewer Alcian blue-positive proteoglycans deposited in the neointima of tenascin-C-deficient mice than in wild-type mice. These results suggest that tenascin-C promotes neointimal cell migration and proliferation, and the deposition of proteoglycans.

Conclusions: We have presented direct evidence that tenascin-C is a crucial molecule in neointimal hyperplasia at anastomotic sites.

KEYWORDS Cardiovascular surgery; Coronary disease; Remodeling; Transgenic animal models; Extracellular matrix

One of the most serious problems during coronary artery bypass grafting (CABG) is stenosis caused by intimal hyperplasia at the site of anastomosis, which eventually results in the occlusion of the artery graft [1]. Intimal hyperplasia can be defined as the abnormal migration and proliferation of vascular smooth muscle cells (SMCs) with the deposition of extracellular matrix (ECM) proteins [2].

It has been suggested that tenascin-C (TN-C), a large ECM glycoprotein, may play important roles in a variety of lesions [3]. In human restenotic neointima after percutaneous transluminal coronary angioplasty (PTCA), TN-C is transiently expressed in neointima at early stages [4]. A marked deposition of TN-C has also been found in neointima of rat balloon-injured arteries [5]. In vitro studies showed that TN-C blocks adhesion of SMC to fibronectin [6] and promotes migration [7]. In addition, stimulation of platelet-derived growth factor (PDGF) and angiotensin II markedly upregulates the synthesis of TN-C in cultured SMCs [6,8].

Recently, we demonstrated that neointimal hyperplasia in the free artery graft stenosis of a rat model was closely associated with TN-C expression [9]. Although these findings indicate the involvement of TN-C in neointimal hyperplasia, direct evidence of its contribution has yet to be demonstrated. In this study, a simple aortotomy model is constructed using TN-C-deficient (TNKO) and wild-type (WT) mice, and neointimal formation around the suture lines is examined.


   1. Materials and methods
Top
 Abstract
 1. Materials and methods
2. Statistical analysis
 3. Results
 4. Discussion
 References
 
1.1. Animals and aortotomy model
Female TNKO mice of the BALB/c strain and WT littermates, aged 8–9 weeks old, were used [10]. All studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and Mie University Animal Experiment and Care Committee. Mice were anesthetized by intraperitoneal injection of 50 mg/kg of sodium pentobarbital. Abdominal aortas were exposed through a midline incision in the abdomen as previously described in rats [11]. Briefly, the aorta was clamped and a longitudinal aortotomy (3 mm in length) was made. The closure of the aortotomy was then immediately performed by interrupted 11–0 nylon sutures without injuring the intima and the abdominal wall was closed in layers.

1.2. Morphometric analysis
Aortas were harvested at days 7, 14 and 28 (5–6 mice/group at each time point) under anesthesia. Mice were then perfused with 20 ml of heparin-prepared saline followed by 50 ml of 10% neutral buffered formalin solution, and aortas were removed, post-fixed in the same fixative at 4 °C for 1 day and embedded in paraffin. For histological analysis of the suture sites, cross sections (5 µm thick) were cut from the center of the longitudinal aortotomy. Four sections were selected and stained with elastica van Gieson to demarcate the internal elastic lamina. Neointima at the suture sites of aortotomy was defined as the area, which contained fine elastic fibers. With each section, the luminal area and the ratio between neointima and media were calculated using an image analysis system (NIH Image version 1.61, Macintosh) as previously described [9].

1.3. Immunohistochemistry and histochemistry
Immunohistochemical staining for TN-C was performed using a rabbit anti-human polyclonal antibody (1 µg/ml) according to a method previously reported [12]. To detect monocytes or macrophages, a rat anti-mouse Mac-3 monoclonal antibody (1:20; BD Pharmingen, San Diego, U.S.A.) was used. The sections were then incubated with peroxidase-conjugated anti-rabbit or anti-rat IgG (1:200; MBL, Nagoya, Japan), followed by color development with diaminobenzidine/H2O2 solution. Light counterstaining with hematoxylin was performed. Rabbit and rat control IgGs were used instead of primary antibodies as negative controls of immunostaining. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and {alpha}-smooth muscle actin ({alpha}-SMA) was performed using peroxidase-conjugated anti-{alpha}-SMA antibody (EPOS, DAKO, Tokyo, Japan) and mouse monoclonal antibody against PCNA (PC10, EPOS, DAKO), respectively [9]. The PCNA labeling index was determined by dividing the number of PCNA-positive cells by the total number of nucleated cells in neointima taken from each section.

Collagen fibers were stained with Sirius red as previously reported [13] and examined under a polarization microscope. Alcian blue staining was used to stain the proteoglycans. Briefly, the sections were pretreated with 3% acetic acid for 1 min, treated with 1% Alcian blue, pH 2.5, for 20 min, and then with 0.1% nuclear fast red for 1 min.

1.4. In situ hybridization
TN-C mRNA expression was detected by in situ hybridization using a method previously reported [12]. Vascular tissue sections were treated with proteinase K for 15 min, and hybridization signals were visualized with alkaline phosphatase-conjugated anti-digoxigenin antibody, followed by incubation in nitrotetrazolium blue/5-bromo-4-chloro-3-indolyl phosphate solution.


   2. Statistical analysis
Top
 Abstract
 1. Materials and methods
 2. Statistical analysis
3. Results
 4. Discussion
 References
 
Values are expressed as the mean ± standard deviation (S.D.). Statistical analysis between the groups was performed using the Mann–Whitney U-test. Differences between the groups were considered significant at P<0.05.


   3. Results
Top
 Abstract
 1. Materials and methods
 2. Statistical analysis
 3. Results
4. Discussion
 References
 
3.1. Neointimal hyperplasia in mouse aortotomy model
There were no significant differences in the geometry of the abdominal aorta between unoperated TNKO and WT mice.

In WT mice, neointimal hyperplasia was seen at the suture sites of aortas at postoperative day 14 and had progressed markedly by day 28 (Fig. 1). The mean neointima/media area ratio at day 28 was significantly increased compared with that at day 14 (Fig. 2B). The luminal areas of the aortotomy sites at day 28 were significantly less than those of the proximal sites without aortotomy (0.0572 ± 0.0190 vs. 0.0985 ± 0.0226 mm2, P=0.01).


Figure 1
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  		Fig. 1 Neointimal formation and expression of TN-C at the suture sites of aortotomy in wild-type mice. (a–c) Elastica van Gieson-stained cross-sections. Neointimal hyperplasia is seen at the suture line at POD 14 and markedly progresses at POD 28. (d–f) Immunostaining for TN-C. Immunostaining of TN-C is seen in media and periadventitia around the suture line at POD 7, and is predominantly detected in both neointima and media at POD 14. TN-C-positive staining becomes weaker in media at POD 28. (g–i) Localization of TN-C by in situ hybridization. TN-C mRNA is detected in media and adventitia around the suture line at POD 7, and predominantly in neointima at POD 14. On POD 28, TN-C mRNA is not detected in either media or neointima. (a, d, g) POD 7, (b, e, h) POD 14, (c, f, i) POD 28. Arrow heads indicate internal elastic lamina in (b), (c), (e) and (f). A dotted line indicates internal elastic lamina in (h). Scale bar in (i): 50 µm for (g)–(i) and 100 µm for (a)–(f). POD, postoperative day; Ad, adventitia; Med, media; Neo, neointima.

 

Figure 2
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  		Fig. 2 Neointimal formation at suture sites of aortotomy in WT and TNKO mice. (A) Elastica van Gieson-stained cross-sections. (a, b) WT mice, (c, d) TNKO mice, (a, c) POD 14, (b, d) POD 28. In TNKO mice, hyperplastic neointima is obviously smaller than in WT mice at PODs 14 and 28. Arrow heads indicate internal elastic lamina. Scale bar in (d): 100 µm. (B) Neointima/media area ratio at suture sites of aortotomy. Four sections per animal were selected and data are mean ± S.D. of the neointima/media area ratio from five animals per group at each time point. A difference between PODs 14 and 28 in the WT group was significant (*P=0.038). Significant differences between WT and TNKO groups at PODs 14 and 28 were present (POD 14: **P=0.025, POD 28: ***P=0.005).

 
3.2. Expression of TN-C in suture sites of mouse aortas
In WT mice, immunostaining of TN-C was seen in the media and periadventitia around the suture line on day 7 after surgery. At day 14, TN-C staining was markedly detected in both neointima and media. At day 28, TN-C labeling became weaker in the media, but remained in the neointima, especially beneath endothelia (Fig. 1).

In WT mice, in situ hybridization revealed TN-C mRNA-positive cells in the media and adventitia around the suture line on postoperative day 7. At day 14, TN-C-expressing cells were observed predominantly in neointima. At day 28, the expression of TN-C mRNA was no longer detected in either media or neointima (Fig. 1).

3.3. Decrease in neointimal hyperplasia in TN-C-deficient-mice
The neointimas of TNKO mice were obviously smaller than those of WT mice at days 14 and 28 (Fig. 2A). Mean neointima/media area ratios in TNKO mice were significantly lower than those in WT mice at day 14 (0.08 ± 0.055 vs. 0.152 ± 0.073, P=0.025) and day 28 (0.107 ± 0.060 vs. 0.312 ± 0.227, P=0.005) (Fig. 2B). The mean neointima/media area ratio in TNKO mice was reduced to 52.8% and 34.3% at postoperative days 14 and 28, respectively, as compared to WT mice.

3.4. Cell proliferation in neointima
To assess the extent of differentiation and proliferation of neointimal cells, cross sections at days 14 and 28 were stained using a monoclonal antibody against PCNA and the labeling indices in the neointima at the suture site were evaluated. PCNA indices in WT and TNKO mice were 26.7 ± 13.3% and 13.6 ± 6.0% (P=0.044), and 21.2 ± 9.0% and 13.3 ± 5.7% (P=0.178) at postoperative days 14 and 28, respectively (Fig. 3). At day 14, the PCNA indices in WT mice were twice those in TNKO mice. At day 28, PCNA indices tended to be higher in WT mice than in TNKO mice (Fig. 3).


Figure 3
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  		Fig. 3 PCNA index in neointima at the suture sites of aortotomy. Four sections per animal were selected, and data are mean ± S.D. of PCNA index from five animals per group at each time point. A significant difference between WT and TNKO groups at POD 14 was observed (*P=0.044). POD, postoperative day.

 
3.5. Histological characterization of neointima
A significant number of {alpha}-SMA-positive cells were seen in neointima and media of WT mice at day 14 (Fig. 4). The number of {alpha}-SMA-positive cells in the whole neointima at day 14 was 32.3 ± 5.91 in the WT mice and 14.3 ± 6.89 in the TNKO mice (P=0.028). There were fewer {alpha}-SMA-positive cells in the neointima of TNKO mice than in WT mice at day 14. However, the density of {alpha}-SMA-positive cells in the neointima did not significantly differ between the groups (WT mice: 4879/mm2, TNKO mice: 3711/mm2, P=0.114, Fig. 4). Dense accumulation of Mac-3-positive cells, namely monocytes or macrophages, was seen in the media and periadventitia near suture lines, while only a small number of Mac-3-positive cells were detected in neointima in both TNKO and WT mice at days 7 and 14 (Fig. 4). No apparent histological differences of monocyte/macrophage infiltration in adventitia were observed between TNKO and WT mice.


Figure 4
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  		Fig. 4 Immunostaining for {alpha}-SMA (a, b) and Mac-3 (c, d) at the suture sites of aortotomy at POD 14. (a, c) WT mice, (b, d) TNKO mice. In TNKO mice, less {alpha}-SMA-positive cells are detected in neointima. Accumulation of Mac-3-positive cells is seen in periadventitia and media around suture lines, while Mac-3-positive cells are rarely detected in neointima in both WT and TNKO mice. Arrow heads indicate internal elastic lamina. Scale bar in (d): 50 µm for (c) and (d), and 100 µm for (a) and (b). POD, postoperative day.

 
Deposition of Alcian blue-positive proteoglycans was observed in the neointima of WT mice at day 14 and was increased at day 28. In the neointima of TNKO mice, Alcian blue-positive proteoglycans were less than in WT mice at days 14 and 28 (Fig. 5). Birefringence of collagen fibrils stained with Sirius red were not detected in neointima of either WT or TNKO mice (data not shown).


Figure 5
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  		Fig. 5 Expression of Alcian blue positive-proteoglycans at suture sites of aortotomy at POD 28. (a) WT mice, (b) TNKO mice. In neointima of TNKO mice, deposition of Alcian blue-positive proteoglycans is less than in WT mice. Arrow heads indicate internal elastic lamina. Scale bar in (b): 100 µm. POD, postoperative day.

 

   4. Discussion
Top
 Abstract
 1. Materials and methods
 2. Statistical analysis
 3. Results
 4. Discussion
References
 
Animal models using transgenic and gene-knockout mice are valuable for investigating gene functions during pathological events. Various models such as transluminal endothelial injury [14], cuff-mediated perivascular injury [15] and flow-restriction vascular injury by ligation [16] have been attempted to induce neointimal hyperplasia in genetically manipulated mice. In this study, to directly present evidence of the contribution of TN-C to neointimal hyperplasia, a simple aortotomy model was employed using TNKO mice, a method previously performed in the rat [11]. The longitudinal aortotomy certainly results in a stenosis from interrupted sutures. A stenosis produces blood turbulence or shear stress at the lesion, which possibly induces certain factors that stimulate SMC proliferation and migration, thus resulting in neointimal hyperplasia. Therefore, the stenotic lesion in the aortotomy model was thought to be comparable with the anastomotic stricture of artery grafts during cardiovascular surgery. In this model, we compared the morphological and histological changes in WT and TNKO mice that occur at the suture site after surgical trauma. Indeed, marked neointimal hyperplasia, which was associated with strong TN-C expression, was observed in WT mice. Furthermore, the changes in the distribution of TN-C expression during the first 28 days after surgery, which seemed to move from adventitia and media to neointima, were similar to those previously observed in anastomotic sites of free artery grafts in rats [9]. The immunohistochemical staining for {alpha}-SMA also showed a large number of positive cells in neointima.

TN-C promotes migration of arterial SMCs [7] and growth factor-dependent proliferation [17]. Marked expression of TN-C has been found in vascular lesions at the active phase, such as in rat balloon-injured artery [5], human coronary atherosclerotic plaque [18] and arterialized human vein grafts [19], as well as in the early stage after PTCA [4]. Furthermore, it is reported that TN-C might contribute to adventitial remodeling, which involves the migration of myofibroblasts from adventitia to neointima [20]. Recently, we established a model of graft stenosis using rat abdominal aortas with neointimal hyperplasia, and demonstrated the strong expression of TN-C in neointima and media of the anastomotic site and graft body in the early stages [9]. In addition, cilostazol administration, which is a specific inhibitor of cAMP phosphodiesterase III, remarkably suppressed both TN-C expression and neointimal hyperplasia at the stenosis, while cilostazol also suppressed the TN-C mRNA expression induced by PDGF-BB in cultured aortic SMCs [9]. Therefore, it is suggested that TN-C plays a crucial role in neointimal hyperplasia at an early stage.

In the present study, neointimal hyperplasia was apparently diminished in the TNKO mice compared with WT mice. The neointima/media area ratio in TNKO mice was as low as one-third of that in WT mice at day 28. Furthermore, as fewer {alpha}-SMA-positive cells were detected in neointima of TNKO mice, the PCNA indices in neointima of TNKO mice were significantly lower than those of WT mice at day 14. In human restenotic neointima after PTCA, TN-C expression was transiently upregulated in the early stages, followed by a marked accumulation of a proteoglycan, PG-M/versican. The volume effect of PG-M/versican deposited in neointima is responsible for narrowing of the vascular lumen [4]. In neointima of stented human coronary arteries, versican staining was also positive, colocalized with {alpha}-SMA-positive cells [21]. In this model, Alcian blue-positive proteoglycans, possibly PG-M/versican, were also shown in neointima of WT mice at days 14 and 28, but to a lesser extent in TNKO mice. These results suggested that TN-C might promote recruitment of {alpha}-SMA-positive cells and deposition of PG-M/versican during neointimal formation. Finally, the study indicates that TN-C is an essential factor for neointimal hyperplasia at anastomotic sites of artery grafts at an early stage. In human coronary atherosclerotic plaques, it was shown that TN-C expression correlated with the infiltration of macrophages [18]. A study on mammary tumor tissues has reported that the TN-C-null stromal compartment contains significantly more monocytes/macrophages than that of WT mice [22]. However, we could not find any marked macrophages infiltrating neointima or any apparent differences of periadventitial inflammation between TNKO and WT mice.

In conclusion, it has been demonstrated that TN-C directly contributes to neointimal formation, implying its role as a target molecule for the prevention of stenosis.


   Acknowledgement
 
This work was supported by a Grant-in-Aid for General Scientific Research (B) (2) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (No. 14370409).


   Notes
 
Time for primary review 18 days


   References
Top
 Abstract
 1. Materials and methods
 2. Statistical analysis
 3. Results
 4. Discussion
 References
 

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