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Eur J Cardiothorac Surg 2004;25:585-590
© 2004 Elsevier Science NL

Perivascular application of C-type natriuretic peptide attenuates neointimal hyperplasia in experimental vein grafts

Thomas Schachnera, Yping Zoua, Alexander Oberhubera, Thomas Mairingerb, Alexandar Tzankovb, Günther Laufera, Harald Otta, Johannes Bonattia*

a Department of Cardiac Surgery, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria
b Department of Pathology, Innsbruck University Hospital, Anichstrasse 35, A-6020, Innsbruck, Austria

Received 17 March 2003; received in revised form 7 July 2003; accepted 8 July 2003.

* Corresponding author. Address: Department of Cardiac Surgery, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel.: +43-512-504-3806; fax: +43-512-504-2528
e-mail: johannes.o.bonatti{at}uibk.ac.at


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A. Conference...
 References
 
Objective: C-type natriuretic peptide (CNP), which is produced by vascular endothelial cells, exhibits anti-proliferative and anti-inflammatory effects. Cytotoxic T-lymphocytes may be involved in vein graft disease. Attenuation of vein graft disease necessitates a remodelling of the arterialized vein towards a more contractile phenotype which is characterized, among other factors, by the calponin amount. We investigated the effects of perivascularly applied CNP in a mouse model of vein graft disease. Methods: C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. In the treatment group, 10-6 mol/l of CNP were applied locally in pluronic gel. The control group did not receive local treatment. Grafts were harvested at 1, 2, 4, and 8 weeks and underwent morphometric analysis as well as immunohistochemical analysis. Results: In grafted veins without treatment (controls) median intimal thickness was 10 (6–29), 12 (8–40) µm, was 47 (12–58), and 79 (62–146) µm after 1, 2, 4 and 8 weeks, respectively. In the treatment groups, which received 10-6 mol/l of CNP, the intimal thickness was 5 (3–6), 6 (4–15), 32 (5–54), and 43 (39–70) µm after 1, 2, 4 and 8 weeks, respectively. This reduction of intimal thickness was significant at 1, 2 and 8 weeks. Immunohistochemically, the reduction of intimal thickness was associated with a decreased infiltration of CD-8 positive cells and an increased amount of calponin in the CNP-treated grafts. Conclusion: We conclude that perivascular application of CNP inhibits neointimal hyperplasia of vein grafts in a mouse model. These results suggest that CNP may have a therapeutic potential for the prevention of vein graft disease.

Key Words: Coronary artery bypass graft • Neointimal hyperplasia • C-type natriuretic peptide • Natriuretic peptide • Vein graft


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A. Conference...
 References
 
Early injury and late degeneration are responsible for the occlusion of venous bypass grafts. One important early pathological feature of veins implanted into the arterial circulation is the formation of neointimal hyperplasia. In conjunction with an inflammatory component the development of vein graft atherosclerosis is eased [1–3].

C-type natriuretic peptide (CNP) is produced by vascular endothelial cells and consists of 22 amino acids. Besides vasodilatory properties, CNP inhibits proliferation of vascular smooth muscle cells and shows anti-inflammatory and anti-thrombotic effects [4,5]. CNP binds to natriuretic peptide receptor B, which inhibits a guanylyl cyclase activity. CNP increases the amount of cyclic guanosine monophosphate in human internal thoracic arteries and saphenous veins [6,7]. In arterial injury models, CNP showed an inhibitory effect on formation of neointimal hyperplasia [8,9].

CD8 markers are found on cytotoxic T-lymphocytes which recognize major histocompatibility complex class-I bound antigens [10]. Their major cytotoxic effector molecules are perforin, granzymes, and tumor necrosis factor. Cytotoxic T-lymphocytes mediate vascular injury in graft versus host disease [11]. An interesting finding is that cytotoxic T-lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro [12]. In human stenotic aortocoronary saphenous vein grafts, accumulations of T-lymphocytes are found which are thought to be involved in immune reactions leading to progression of graft atherosclerosis [13].

Calponin is a smooth muscle specific protein which plays a role in thin filament-based regulation of smooth muscle contraction [14]. Calponin belongs to the differentiation markers of smooth muscle cells.

It was the aim of this study to test the hypothesis that cytotoxic T-lymphocytes are involved in vein graft disease and that perivascularly applied CNP has an effect on neointimal hyperplasia in vein grafts in a mouse model. And we wanted to test if a reduction of neointimal hyperplasia is associated with a remodelling of the arterialized vein graft towards a more contractile phenotype as determined by the calponin and alpha smooth muscle actin amount.

This mouse model for vein graft disease was developed at our University [15]. Pluronic-127 gel has been demonstrated to be an effective carrier for a drug and does not influence neointimal hyperplasia in this animal model [16].


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Conclusion
 Appendix A. Conference...
 References
 
2.1. Mice and vein grafting
Three-month-old male C57BL/6J mice were purchased from Harlan-Winkelmann (Borchen, Germany). They were maintained at 24 °C and received food and water ad libitum. All procedures were performed according to protocols approved by the Austrian Ministry of Science according to Section 8 of the law on animal experiments and all animals were treated according to the ‘Guide for the Use and Care of Laboratory Animals’, published by the National Institutes of Health (NIH publication no. 85-23, revised 1985).

The operation was performed as previously described [15]. In brief, the inferior vena cava was harvested from an isogenic donor mouse and stored in cold Ringer's lactate solution. In the recipient mouse, the right common carotid artery was exposed, ligated, divided and the two stumps were everted over a nylon cuff. The vein from the donor mouse was then interposed between the carotid artery cuffs.

2.2. CNP application and tissue preparation
In the treatment groups, 10-6 mol/l of CNP were applied perivascularly around the grafted vein. As a carrier, we used 0.1 ml of 20% Pluronic-F-127TM gel (BASF, Germany). The control group did not receive local treatment.

For histological analysis, the animals underwent autopsy 1, 2, 4 and 8 weeks postoperatively. The grafts were perfusion-fixed with 4% phosphate buffered formaldehyde via puncture of the left ventricle as described previously [15]. The interposed vein segments were cut out at the cuff ends and were fixed with 4% phosphate-buffered formaldehyde. Due to the small size of the grafts, they were embedded in a piece of mouse liver tissue. Consecutively, the compounds were formalin-fixed and paraffin embedded.

2.3. Histology and lesion quantification
Four micrometre thick sections were cut and were Elastica van Gieson stained for measurement of the intimal thickness. Digital photomicrographs of all vessels were taken using a SONY DSC-70 camera with a resolution of 2048x1586 pixels with a colour depth of 24 bits per pixel in RGB. The microscope used was a Zeiss Axioplan with Plan Flourit optics and a fotoadapter. For getting an overview picture, a 10x magnification objective was used. The zoom objective of the camera was adjusted to full zoom, and afterwards reduced by three microsteps. For measurements, a 20x magnification objective was used with the same camera adjustment.

All photographs were saved in JPEG format. The measurements were done using OPTIMAS 5.0 image analysis software on an IBM compatible PC. For reproducibility reasons, the overview pictures were used to mark the exact locations where the thickness measurements were taken.

The intimal thickness measurements were performed by two experienced observers (T.M. and A.O.). For achieving a reproducible result, the cross-sections of the veins were divided into four quadrants. In each quadrant three measurements were made. The mean value of all measurements was regarded as representative for the intimal thickness.

2.4. Immunohistochemistry
Immunohistochemistry was carried out on paraffin embedded sections of animals 4 weeks postoperatively. The following primary antibodies were used: mouse anti-CD-8 (clone C8/144B IgG1-{kappa}, Dako Inc., Glostrup, Denmark) for detection of T-lymphocytes, mouse anti-metallothionin (clone E9 IgG1-{kappa}, Dako Inc., Glostrup, Denmark), mouse anti-smooth muscle actin (IgG1, Biogenex Inc., San Ramon, CA), mouse anti-platelet derived growth factor receptor {alpha} (PDGFR{alpha}) (Santa Cruz Biotechnology, CA), mouse anti-calponin (IgG1, Sigma Inc., Vienna, Austria). The sections were visualized using NexES IHC® automatic immunohistochemical stainer (Ventana Medical Systems, Tucson, AZ) with diaminobenzidine basic kit (Ventana Medical Systems, Tucson, AZ).

The results were quantified by a pathologist (A.T.) by counting the number of positively staining cells in high-power fields (400x magnification; 0.189 mm2/field). The number of counted cells was extrapolated to 0.2 mm2. Staining intensity was not quantified, but only intensities at least two times stronger than background have been taken into consideration. Since cellular borders of migrated myofibroblasts were hardly ever to be defined, the total area of SMA positive patches was evaluated. In the case of metallothionein and PDGFR{alpha} expression in the neointima, only a description analysis was performed, since the staining was not confined to cells but to the matrix.

2.5. Statistical analysis
The SPSS software (SPSS 10.0) for windows was used for statistical analysis. Neointimal thickness is given as median and range. Comparisons between histological measurements of the intimal thickness were made by Mann–Whitney U test. Results were considered statistically significant at P values of less than 0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Conclusion
 Appendix A. Conference...
 References
 
The intimal thickness in native veins was 1.6 (1.3–2.4) µm. Neointimal hyperplasia developed in all vein grafts (Fig. 1) . After 1 week, intimal thickness in grafted veins without treatment (controls) was 10 (6–29) µm, whereas in CNP-treated vein grafts the intimal thickness was 5 (3–6) µm (P=0.003). After 2 weeks, intimal thickness in controls was 12 (8–40) µm, whereas in CNP-treated vein grafts the intimal thickness was 6 (4–15) µm (P=0.032). After 4 weeks, intimal thickness in controls was 47 (12–58) µm, whereas in CNP-treated vein grafts the intimal thickness was 32 (5–54) µm (P=0.16). After 8 weeks, intimal thickness in controls was 79 (62–146) µm, whereas in CNP-treated vein grafts the intimal thickness was 43 (39–70) µm (P=0.01). This was a reduction of neointimal thickness in CNP-treated vein grafts of 47, 50, 31 and 46% after 1, 2, 4, and 8 weeks, respectively, compared with controls. The difference to controls was statistically significant at 1, 2 and 8 weeks.



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  		Fig. 1. Reduction of neointimal hyperplasia in vein grafts by perivascular application of CNP.

 
Thrombus formation in the vein grafts occurred in no case after 2 weeks. After 4 weeks, thrombi were found in 2/7 (29%) control veins and in 1/9 (11%) CNP-treated veins.

Immunohistochemical staining with anti-calponin antibody showed a predominant expression in the adventitia. In the CNP-treated group, the amount of calponin positive cells was significantly increased as compared with controls (Fig. 2a and b ; Table 1).



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  		Fig. 2. Immunohistochemical staining at 4 weeks postoperatively for calponin in controls (a) and CNP-treated (b) vein grafts. Note the increased number of positively staining cells in the adventitia of the CNP-treated grafts (b). Immunohistochemical staining for CD8 in controls (c) and CNP-treated (d) vein grafts. Note the increased number of positively staining cells in the adventitia of the controls (c) (20-fold magnification).

 

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  		Table 1. Quantitative analysis of calponin, CD-8, metallothionein, smooth muscle actin (SMA) and PDGFR-{alpha} positivity in vein grafts at 4 weeks postoperatively

 
Immunohistochemical staining with anti-CD-8 antibody showed an adventitial distribution of CD-8 positive cells, whereas in the neointima no CD-8 positive cells were found. In the CNP-treated group, the number of CD-8 positive cells was significantly reduced compared with controls (Fig. 2c and d; Table 1).

Immunohistochemical staining with anti-PDGFR{alpha} antibody showed a strong expression in the neointima, media, and adventitia. The amount of PDGFR{alpha} positive cells in the media of CNP-treated vein grafts was reduced by 53% compared with controls. The amount of PDGFR{alpha} positive cells in the adventitia of CNP-treated vein grafts was increased by 29% compared with controls. These differences between the two groups in the amount of PDGFR{alpha} positive cells, however, did not reach statistical significance (Table 1).

Immunohistochemical staining with anti-metallothionein antibody showed a clear expression in the neointima and adventitia. The amount of metallothionein corresponded with the thickness of neointima and adventitia and there was no quantitative difference between controls and CNP-treated groups. However, the amount of positively staining cells in the media of the controls exceeded that in the media of CNP-treated animals (Table 1).

Immunohistochemical staining with anti-smooth muscle actin antibody showed a clear expression predominantly in the neointima and only little in the media and adventitia. There were no significant differences in the average areas of SMA-positive patches between the groups (Table 1).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Conclusion
 Appendix A. Conference...
 References
 
In our experiments, we demonstrated an inhibitory effect of CNP on the development of neointimal hyperplasia in an established mouse model. The reduction was about 60% in the first 2 weeks and about 40% after 8 weeks. Yasuda and co-workers demonstrated that endoluminally applied CNP inhibits neointimal formation in a rabbit iliac artery balloon injury model [9]. One advantage of CNP is its small peptide size which makes it a candidate for use in gene therapy. Ueno and co-workers have shown that local expression of CNP after transfection into injured rat carotid arteries reduced neointimal formation [8]. Ohno and co-workers found decreased thrombus formation and reduced neointimal thickness in rabbit jugular vein grafts transfected with CNP expressing Adenovirus compared with Lac Z expressing Adenovirus transfected controls. But there was a high rate of mural thrombi of 80% after 2 weeks and 100% after 4 weeks in the Lac Z expressing controls [17]. In our study, thrombi occurred in no vein after 2 weeks and in 29% of the controls versus 11% of the CNP-treated veins after 4 weeks.

Calponin is a smooth muscle specific protein which can bind to actin, tropomyosin, Ca2+-calmodulin and myosin. It plays a role in thin filament-based regulation of smooth muscle contraction [27]. Calponin belongs to the differentiation markers of smooth muscle cells. Wolf and co-workers have demonstrated that growing coronary artery collaterals show a weak expression of calponin in the neointima, whereas after remodeling into mature, and thicker vessels the neointima contained more calponin [28].

We found an increase of calponin positive cells in CNP-treated vein grafts which was 16-fold the amount of calponin positive cells in the control group. These findings would be consistent with remodelling of the vein graft towards a more mature contractile type of vessel under the treatment with CNP.

All control vein grafts showed the presence of CD8 positive cells, whereas in CNP-treated veins they were almost completely absent. Inflammatory cell infiltration of the vein graft, which occurs early in the postoperative course is an important pathogenetic factor for neointimal hyperplasia [18]. Cherian and co-workers investigated human stenotic aortocoronary saphenous vein grafts and found an accumulation of T-lymphocytes, which are thought to be involved in immune reactions leading to progression of graft atherosclerosis [13]. In accordance with these data, we found an adventitial infiltration of the grafted veins with CD8 positive lymphocytes which were reduced in veins treated with CNP.

Different growth factors are associated with the development of neointimal hyperplasia one of which is platelet derived growth factor (PDGF) [3,19]. PDGF stimulates migration and proliferation and it inhibits apoptosis. There are two different protein subunits that form either homodimers (PDGF-AA, PDGF-BB) or heterodimers (PDGF-AB). There are two corresponding receptors (PDGFR{alpha}, PDGFRß). All PDGF isoforms can bind to PDGFR{alpha}, whereas PDGF-AA and PDGF-AB cannot bind to PDGFRß [19]. In native human saphenous veins, PDGFR{alpha} expression is less than expression of PDGFRß [20]. Sirois and co-workers found that both, PDGFR{alpha} and PDGFRß, were overexpressed in balloon injured rat carotid arteries 2 weeks after injury [21]. PDGFR blockade inhibited intimal hyperplasia in balloon injury models [22,23], thus suggesting a role in vein graft disease too. We found a strong presence of PDGFR{alpha} positive cells in controls as well as in CNP-treated veins. The amount of PDGFR{alpha} positive cells in the media of CNP-treated animals showed a trend towards reduction compared with controls.

Metallothionein is a highly conserved, ubiquitously expressed low molecular weight protein. The expression of metallothionein is induced by heavy metals, heat, inflammation and other stress conditions. Kang and co-workers demonstrated that metallothionein inhibits ischemia reperfusion injury in the mouse heart [24]. Metallothioneins can protect against oxidative damage by scavenging harmful oxygen radicals which can be generated by activated leucocytes [14]. In our study, we found a reduced metallothionein amount in the media of CNP-treated vein grafts compared with controls, whereas in the adventitia there was no difference in the metallothionein amount between the two groups. An interesting finding was that metallothionein was more often found in the neointima and in the adventitia than in the media. This points out an active role of both intima and adventitia in the remodelling process of arterialized vein grafts.

Alpha smooth muscle actin is associated with the contractile apparatus, and it is decreased in neointimal SMCs compared with medial SMCs [25]. Cultured media SMCs from porcine coronary arteries show a strong expression of alpha smooth muscle actin [26]. In our experiments, CNP-treated vein grafts showed a trend towards a lower expression of smooth muscle actin positive cells compared with controls.

An interesting finding of our study was that the adventitia and the neointima of the arterialized vein grafts seemed to be the zones of more remodelling activity than the media. This was particularly true for the expression of metallothionein and calponin in neointimal and adventitial cells. A perivascular pharmacological approach is supported by these results.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
Appendix A. Conference...
 References
 
We conclude that perivascular application of CNP significantly inhibits neointimal hyperplasia of vein grafts in a mouse model. This reduction of vein graft disease is associated with a decreased amount of infiltration of CD-8 positive cells and an increased amount of calponin in the CNP-treated grafts. These results suggest that CNP may have a therapeutic potential for the treatment of clinical vein graft disease.


   Footnotes
 
Presented at the joint 17th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 11th Annual Meeting of the European Society of Thoracic Surgeons, Vienna, Austria, October 12–15, 2003.


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A. Conference...
References
 
Dr B. Walpoth (Geneva, Switzerland): I'm not completely aware of the model you use. Can you tell us how many of these grafts were patent after your different time points. What were your problems and patency rate? How did you connect it into the carotid artery? By anastomosis or cuff technique?

Dr Schachner: The technique we used was a cuff technique of the carotid artery, and the vein graft was connected to the carotid artery by a ligature.

Regarding your other question, we have found thrombosis in the vein grafts. Not after two weeks, we found no grafts thrombosed; but after four weeks, we found thrombosis in about 10% of the CNP-treated vein grafts and about twice that amount, about 20%, in controls. The difference was not significant; it was one and two animals in each group.

Dr Walpoth: Where was this thrombosis, at the cuff or in the vein graft?

Dr Schachner: In the vein graft

Dr Walpoth: Did you exclude those animals from your results?

Dr Schachner: Yes.

Dr R. Poston (Baltimore, Maryland, USA): I want to know if the peptide’s benefit lasts after the stuff applied to the adventitia wears off. One thing that would suggest this is that, at your later time points, do you have something that you quickly mentioned in your conclusion slide: arterial remodeling of the vein. A thicker media in the group with less neointimal hyperplasia would suggest that the vein remodeled to respond to the arterial blood pressure stress by this medialization, or "arterialization" is the term people use to describe that. Did you see any of that?

Dr Schachner: This is an interesting question. But in the vein grafts of the mouse, the media is too small at all and we couldn’t measure or find differences regarding remodeling of the media in our series.

Dr Poston: Initially, the media is thin in any vein. There is an ongoing clinical trial called the PREVENT Trial that has treated saphenous vein grafts with perioperative DNA. These investigators found in some of their preclinical models that when the neointima is inhibited in vein grafts, the media grows. So you might have that in your grafts if you specifically look for that phenomenon.

Dr Schachner: We haven’t found that so far in our series.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 Appendix A. Conference...
 References
 

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R. S. Scotland, M. Cohen, P. Foster, M. Lovell, A. Mathur, A. Ahluwalia, and A. J. Hobbs
C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression
PNAS, October 4, 2005; 102(40): 14452 - 14457.
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 Eur. J. Cardiothorac. Surg.Home page
T. Schachner, A. Oberhuber, Y. Zou, A. Tzankov, H. Ott, G. Laufer, and J. Bonatti
Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts
Eur. J. Cardiothorac. Surg., February 1, 2005; 27(2): 302 - 306.
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 Arterioscler. Thromb. Vasc. Bio.Home page
Q. Xu, M. Sata, and R. Nagai
Mouse Models of Vein Grafts
Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): e185 - e187.
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