Skip Navigation

Cardiovascular Research 2005 67(2):326-332; doi:10.1016/j.cardiores.2005.03.027
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Fogelstrand, P.
Right arrow Articles by Mattsson, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fogelstrand, P.
Right arrow Articles by Mattsson, E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2005, European Society of Cardiology

Reduced neointima in vein grafts following a blockage of cell recruitment from the vein and the surrounding tissue

Per Fogelstranda, Klas Österberga,b and Erney Mattssona,b,*

aWallenberg Laboratory for Cardiovascular Research, The Cardiovascular Institute, The Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden
bDepartment of Vascular Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

* Corresponding author. Sahlgrenska University Hospital, Bruna sträket 11B, plan 1. Department of Vascular Surgery, SE-413 45 Gothenburg, Sweden. Tel.: +46 31 342 10 00; fax: +46 31 82 72 36. Email address: erney.mattsson{at}wlab.gu.se

Received 20 July 2004; revised 18 March 2005; accepted 30 March 2005


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Accumulation of intimal smooth muscle cells (SMC) is an important event in vein graft-stenosis. Different SMC sources have been reported, but their interrelations have been poorly studied. In a mouse vein graft model we investigated whether recipient-derived intimal SMCs are recruited from the surrounding tissue and whether blockage of SMC recruitment from the surrounding tissue and/or the donor vein will reduce neointimal formation.

Methods: To detect recipient-derived cells, wild-type veins were implanted into ROSA26 transgenic mice. To block cell recruitment from the surrounding tissue, implanted veins were isolated with a tube-shaped plastic film. To exclude vein-derived cells in the neointimal formation, acellular veins were implanted.

Results: In vein grafts isolated from the surrounding tissue the recipient contribution became minimal, but the total number of SMCs was not decreased. Acellular grafts contained an equal number of intimal SMCs as cellular controls after 4 weeks. Isolation of acellular grafts from the surrounding tissue decreased the number of intimal SMCs by 90%.

Conclusions: Recipient-derived SMCs are mainly recruited from the surrounding tissue. Cell recruitment from either the vein or the surrounding tissue is enough to form a neointima. Therefore, a simultaneous inhibition of both these sources is needed to reduce accumulation of intimal SMCs.

KEYWORDS Cardiovascular surgery; Veins; Remodeling; Smooth muscle


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Insertion of vein grafts is widely used to overcome clinical symptoms of atherosclerosis in coronary arteries. In the arterial system the vein remodels and becomes thicker. An exaggerated thickening of the innermost layer, the intima, leads to vein graft-stenosis with subsequent impeded or blocked luminal blood flow. In addition, intimal hyperplasia is an atherosclerosis-prone tissue [1] and atherosclerotic lesions can be seen in vein grafts already one year after implantation [2]. To be able to reduce neointimal formation, its cellular sources and their dynamics must be known. The most prominent cell type in the neointima is smooth muscle cells (SMCs). Intimal SMCs have been thought to be derived from the vessel wall media [3], but other origins are also possible. In pigs and rats, myofibroblasts from the adventitia and the surrounding tissue have been shown to migrate and participate in the neointimal formation [4–8]. Furthermore, studies on bone marrow-transplanted rodents suggest the blood as an additional source for intimal SMCs following vascular injury [9–11]. Although different SMC sources have been reported, very little is known about their interrelations, e.g. if inhibition of one cellular pool will reduce the neointimal formation or if it will be compensated for by the remaining sources.

In a mouse vein graft model both the recipient animal and the donor vein have been shown to contribute intimal SMCs [12,13]. In those studies, the recipient-derived SMCs did not seem to be of bone marrow origin. Therefore, the aim of this study was to investigate if recipient-derived SMCs are recruited from the surrounding tissue. We further investigated whether the neointimal formation can be reduced by blocking cell recruitment from the surrounding tissue and/or the donor vein.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animals
All procedures were approved by the Animal Ethics Committee at Göteborg University. The investigation conforms 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). Wild-type C57BL/6 mice were purchased from Charles River (Germany) and heterozygous ROSA26 mice of the C57BL/6 strain were obtained from the Jackson Laboratories (Bar Harbor, ME, stock no: 002192). Tissue transferred between the mice should be regarded as isografts, since all mice were of the same strain. ROSA26 are LacZ transgenic mice that express β-galactosidase (β-gal) in all adult tissues. The β-gal activity is mainly localized close to the nucleus and stains turquoise blue with the substrate X-gal. To assure that the transgenic mice expressed β-gal, an X-gal staining of the inferior caval vein and the aorta were performed on all ROSA26 mice after sacrifice. All mice in the study were males (weight: 29–35 g).

2.2. Surgical procedures
The mice were anesthetized with isoflurane during spontaneous breathing. The vein graft procedure was similar to that described by Zou et al. [14]. Briefly, the right common carotid artery was divided and each artery end was everted over a cuff. The inferior caval vein from a donor mouse was grafted in position by ligating its ends to the everted arteries with silk sutures.

2.3. External shielding
In some animals the graft was isolated from the surrounding tissue with a tube-shaped polyethylene film (Quickpack, Renningen, Germany). The external plastic shielding was tightly ligated to the cuffs in the anastomoses. The shielding was impermeable to cells and was not bioabsorbable in order to inhibit cell recruitment from the surrounding tissue during the whole studied period of time.

2.4. Acellular veins
Acellular veins were produced according to the protocol of Probst et al. [15]. Briefly, the veins were treated with sodium azide to permeabilize the cells, DNase to digest the DNA and finally, sodium deoxycholate to wash away membrane lipids. Before implantation, the acellular veins were treated with heparin (250 U/mL). The absence of cells was confirmed by the absence of nuclei. Sections, taken every 50 µm throughout an acellular vein, were nuclear stained with hematoxylin and analyzed under a microscope. An untreated vein was used as positive control.

2.5. Study design
Wild-type veins were implanted into ROSA26 transgenic mice. The veins were either isolated (n = 5) or not isolated (n = 6) from the surrounding tissue. The animals were sacrificed after six weeks. Acellular veins and cellular controls (n = 7) were implanted into wild-type mice. The acellular veins were either isolated (n = 4) or not isolated (n = 7) from the surrounding tissue. The animals in these groups were sacrificed after four weeks, instead of six, to lower the risk for aneurysmal development in acellular veins. For proliferation analyses, wild-type mice with acellular (n = 6) and cellular vein grafts (n = 7) were sacrificed after 3 weeks. These mice were injected with 5-bromo-2-deoxyuridine (BrdU, Roche Diagnostics, Switzerland, 170 mg/kg, subcutaneously) 12 and 24 h before sacrifice.

2.6. Tissue samples
For paraffin sections, the mice were anesthetized with pentobarbital sodium (50 mg/kg body weight) and perfused with saline and 4% formalin (phosphate buffered, pH 7.2) at 75 mm Hg. The vein grafts were post-fixed for 4 h in 4% formalin, dehydrated, and embedded in paraffin. For frozen sections, the vein grafts were harvested after saline perfusion. The grafts were mounted in O.C.T compound (Sakura Finetek, Netherlands), snap frozen in liquid nitrogen and stored at –70 °C. Transverse sections (paraffin and frozen, 5 and 8 µm respectively) were cut onto slides and stained for β-gal and {alpha}-actin.

2.7. X-gal staining and immunohistochemistry
β-gal was detected with X-gal staining. Frozen sections were fixed in 4 °C PBS, containing 2% formalin and 0.2% glutaraldehyde, for 5 min and incubated at 37 °C for 18 h in PBS supplemented with 1 mg/mL X-gal (Roche Diagnostics), 5 mmol/L potassium ferricyanide, 5 mmol/L potassium ferrocyanide and 2 mmol/L magnesium chloride. ROSA26 veins implanted into ROSA26 mice were used as positive controls and wild-type veins implanted into wild-type mice as negative controls. Sections were rinsed with PBS. For double staining of β-gal and {alpha}-actin the slides were further fixed in formalin/glutaraldehyde solution (4 °C) for 18 min and pre-incubated with 5% milk powder solution (Semper, Sweden). The slides were incubated 40 min in 37 °C with a monoclonal primary antibody (1:20, mouse anti-human smooth muscle {alpha}-actin, Cedarlane, UK) followed by 30 min incubation at room temperature with a secondary antibody labeled with alkaline phosphatase (1:200, goat anti-mouse IgG2a, Southern Biotechnology Associates, Birmingham, AL). The antibodies were diluted in 5% milk powder solution. Sections were developed with fast red (Fast red kit, DAKO).

For {alpha}-actin detection in paraffin sections, the specimen were de-waxed and pre-treated with proteinase K (300 µg/mL, 5 min), 3% hydrogen peroxidase (5 min), and 5% dry milk powder solution (15 min). The specimens were incubated with the primary antibody (1:500, mouse anti-human smooth muscle {alpha}-actin, clone 1A4, DAKO, Denmark) at 4 °C over night, followed by 30 min with a secondary antibody conjugated with horseradish peroxidase (1:80, peroxidase anti-mouse IgG2a, Amersham Biosciences, UK). Diaminobenzidine (DAB kit, DAKO) was used for visualization. A mouse IgG2a monoclonal antibody (DAKO), non-immune to mammalian tissue, was used as negative control in both paraffin and frozen sections.

BrdU-positive cells were detected with a Cell Proliferation Kit (Amersham Biosciences). The sections were double stained for {alpha}-actin with fast red as described above for frozen sections. In addition, consecutive sections were double stained for BrdU and the leukocyte marker CD18. For CD18 staining, a rat anti-mouse CD18 primary antibody (PharMingen, San Diego, CA) and an alkaline phosphatase conjugated goat anti-rat secondary antibody (Southern Biotechnology Associates) were used.

2.8. Cell counting
Mid-graft sections (>500 µm from the cuffs) were analyzed in the study. In the ROSA26 mice, identification of SMCs ({alpha}-actin positive) and their origin (β-gal positive or negative) were determined in frozen sections, triple-stained for {alpha}-actin, β-gal, and nuclei. The slides were mounted with water, and photographed at x 630 magnification. Since β-gal staining can be disguised underneath strong {alpha}-actin staining, the cover was removed and the red {alpha}-actin staining was washed away with xylene after dehydration in ethanol. The nuclear staining was then enhanced and new photos of the same sections were taken and laid on top of the first pictures in PhotoShop (in different layers). From these pictures it was easy to determine which SMCs stained positive for β-gal (Fig. 1).


Figure 1
View larger version (96K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Wild-type vein implanted into a ROSA26 recipient mouse. (A) Triple-stained section for β-gal (turquoise blue), {alpha}-actin (red) and nuclei (lilac). The nuclei of one {alpha}-actin negative cell (arrowhead) and five {alpha}-actin positive cells are seen. (B) The same section after removal of red {alpha}-actin staining. The {alpha}-actin negative cell is negative for β-gal (arrowhead). The others stain positive x 630 magnification.

 
The acellular and cellular vein grafts in wild-type mice were stained for {alpha}-actin and nuclei in paraffin sections. {alpha}-actin positive cells in the neointima were counted manually. For proliferation analyses, proliferation indices for both {alpha}-actin positive cells and {alpha}-actin negative cells were calculated. To exclude leukocytes, CD18 positive cells were counted in consecutive sections and subtracted from the number of {alpha}-actin negative cells. No intimal leukocytes stained positive for BrdU.

2.9. Statistics
For comparisons between groups the Mann–Whitney U test was used. The analyses were performed with the SPSS 11.0 software package for Windows. A p<0.05 was regarded as statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Both vein-derived and recipient-derived cells formed the neointima
To investigate if both the recipient animal and the donor vein can contribute intimal SMCs, we implanted cellular wild-type veins into ROSA26 mice that express β-gal in all tissues. The vein grafts were harvested after 6 weeks and mid-graft sections were triple-stained for β-gal, {alpha}-actin and nuclei. This triple staining enabled us to identify SMCs and their origin (β-gal positive or negative) in the same specimen (Fig. 1). SMCs of recipient origin were found in all specimens although there was a great variation between individual grafts, from 0.2% to 82% (Fig. 2A and B). The degree of recipient contribution did not affect the total number of SMCs (data not shown). The morphology did not differ between grafts with predominantly recipient-derived SMCs and grafts with predominantly vein-derived SMCs. The data show that the neointimal formation was a process that involved cells from both the recipient animal and the vein itself.


Figure 2
View larger version (88K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 (A)–(C) Wild-type veins six weeks after implantation into ROSA26 recipient mice. Sections are stained for β-gal (turquoise blue), {alpha}-actin (red) and nuclei (lilac). (A) Non-isolated graft with few SMCs of recipient origin (β-gal positive). (B) Non-isolated graft with many SMCs of recipient origin. (C) Isolated graft with few SMCs of recipient origin. Arrowheads point at β-gal positive SMCs in (A) and (C). (D)–(G) Positive and negative controls for the β-gal stainings. (D), (E) The inferior caval vein and aorta, respectively, from a ROSA26 mouse. (F),(G) The inferior caval vein and aorta, respectively, from a wild-type mouse. (H) ROSA26 vein implanted in ROSA26 mouse. (I) Wild-type vein implanted in wild-type mouse. Scale bars=50 µm.

 
3.2. Recipient-derived SMCs were recruited from the surrounding tissue
We isolated cellular wild-type veins in ROSA26 mice to investigate if recipient-derived cells were recruited from the surrounding tissue and if a decreased recipient contribution would reduce the total number of intimal SMCs. There was a significant decrease of recipient-derived SMCs in the isolated cellular grafts (Figs. 2C and 3AGo). However, the decreased recipient contribution was not accompanied by a decrease in the total number of SMCs (Fig. 3B). This strongly suggests the surrounding tissue as the main source of recipient-derived SMCs and it shows that vein-derived cells by themselves could form a thick neointima.


Figure 3
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 (A) The percentage of recipient-derived intimal SMCs in non-isolated and isolated grafts. (B) The total number of intimal SMCs in non-isolated and isolated grafts. The results are expressed as mean ± SD (*p<0.05).

 
3.3. Equal neointima in cellular and acellular vein grafts
With the use of acellular veins we investigated if removal of vein-derived cells would reduce the accumulation of intimal SMCs. The removal of cells was successful and acellular veins had a total lack of nuclei (Fig. 4). Three weeks after implantation, there was a tendency towards a reduced number of {alpha}-actin positive cells in acellular grafts, although not statistically significant (151 ± 67 cells in cellular grafts, 37 ± 15 cells in acellular grafts, p = 0.23). However, at this time-point, the majority of the neointimal cells were {alpha}-actin negative (70 ± 12% in cellular grafts, 86 ± 5.4% in acellular grafts) and the total number of neointimal cells was significantly lower in acellular grafts (432 ± 39 cells in cellular grafts, 281 ± 61 cells in acellular grafts, p<0.05). There was no difference in proliferation indices between the groups. The proliferation index among {alpha}-actin positive cells in cellular and acellular grafts was 11 ± 3.6 and 11 ± 2.6%, respectively (p = 0.95). {alpha}-actin negative cells had a proliferation index of 26 ± 2.9 and 32 ± 2.8% in cellular and acellular grafts, respectively (p = 0.23).


Figure 4
View larger version (84K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Hematoxylin and eosin stained sections of a cellular (A) and an acellular (B) vein. Note the absence of nuclei and cytoplasmic eosin staining in the acellular vein. Scale bar=200 µm.

 
Four weeks after implantation, both cellular and acellular grafts contained a defined neointima with {alpha}-actin expressing cells. The morphology was indistinguishable between the groups and the number of intimal SMCs was equal (Figs. 5A, B and 6Go). The only apparent difference was an occasional aneurysmal development in acellular grafts (2 out of 9 grafts, excluded from the study). The data show that vein-derived cells were not necessary for the neointimal formation, since recipient-derived cells had the ability to alone form a thick neointima. The absence of vein-derived cells did not seem to alter the proliferation rate of recipient-derived cells in the neointima.


Figure 5
View larger version (44K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 {alpha}-actin staining (brown colour) of a cellular (A), an acellular (B), and an isolated acellular vein graft (C) four weeks after implantation into wild-type mice. Scale bar=50 µm.

 

Figure 6
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 The total number of intimal SMCs in cellular, acellular, and isolated acellular vein grafts four weeks after implantation into wild-type mice. The results are expressed as mean ± SD (**p<0.01 compared with cellular and acellular).

 
3.4. Reduced neointima in acellular vein grafts isolated from the surrounding tissue
We isolated the acellular grafts to investigate if a combined blockage of cell recruitment from both the surrounding tissue and the vein would inhibit the neointimal formation. In this setting only the luminal blood and the adjacent artery could contribute neointimal cells. Four weeks after implantation there was a 90% decrease of intimal SMCs in the isolated acellular grafts compared with unshielded grafts (Figs. 5C and 6Go). One out of five grafts developed an aneurysm. The result shows that cell recruitment from both the vein and the surrounding tissue needed to be blocked to obtain a reduced neointima. The luminal blood and/or the adjacent artery could contribute intimal SMCs, but not in a quantity to fully compensate for the blocked cell recruitment from the vein and the surrounding tissue.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
To understand the pathophysiology of graft-stenosis it is important to know the origin of intimal SMCs. Several sources have been proposed, but their interrelations have been poorly investigated. In the present study we showed that the vein and the surrounding tissue were the two main sources for intimal SMCs in the mouse vein graft model. These sources could fully compensate each other and thereby the neointima could not be reduced by blocking either of them. Only when cell recruitment from both the vein and the surrounding tissue was simultaneously blocked the number of intimal SMCs significantly decreased.

Hu et al. [12] and Zhang et al. [13] recently showed that both the vein and the recipient animal contribute neointimal SMCs in the mouse vein graft model. More than 40% of the intimal SMCs arose from the recipient animal and these cells did not seem to be derived from the bone marrow [12,13]. A possible source is the surrounding tissue. A contribution from the surrounding tissue has been reported in a corresponding vein graft model in pig [5]. In the present study we showed that the recipient contribution was significantly reduced when grafts (both cellular and acellular) were isolated from the surrounding tissue. This strongly suggests that the surrounding tissue is the main source of recipient-derived cells in the mouse vein graft model. It is possible that SMCs recruited from the surrounding tissue are myofibroblasts. The ability of fibroblasts to express {alpha}-actin and participate in neointimal formation has been demonstrated in several animal models [4–8].

A main finding in this study was that both the vein and the surrounding tissue could provide sufficient number of cells for neointimal formation. Therefore, the neointima could not be reduced by blocking cell recruitment from either the vein or the surrounding tissue. However, when both these sources were inhibited at the same time, there was a remarkable reduction of intimal SMCs. Indications of a dynamic relationship between the vein and the recipient animal were also seen in unmanipulated vein grafts. Wild-type veins implanted in ROSA26 mice showed a great variability in the composition of vein-derived and recipient-derived SMCs between individual grafts, but the total number of SMCs and the morphology were not influenced by this variation. Taken together, it did not seem to matter if intimal SMCs were recruited from the vein itself or from the recipient animal to the neointimal formation.

Besides from the vein and the surrounding tissue, intimal SMCs may also be recruited from the luminal blood and the adjacent artery. As previously mentioned, bone marrow-derived SMCs do not seem to participate in the mouse vein graft model under normal circumstances [12,13]. However, in the isolated acellular grafts it is possible that the blood contributed intimal SMCs. Tanaka et al. recently showed that the contribution of bone marrow-derived SMCs differ between different mouse models of intimal thickening [10]. In that study the biggest contribution was achieved with an endoluminal wire injury, which causes an acellular intima and media. The cellularity remains low in the media for more than one week. As the authors point out, it is most likely that the high content of bone marrow-derived cells was due to a shortage of local mesenchymal cells for the healing process. Likewise, a participation from the blood in the neointimal formation has been observed in pigs following a thermal vascular injury, which abolished all medial cells and caused a cell barrier towards the adventitia and the surrounding tissue [16]. Thus, in the present study, the absence of cells in the vein combined with a blockage of cell recruitment from the surrounding tissue might have promoted a contribution of intimal SMCs from the blood.

What factors influence the proportion of vein-derived and recipient-derived SMCs? In cellular grafts an important factor might be the degree of cell loss in the vein after implantation. Shortly after implantation there is a cell loss in the vein due to the increased blood pressure in the arterial circulation [14,17]. A minor cell loss might favour cells in the vein to form the neointima, while an extensive cell loss might favour recipient-derived cells. In accordance with this hypothesis, we showed that a total cell loss in the vein was completely compensated for by recipient-derived cells. This compensation should be a result of increased proliferation and/or migration of recipient-derived cells. Proliferation analyses of cellular and acellular grafts at an early stage of the neointimal formation did not show any difference in neointimal proliferation. This implies that an increased participation of recipient-derived cells is not a result of increased proliferation.

As shown in the present study, the origin of neointimal cells does not influence the neointimal size. A main determinant for the neointimal size in vein grafts might be mechanical forces from the blood, such as shear stress and tensile stress (the circumferential stretch in the vessel wall from blood pressure) [18–20]. For example, it has been shown that intimal and medial proliferation stops in rabbit vein grafts when the tensile stress in the graft is equal to the tensile stress in the adjacent arteries [18]. Furthermore, an established intimal thickening can regress by re-implanting a vein graft into the venous circulation [19]. Thus, it is likely that the neointimal size is locally regulated by mechanical forces and therefore a similar neointimal thickness will be formed as long as there is a sufficient supply of cells. Only in the case of isolated acellular veins the supply of cells seemed to be a limiting factor for the neointimal size.

The methods we used to interfere with cell recruitment might also have affected the neointimal formation in other ways. The use of acellular veins might seem artificial, but the endothelium and the media become almost acellular also in cellular veins shortly after implantation (Zou et al. [14] and own unpublished observations). Therefore, the fate of an acellular vein graft likely resembles the fate of a normal vein graft. Loss of cells in vein grafts has also been observed in rats, pigs and humans [7,21,22]. The external shielding in the present study might have interfered with mechanical forces, such as shear or tensile stress, which are known to influence intimal hyperplasia [18–20]. An external support in direct contact to the vessel wall has been shown to reduce intimal thickening in vein grafts [23,24] as well as in balloon-injured arteries [25]. However, the shielding in this study was not in close contact with the vessel wall. Furthermore, our shielding inhibited the neointima only in acellular veins. We would have seen a reduced neointima also in isolated cellular veins if the shielding affected the mechanical forces on the vessel wall. Other possible effects of the plastic shielding might have been an increased inflammatory response to the foreign material and a prolonged retention of cytokines and growth factors in the vessel wall. Both these effects would have increased the neointimal formation, but that was not the case.

In conclusion, recipient-derived cells in mouse vein grafts are mainly recruited from the surrounding tissue. Cell recruitment from either the vein or the surrounding tissue is enough to form a neointima. Therefore, a simultaneous inhibition of both these sources is needed to reduce accumulation of intimal SMCs. The results imply that all bases for cellular recruitment need to be taken into consideration to reduce vein graft-stenosis.


   Acknowledgements
 
This work was supported by grants from the Sahlgrenska University Hospital and from the Swedish Medical Research Council (K2005-71X-14246-04A).


   Notes
 
Time for primary review 20 days


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

  1. Schwartz S.M., deBlois D., O'Brien E.R. The intima. Soil for atherosclerosis and restenosis. Circ Res (1995) 77:445–465.[Free Full Text]
  2. Kalan J.M., Roberts W.C. Morphologic findings in saphenous veins used as coronary arterial bypass conduits for longer than 1 year: necropsy analysis of 53 patients, 123 saphenous veins, and 1865 five-millimeter segments of veins. Am Heart J (1990) 119:1164–1184.[CrossRef][ISI][Medline]
  3. Davies M.G., Hagen P.O. Pathobiology of intimal hyperplasia. Br J Surg (1994) 81:1254–1269.[ISI][Medline]
  4. Shi Y., O'Brien J.E., Fard A., Mannion J.D., Wang D., Zalewski A. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation (1996) 94:1655–1664.[Abstract/Free Full Text]
  5. Shi Y., O'Brien J.E. Jr., Mannion J.D., Morrison R.C., Chung W., Fard A., et al. Remodeling of autologous saphenous vein grafts. The role of perivascular myofibroblasts. Circulation (1997) 95:2684–2693.[Abstract/Free Full Text]
  6. Siow R.C., Mallawaarachchi C.M., Weissberg P.L. Migration of adventitial myofibroblasts following vascular balloon injury: insights from in vivo gene transfer to rat carotid arteries. Cardiovasc Res (2003) 59:212–221.[Abstract/Free Full Text]
  7. Tomas J.J., Stark V.E., Kim J.L., Wolff R.A., Hullett D.A., Warner T.F., et al. Beta-galactosidase-tagged adventitial myofibroblasts tracked to the neointima in healing rat vein grafts. J Vasc Res (2003) 40:266–275.[CrossRef][ISI][Medline]
  8. Li G., Chen S.J., Oparil S., Chen Y.F., Thompson J.A. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation (2000) 101:1362–1365.[Abstract/Free Full Text]
  9. Han C.I., Campbell G.R., Campbell J.H. Circulating bone marrow cells can contribute to neointimal formation. J Vasc Res (2001) 38:113–119.[CrossRef][ISI][Medline]
  10. Tanaka K., Sata M., Hirata Y., Nagai R. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res (2003) 93:783–790.[Abstract/Free Full Text]
  11. Religa P., Bojakowski K., Maksymowicz M., Bojakowska M., Sirsjo A., Gaciong Z., et al. Smooth-muscle progenitor cells of bone marrow origin contribute to the development of neointimal thickenings in rat aortic allografts and injured rat carotid arteries. Transplantation (2002) 74:1310–1315.[ISI][Medline]
  12. Hu Y., Mayr M., Metzler B., Erdel M., Davison F., Xu Q. Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res (2002) 91:e13–e20.[Abstract/Free Full Text]
  13. Zhang L., Freedman N.J., Brian L., Peppel K. Graft-extrinsic cells predominate in vein graft arterialization. Arterioscler Thromb Vasc Biol (2004) 24:470–476.[Abstract/Free Full Text]
  14. Zou Y., Dietrich H., Hu Y., Metzler B., Wick G., Xu Q. Mouse model of venous bypass graft arteriosclerosis. Am J Pathol (1998) 153:1301–1310.[Abstract/Free Full Text]
  15. Probst M., Dahiya R., Carrier S., Tanagho E.A. Reproduction of functional smooth muscle tissue and partial bladder replacement. Br J Urol (1997) 79:505–515.[ISI][Medline]
  16. Bayes-Genis A., Campbell J.H., Carlson P.J., Holmes D.R. Jr., Schwartz R.S. Macrophages, myofibroblasts and neointimal hyperplasia after coronary artery injury and repair. Atherosclerosis (2002) 163:89–98.[CrossRef][ISI][Medline]
  17. Moore M.M., Goldman J., Patel A.R., Chien S., Liu S.Q. Role of tensile stress and strain in the induction of cell death in experimental vein grafts. J Biomech (2001) 34:289–297.[CrossRef][ISI][Medline]
  18. Zwolak R.M., Adams M.C., Clowes A.W. Kinetics of vein graft hyperplasia: association with tangential stress. J Vasc Surg (1987) 5:126–136.[CrossRef][ISI][Medline]
  19. Davies M.G., Klyachkin M.L., Dalen H., Svendsen E., Hagen P.O. Regression of intimal hyperplasia with restoration of endothelium-dependent relaxing factor-mediated relaxation in experimental vein grafts. Surgery (1993) 114:258–270. discussion 70-71.[ISI][Medline]
  20. Lehoux S., Tedgui A. Cellular mechanics and gene expression in blood vessels. J Biomech (2003) 36:631–643.[CrossRef][ISI][Medline]
  21. Kockx M.M., Cambier B.A., Bortier H.E., De Meyer G.R., Van Cauwelaert P.A. The modulation of smooth muscle cell phenotype is an early event in human aorto-coronary saphenous vein grafts. Virchows Arch, A Pathol Anat Histopathol (1992) 420:155–162.[CrossRef][ISI][Medline]
  22. Rodriguez E., Lambert E.H., Magno M.G., Mannion J.D. Contractile smooth muscle cell apoptosis early after saphenous vein grafting. Ann Thorac Surg (2000) 70:1145–1153.[Abstract/Free Full Text]
  23. Izzat M.B., Mehta D., Bryan A.J., Reeves B., Newby A.C., Angelini G.D. Influence of external stent size on early medial and neointimal thickening in a pig model of saphenous vein bypass grafting. Circulation (1996) 94:1741–1745.[Abstract/Free Full Text]
  24. Lardenoye J.H., De Vries M.R., Grimbergen J.M., Havekes L.M., Knaapen M.W., Kockx M.M., et al. Inhibition of accelerated atherosclerosis in vein grafts by placement of external stent in apoE*3-Leiden transgenic mice. Arterioscler Thromb Vasc Biol (2002) 22:1433–1438.[Abstract/Free Full Text]
  25. Fogelstrand P., Risberg B., Mattsson E. External collar inhibits balloon-induced intimal hyperplasia in rabbits. J Vasc Res (2002) 39:361–367.[CrossRef][ISI][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Circ. Res.Home page
R. N. Mitchell and P. Libby
Vascular Remodeling in Transplant Vasculopathy
Circ. Res., April 13, 2007; 100(7): 967 - 978.
[Abstract] [Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
T. Schachner, G. Laufer, and J. Bonatti
In vivo (animal) models of vein graft disease.
Eur. J. Cardiothorac. Surg., September 1, 2006; 30(3): 451 - 463.
[Abstract] [Full Text] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
T. Schachner
Pharmacologic inhibition of vein graft neointimal hyperplasia
J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 1065 - 1072.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Fogelstrand, P.
Right arrow Articles by Mattsson, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fogelstrand, P.
Right arrow Articles by Mattsson, E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?