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Animal Model |
From the Institute for Biomedical Aging Research,*
Austrian Academy of Sciences, and Institute for General and
Experimental Pathology,
University of
Innsbruck Medical School, Innsbruck, Austria
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-actin+) to constitute neointimal lesions
between 4 and 16 weeks. Similar vein graft lesions were obtained when
external jugular veins or vena cava were isografted into carotid
arteries of C57BL/6J mice. Moreover, no significant intima
hyperplasia in vein-to-vein isografts was found, although there
was leukocyte infiltration in the vessel wall. Thus, this
model, which reproduces many of the features of human vein
graft arteriosclerosis, should prove useful for our
understanding of the mechanism of vein graft disease and to evaluate
the effects of drugs and gene therapy on vascular
diseases.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several animal models manifesting lesions resembling human vein graft arteriosclerosis have been developed3-7 and have helped address specific interventional issues, but they have not helped to clarify the underlying mechanism of the disease. Attracted by the well-defined genetic systems, a number of investigators have begun to use the mouse as an experimental system for atherosclerosis research.8-11 Hundreds of inbred lines have been established, the genetic map is relatively well defined, and both congenic strains and recombinant strains are available to facilitate genetic experimentation. In just a few years, murine lipoproteins have been characterized, genetic variants of apolipoproteins have been identified,12,13 and genetic variation in susceptibility to atherosclerosis among inbred mouse strains has been demonstrated. The study of vein graft arteriosclerosis in such strains should make it possible to define the specific relations of many genes and cell types to the pathogenesis of this lesion. For example, it has been postulated that hypercholesterolemia is a risk factor for the development of lesions in vein grafts,14 and it is now possible to study mice that lack apolipoprotein E-containing lipoproteins or low-density lipoprotein receptors.13,15 Mice are also available that have deficient macrophage function16 or lack endothelial adhesion molecules17,18 or nitric oxide synthases,19,20 which might be important molecules in the development of venous bypass graft arteriosclerosis.
In the present study, we describe a simple model wherein external jugular or vena cava veins were auto- or isografted into carotid arteries in C57BL/6J mice. We observed intimal lesions within 14 days that progress to marked stenosis in the grafted vessel within 16 weeks. We demonstrated that inflammatory features appeared in the lesions at the early stages followed by smooth muscle cell proliferation and extracellular matrix deposition in the vein graft neointima.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Three month-old male C57BL/6J were purchased from the Charles River Laboratory (Sulzfeld, Germany) and maintained for 1 week on a light/dark (12-hour/12-hour) cycle at 24°C and received food and water ad libitum before experimentation. All procedures were performed according to protocols approved by the Institutional Committee for Use and Care of Laboratory Animals. C57BL/6J mice were used as donors and recipients for vein grafts, because these mice are susceptible to atherosclerosis when a cholesterol-enriched diet is administered.8-13 In addition, many mutant or knockout mice are available with this genetic background.
Vein Graft Procedure
Mice were anesthetized with pentobarbital sodium (50 mg/kg body weight, intraperitoneally). Atropine sulfate (1.7 mg/kg body weight) was administered to maintain the respiratory tract in good condition. The operation was performed under a dissecting microscope (Wild M8, Basel, Switzerland). The mouse was fixed in a supine position with its neck extended. A midline incision was made on the ventral side of the neck from the lower mandible to the sternum. The right cleidomastoid muscle was resected.
The vein-grafting procedure is schematically illustrated in Figure 1
. The right common carotid artery was
mobilized free from the bifurcation in the distal end toward the
proximal end as far as possible. The vessel was ligated with an 8-0
silk suture and dissected between the middle ties. The proximal and
distal portions of the artery were passed through cuffs made of a
polyethylene cannula 0.65 mm in diameter outside and 0.5 mm inside
(Portex LTD, London, United Kingdom). The cuff length was 1 mm with a
1-mm handle or extension. The vessel, together with the handle, were
fixed by microhemostat clamps (4 mm in length; Martin, Tuttlingen,
Germany). The suture at the end of the artery was removed, and a
segment of the artery was everted over the cuff body with a stent and
fine tweezers and fixed to the cuff with an 8-0 silk suture. Another
portion of the artery was similarly prepared (Figure 1, a through d)
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The vein segment was grafted between the two ends of the carotid artery
by sleeving the ends of the vein over the artery cuff and ligating them
together with the 8-0 suture (Figure 1e)
. The cuff handle was cut off
after completion of the anastomoses, the vascular clamps were removed,
and evidence of pulsations was sought in both the grafted and native
vessels. If there were no pulsations or pulsations diminished within a
few minutes of restoration of blood flow, clot formation or occlusion
of output was assumed, and the procedure was considered a surgical
failure. If there were vigorous pulsations in the grafted vessel, the
skin incision was closed with a 6-0 interrupted suture. One hour was
needed to perform the whole operation, and the ischemia time of vein
segments was about 15 minutes.
For histological analysis, perfusion was performed as described previously.21 Briefly, mice were anesthetized and perfused with 0.9% NaCl solution via cardiac puncture in the left ventricle, and subsequently perfusion fixed with 4% phosphate-buffered formaldehyde (pH 7.2) for 2 and 5 minutes, respectively. The vein grafts were harvested at 1, 2, 4, 8, and 16 weeks postoperatively (six to eight randomly chosen mice at each time point) by cutting the transplanted segments from the native vessels at the cuff end. Samples were fixed with 4% phosphate-buffered formaldehyde at 4°C for 24 hours. For frozen section preparation, mice were sacrificed by cervical dislocation, and vein grafts were harvested, immediately frozen in liquid nitrogen, and stored at -80°C.
Histology and Lesion Quantification
After fixation, the grafts were cut in the middle of the vein segments, dehydrated in graded ethanol baths, cleared in xylol, and embedded in paraffin.22 Histological sectioning began at the center of the graft to avoid the effects of the cuff. Routinely, 7 µm-thick sections were made throughout the dissected fragments, stained with hematoxylin and eosin (H&E), and examined microscopically (Leitz, Munich, Germany).
Because the venous media is very thin (one or two layered cells or 10 to 20 µm thick), the thickness of the normal and lesioned vessel walls was simultaneously measured and calculated microscopically. The intima and media were defined as the region between the lumen and the adventitia. The thickness of the vessel wall was determined by measuring four regions of a section along a cross and recorded in micrometers (means ± SD). Ten cross-sections were obtained by selecting the first of every three sections from each animal. Cell counts in the intima and media were performed on two regions of each section and expressed as the number of nuclei per 100 µm of the vessel wall.
Immunohistochemical Staining
The procedure used in the present study was similar to that
described previously.23
Briefly, serial 5 µm-thick frozen
sections were cut from cryopreserved tissue blocks, fixed in a cold 1:1
acetone-chloroform mixture for 10 minutes, and washed with
phosphate-buffered saline (PBS) for 20 minutes. The sections were
subsequently placed in a humidified chamber, where they were
overlayered with a rat monoclonal antibody (CD11b/18) against mouse
MAC-1 leukocytes (PharMingen, San Diego, CA) and incubated for 1 hour
at room temperature. After washing with PBS, sections were incubated
with rabbit anti-rat immunoglobulin (Dakopatts, Copenhagen, Denmark)
for 1 hour. Sections were washed in PBS three times, incubated with
alkaline phosphatase-anti-alkaline phosphatase complex (Dakopatts) for
30 minutes, washed in PBS three times, and developed for 20 minutes at
room temperature on a shaker using a substrate solution containing 9.8
ml of Tris buffer (0.1 mol/L, pH 8.2), 0.2 ml of dimethylformamide, 8
mg of naphthol AS-MX phosphate, 3 mg of levamisole, and 10 mg of fast
red TR salt (Sigma Chemical Co., St. Louis, MO). A counterstaining with
hematoxylin was performed at room temperature for 3 minutes. For smooth
muscle cell staining, a mouse monoclonal antibody against -actin
(Sigma) labeled with phosphatase was used. The procedure was similar to
that described for CD11b/18 labeling except for omission of the second
antibody. Semiquantitive evaluation was performed at 10 x
25 magnification. Positive-stained cells in the intima and media
were counted on two regions of each section and expressed as the range
of the cell number or the percentage of total nuclei per 100 µm of
the vessel wall.
Statistical Analysis
Statistical analyses were performed on a Macintosh computer with StatView SE+Graphics software using the Mann-Whitney U test and analysis of variance, respectively. Results are given as means ± standard deviations (SD). A P value <0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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schematically represents the procedure of grafting a vein
segment to the carotid artery using the cuff technique. This method is
technically simple, easy to learn, and less traumatic than the suturing
technique. Using this method, a total of 57 vein grafts in C57BL/6J
mice were studied, with a surgical success rate of about 90%.
Fifty-four of 57 animals survived until their designated time of
harvest, and all vein grafts were patent at the time of harvest. Three
vein grafts were nearly occluded because of thrombosis. All control
veins and vein grafts were histologically examined, and five per group
were immunohistochemically analyzed. Neointima Formation in Jugular Vein Autografts
Representative histological sections of control external jugular
vein and vein grafts are shown in Figure 2
. In the control vein, only two layers
of cells, presumably a monolayer each of endothelial and smooth
muscle cells, respectively, formed the intima and media, whereas the
adventitia was composed of connective tissues, including vasa vasorum
(Figure 2A)
. Interestingly, significant cell loss and vessel wall
degeneration in the vein graft was observed 1 week after implantation
simultaneous to connective tissue deposition and mononuclear cell
infiltration in adventitia (Figure 2B)
. Concordant with these
observations is a report that a loss of endothelial and smooth muscle
cells in human saphenous vein bypass grafts was demonstrated 1 to 10
days postoperatively,24
suggesting that changes in the
early stage of grafts in this mouse model are similar to those in
humans. By 2 weeks, mononuclear cells infiltrated into the vessel wall
from both lumen and adventitia sides (Figure 2C)
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showed neointima hyperplasia that thickened rapidly.
Obviously, three changes can be found: thickening of the vessel wall up
to 10 or 20 layers of cells, declining infiltrated mononuclear cells,
and increasing matrix protein accumulation in neointima. The 16-week
lesion especially showed a lower cell number and an abundance of matrix
proteins (Figure 2F)
. Neointima hyperplasia significantly narrowed the
lumen to 20% of the original size by 16 weeks, and no
neovascularization in the lesion was observed (Figure 3)
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summarizes data of neointima thickness
measured microscopically. Thickening of the vein grafts began as early
as 1 week after surgery, although no significant difference was found
compared with controls. The thickness of the vessel wall increased
significantly in 2-week vein grafts, and neointima hyperplasia
progressed throughout all time points. During vein graft remodeling,
4-, 10-, 15-, and 18-fold increases in vessel wall thicknesses were
found in 2, 4, 8 and 16 week grafts, respectively (Figure 4B)
. When
cell nuclei in the intima and media of control veins and neointima of
grafted vessels were counted in 100 µm length, total cell numbers
increased significantly in 2-week grafts, were markedly higher in 4-
and 8-week grafts, and then began to decline (Figure 5)
, observations similar to those in
other animal models such as rats, rabbits, and pigs.3-7
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To determine the role of a specific gene or protein in the
development of neointima in vein grafts, an animal model of vein
isografts is needed. For instance, the effect of low-density
lipoprotein receptors of endothelial and smooth muscle cells on vein
graft remodeling in normocholesterolemia can be identified by
isografting low-density lipoprotein receptor-deficient vein segments
into arteries of wild-type littermates. We therefore established
several isograft animal models, including vena cava segments isografted
to external jugular veins and vena cava or external jugular vein
segments isografted to the arteries. Data shown in Figure 6
indicate the process of vein graft
remodeling. The structure and diameter (about 0.9 mm) of the vena cava
vessel were similar to those of external jugular veins (Figure 6, A and B)
. Both vein segments can be used as graft sources in bypass graft
models. In addition, intima thickening in vein-to-vein isografts was
much less significant than that of vein-to-artery isografts 4 weeks
after surgery (Figure 6C)
, although there was leukocyte infiltration in
the vessel wall.
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, provide evidence that the
formation of neointima in grafted veins was similar in both vena cava
isografts and jugular vein autografts. Likewise, mononuclear cell
infiltration and matrix protein deposition in the neointima were
demonstrated in all three types of grafts. To statistically compare the
three vein bypass grafts, the thickness of neointima was measured as
described in Figure 4
and as summarized in Figure 7
, indicating that neointima hyperplasia
occurred in all three grafts. No significant difference in the lesioned
areas of either autografts or isografts was seen, suggesting that
comparable results can be obtained from both animal models.
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There is evidence that lesions of vein graft-induced neointima
derived from other animal models and human specimens contain
macrophages and smooth muscle cells.25,26
To analyze the
kinetics of cell components in the development of neointima hyperplasia
of vein grafts, immunohistochemical staining using monoclonal
antibodies against MAC-1+ (CD11b/18) leukocytes and
-actin+ smooth muscle cells was performed on frozen
sections.
The results shown in Figure 8
indicate
MAC-1+ cell infiltration in vein graft lesions. It is known
that MAC-1+ cells are monocytes/macrophages, natural killer
cells, and granulocytes. We found that the majority of infiltrated
cells in neointima were mononuclear cells, ie, monocytes/macrophages.
In control veins, MAC-1+ monocytes/macrophages were rarely
seen in the intima and media, whereas abundant infiltration of these
positive cells were found in intima and/or adventitia of 1- and 2-week
vein grafts (Figure 8, B and C)
. MAC-1+
monocytes/macrophages were detected at the luminal surface at 1 and 2
weeks postengraftment and were seen transmurally by 4 and 8 weeks
(Figure 8, D and E)
. MAC-1+ cells were predominant in the
neointima of 2- and 4-week grafts (Table 1)
, were distributed in both luminal and
adventitial sites in 8-week vein grafts, and were found occasionally in
the lesions of 16-week vein grafts (Figure 8, D through F
; Table 1
).
Thus, the numbers of MAC-1+ monocyte/macrophage
infiltration increased during the first 4 weeks and decreased
thereafter.
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-Actin is widely used as a
marker of vascular smooth muscle cells, although not all smooth muscle
cells positively stain with antibodies against -actin. Figure 9
and Table 1
demonstrate the presence of
abundant smooth muscle cells in venous bypass graft lesions 4 to 16
weeks after surgery. Initially, a monolayer of smooth muscle cells in
normal vein walls stained strongly positive (Figure 9A)
, and very weak
staining, if any, was observed at 1 and 2 weeks. No staining was seen
in vein segments stained with normal rat serum as a negative control
(data not shown). Importantly, -actin+ smooth muscle
cells became abundant in neointima of 4-week vein graft neointima
(Figure 9B
; Table 1
) and constituted a majority of cell components in
8- and 16-week lesions (Figure 9, C and D
; Table 1
). Our results
indicate that smooth muscle cell proliferation is a main cause of
lesion formation in venous bypass grafts in the mouse model, similar to
human vein graft remodeling.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, many investigators have developed murine genetic models in which genes are either overexpressed, deleted, or mutated. Such mouse models have considerable advantages over other animal systems in that they overcome the need to administer factors or their inhibitors, which can be problematic and often difficult to quantify. In the present report, we establish and characterize a new model for the study of neointima formation of venous bypass grafts in mice. When used with vein autografts in mice subjected to targeted gene deletion, the model could provide a powerful tool for dissecting the relative contributions of such genes, including low-density lipoprotein receptors, endothelial adhesion molecules, nitric oxide synthase, and growth factors, in the development of neointima hyperplasia. When used with vein isografts that can be treated ex vivo with drugs or gene transfer, the thinner vessel wall allows easy penetration by small molecules and plasmids from the adventitia side. By using this model, we believe that significant progress in understanding the pathogenesis and treatment of vein graft disease may be seen in the near future.
In many respects, the morphological features of this murine vascular
graft model resemble those of human venous bypass graft
disease.25,26
First, a marked loss of smooth muscle cells
has been observed in lesions in the early stage of vein grafts of
humans and mice (Ref. 24
; Figure 2B
). Secondly, the human lesions have
an inflammatory nature characterized by mononuclear cell infiltration
in the early stage of vein bypass grafts, and the lesions seen in our
mouse models contain abundant MAC-1+ monocytes/macrophages
(Ref. 31
; Figure 8
). Finally, both the human and mouse lesions are
characterized by concentric intimal proliferation with a dominance of
smooth muscle cells in late specimens (Ref. 26
; Figures 3 and 9
). Thus,
this model could be useful in the study of human venous bypass graft
arteriosclerosis.
Because differences exist between all animal models and human diseases, we should point out where the mouse model is not consistent with the human condition. For example, it appears that there is more inflammation in the adventitia in the mouse model than is seen in the human condition, although the mechanism resulting in this difference is not clear. Atherosclerotic lesions, including foam cell accumulation and necrotic core formation in the intima, can be found in human vein grafts beyond the 1st year after bypass surgery.26,32 It would be difficult to study late-stage atherosclerosis using the mouse model because of the shorter life span and lack of spontaneous atherosclerosis in mice. In addition, mural microthrombi, fibrin deposition, and acute inflammation leading to thrombosis are often observed in human venous bypass grafts.26,32 In the mouse model, the rate of thrombus formation is very low, possibly because of the shorter time of ischemia and lower degree of mechanical injury to the mouse graft.
Possible Mechanism of Neointima Hyperplasia
Understanding the pathogenesis of vein graft arteriosclerosis is
often extrapolated from studies on (spontaneous) atherosclerosis in
arteries,33
but the features of lesions and pathogenic
processes of graft-induced arteriosclerosis differ from those of
spontaneous atherosclerosis. For instance, the development of
arteriosclerosis in vein grafts is rather rapid compared with that in
the arteries, which begins in childhood. In the present study, we
demonstrate that early changes of grafted vein segments included
leukocyte infiltration followed by smooth muscle cell proliferation.
Surgical or traumatic and ischemic injury to the vein segments may be
partially responsible for the lesion formation at the early stage in
the vein grafts. However, accumulating evidence indicates that
mechanical stress plays a crucial role in the neointima formation via
enhancing gene expression of adhesion molecules, growth factors,
cytokines, and matrix proteins.34
It has been demonstrated
that exposure of endothelial cells to shear (mechanical) stress results
in increased expression of intercellular adhesion molecule-1, vascular
cell adhesion molecule-1, and monocyte chemotactic protein-1 via
activation of transcription factor nuclear factor-
B and activator
protein-1.35-39
These molecules are essential for
leukocyte-endothelial cell interaction and subsequently cell
infiltration, which is characteristic for the early lesions of vein
grafts that undergo elevated blood pressure. Thus, our observations,
together with those of others, suggest that mechanical stress is one of
the most important factors in initiating inflammation of vein graft
arteriosclerotic lesions.
Following vein graft inflammation is smooth muscle cell proliferation,
a hallmark of late-stage lesions. Although the precise mechanism
initiating such cell proliferation remains to be elucidated, evidence
indicates a role for mechanical stress.40
In hypertension,
mechanical force on the arterial wall increases up to 30%, resulting
in marked alterations in signal transduction and gene expression in
vascular smooth muscle cells, which contribute to cell differentiation,
proliferation, and matrix protein synthesis.40-43
In
grafted veins, mechanical force on the vessel segment suddenly
increases more than 10-fold (arterial versus venous blood
pressure), which provides a strong stimulus to smooth muscle cells. How
the mechanical stimuli are converted into a biological signal in cells
in vivo remains to be studied. We previously demonstrated
that acutely elevated blood pressure, mechanical stress, or balloon
injury to the carotid artery induce activation of mitogen-activated
protein kinases, an essential signal transducer for cell
growth.44,45
Recently, we observed that physical forces
rapidly induced phosphorylation of platelet-derived growth factor
receptor , supporting the mechanical stress-stimulated activation of
platelet-derived growth factor receptor .46
Thus,
mechanical stresses may directly perturb the cell surface or alter
receptor conformation, thereby initiating signaling pathways normally
used by growth factors.
In summary, we have established a new model of vein graft arteriosclerosis in mice. The lesion was characterized by mononuclear cell infiltration followed by smooth muscle cell proliferation and matrix protein deposition. Although the pathogenetic mechanism remains unknown, we hypothesize that increased mechanical force is an initial signal that stimulates gene expression of adhesion molecules, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemotactic protein-1, which evokes an inflammation process in the grafted veins. Mechanical force may also be responsible for initiating the growth factor-mitogen-activated protein kinase signal pathways essential for cell growth. Further studies using this animal model could significantly enhance our understanding of the mechanism of vein graft arteriosclerosis and provide valuable information for therapeutic intervention in vascular diseases.
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Acknowledgements |
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Footnotes |
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Supported by grants P12847-MED and P12568-MED from the Austrian Science Fund and P6286 from the Jubiläumsfonds of the Austrian National Bank.
Accepted for publication July 18, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B interacts functionally with the platelet-derived growth factor B-chain shear-stress response element in vascular endothelial cells exposed to fluid shear stress. J Clin Invest 1995, 96:1169-1175
in vascular smooth muscle cells by mechanical stress. FASEB J 1998, 12:1135-1142This article has been cited by other articles:
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  S.-A. Hassantash, B. Bikdeli, S. Kalantarian, M. Sadeghian, and H. Afshar Pathophysiology of Aortocoronary Saphenous Vein Bypass Graft Disease Asian Cardiovasc Thorac Ann, August 1, 2008; 16(4): 331 - 336. [Abstract] [Full Text] [PDF]
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 Y. Diao, S. Guthrie, S.-L. Xia, X. Ouyang, L. Zhang, J. Xue, P. Lee, M. Grant, E. Scott, and M. S. Segal Long-Term Engraftment of Bone Marrow-Derived Cells in the Intimal Hyperplasia Lesion of Autologous Vein Grafts Am. J. Pathol., March 1, 2008; 172(3): 839 - 848. [Abstract] [Full Text] [PDF]
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 L. Zhang, P. Sivashanmugam, J.-H. Wu, L. Brian, S. T. Exum, N. J. Freedman, and K. Peppel Tumor Necrosis Factor Receptor-2 Signaling Attenuates Vein Graft Neointima Formation by Promoting Endothelial Recovery Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 284 - 289. [Abstract] [Full Text] [PDF]
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J. Cheng and J. Du Mechanical Stretch Simulates Proliferation of Venous Smooth Muscle Cells Through Activation of the Insulin-Like Growth Factor-1 Receptor Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1744 - 1751. [Abstract] [Full Text] [PDF]
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F. A. Kudo, A. Muto, S. P. Maloney, J. M. Pimiento, S. Bergaya, T. N. Fitzgerald, T. S. Westvik, J. C. Frattini, C. K. Breuer, C. H. Cha, et al. Venous Identity Is Lost but Arterial Identity Is Not Gained During Vein Graft Adaptation Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1562 - 1571. [Abstract] [Full Text] [PDF]
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 G. J. Murphy, T. W. Johnson, M. H. Chamberlain, S. I. Rizvi, M. Wyatt, S. J. George, G. D. Angelini, K. R. Karsch, M. Oberhoff, and A. C. Newby Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts Cardiovasc Res, February 1, 2007; 73(3): 607 - 617. [Abstract] [Full Text] [PDF]
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 A. Schepers, M.R. de Vries, C.J. van Leuven, J.M. Grimbergen, V.M. Holers, M.R. Daha, J.H. van Bockel, and P.H.A. Quax Inhibition of Complement Component C3 Reduces Vein Graft Atherosclerosis in Apolipoprotein E3-Leiden Transgenic Mice Circulation, December 19, 2006; 114(25): 2831 - 2838. [Abstract] [Full Text] [PDF]
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 T. Schachner Pharmacologic inhibition of vein graft neointimal hyperplasia J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 1065 - 1072. [Abstract] [Full Text] [PDF]
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 R. Sharony, G. Pintucci, P. C. Saunders, E. A. Grossi, F. G. Baumann, A. C. Galloway, and P. Mignatti Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2 Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1651 - H1659. [Abstract] [Full Text] [PDF]
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 U. Mayr, Y. Zou, Z. Zhang, H. Dietrich, Y. Hu, and Q. Xu Accelerated Arteriosclerosis of Vein Grafts in Inducible NO Synthase-/- Mice Is Related to Decreased Endothelial Progenitor Cell Repair Circ. Res., February 17, 2006; 98(3): 412 - 420. [Abstract] [Full Text] [PDF]
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P. Fogelstrand, K. Osterberg, and E. Mattsson Reduced neointima in vein grafts following a blockage of cell recruitment from the vein and the surrounding tissue Cardiovasc Res, August 1, 2005; 67(2): 326 - 332. [Abstract] [Full Text] [PDF]
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A. Zampetaki, Z. Zhang, Y. Hu, and Q. Xu Biomechanical stress induces IL-6 expression in smooth muscle cells via Ras/Rac1-p38 MAPK-NF-{kappa}B signaling pathways Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2946 - H2954. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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T. Sakaguchi, T. Asai, D. Belov, M. Okada, D. J. Pinsky, A. M. Schmidt, and Y. Naka Influence of ischemic injury on vein graft remodeling: Role of cyclic adenosine monophosphate second messenger pathway in enhanced vein graft preservation |
