© 1997 American Heart Association, Inc.
Articles |
Monocyte Chemotactic Protein-1 Expression Is Associated With the Development of Vein Graft Intimal Hyperplasia
From the Departments of Surgery and Pathology (T.F.W.), University of Wisconsin, Madison.
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Abstract |
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Abstract Infiltration of immunologically active cells into vein grafts is concomitant with the development of intimal hyperplasia (IH) and often leads to obliterative stenosis and graft failure. Previous work has demonstrated the prolonged presence of monocytes and macrophages in vein grafts. The stimuli attracting these macrophages remain unidentified. Monocyte chemotactic protein-1 (MCP-1), a potent and specific chemokine for monocytes/macrophages, is secreted by smooth muscle cells, endothelial cells, fibroblasts, and leukocytes, all of which are present in grafted veins. In this study, we examined the temporal profile of MCP-1 gene expression in rat vein grafts by using reverse transcription–polymerase chain reaction (PCR) and immunohistochemistry. Epigastric vein–to–femoral artery bypass grafts were microsurgically placed and harvested at various time points after grafting. Histological analysis confirmed the consistent development of IH. PCR was performed and relative levels of MCP-1 quantified by autoradiography. Our results show that MCP-1 mRNA levels increased 28-fold by 4 hours after grafting and up to 117-fold by 1 week. After this time MCP-1 mRNA levels decreased; nonetheless, even at 8 weeks after grafting, message levels remained elevated 7-fold above baseline. Immunoreactive MCP-1 protein and ED1+ macrophages were detected at all time points; the degree of immunostaining correlated with MCP-1 mRNA levels. Our results support the hypothesis that upregulation of MCP-1 gene expression in vein grafts results in the recruitment of monocytes and tissue macrophages to the vein wall, which leads to IH. The correlation between monocyte/macrophage infiltration and IH suggests a critical role for these cells in IH development.
Key Words: vein graft • intimal hyperplasia • cytokines • macrophages • MCP-1
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Introduction |
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Autologous vein grafts remain the only surgical alternative for many types of vascular reconstruction; unfortunately, the failure rate of these grafts after 1 year approaches 20%.1 The principal cause of graft failure is the development of IH, a fibroproliferative thickening of the neointima often leading to obliterative stenosis. Although the hallmarks of IH—the migration/proliferation of smooth muscle–like cells and the deposition of extracellular matrix—are well described,2 the etiology of this process remains poorly understood, and no successful clinical interventions have been identified.
IH develops after diverse interventions such as vein and prosthetic arterial bypass grafts, creation of arteriovenous fistulas, and percutaneous transluminal balloon angioplasty, all of which cause substantial injury to the involved vessels. Thus, the resulting IH can be considered an overexuberant vascular wound-healing response. Central to wound healing and inflammation are activated monocytes and macrophages. In addition to their phagocytic functions, monocytes and macrophages are secretory cells, producing mitogenic, fibrogenic, and angiogenic factors that can influence tissue remodeling3 4 and thus may play a role in IH development.
In a Lewis rat model of vein graft IH, we have demonstrated sustained macrophage infiltration into the vein wall and development of IH after acute inflammation has subsided.5 We have also detected mRNA transcripts of macrophage-associated cytokines (IL-1, PDGF, and TGF-ß) in vein graft tissue at several postoperative time points.6 Our observations and the work of others point to continuous involvement of macrophages within vein bypass grafts, possibly modulating the events of IH via their cytokines.
The mechanism by which monocytes/macrophages are continuously recruited to healing vein grafts is unknown. The most potent and specific chemotactic and activating factor described for these cells is MCP-1.7 It is secreted by various cells, including endothelial cells, smooth muscle cells, and fibroblasts, all of which are present in vein grafts. In previous work, we detected the presence of MCP-1 mRNA at several time points after vein graft implantation. In the present study, we demonstrate semiquantitatively the bimodal upregulation of MCP-1 mRNA expression in rat vein grafts, followed closely by a marked increase in MCP-1 immunoreactive protein, monocyte/macrophage infiltration, and IH development.
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Methods |
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Microsurgical Vein Grafting and Harvest
Epigastric vein–to–common femoral artery interposition grafts were placed in 82 male Lewis rats (350 to 450 g) via aseptic microsurgical techniques as previously described.5 In brief, each animal was anesthetized intraperitoneally with ketamine and xylazine, and the epigastric vein and common femoral artery were dissected. An 8-mm segment of relaxed epigastric vein was excised, reversed, and interposed into a 3-mm arterial defect, rendering a 1-cm completed graft. Each anastomosis was completed with 8 to 10 interrupted sutures of 10-0 nylon. After a 45-minute total ischemic time hemostasis was restored, patency was confirmed, and the wound was irrigated and closed. The animal was closely observed until recovery. Animal care complied with the Principles of Laboratory Animal Care (formulated by the National Society for Medical Research) and the Guide for the Care and Use of Laboratory Animals (NIH publication No. 80-23, revised 1985). Harvest time points in this study included 1 and 4 hours; 1 and 4 days; and 1, 2, 4, and 8 weeks. All grafts were compared with nongrafted contralateral epigastric vein controls.
Histology and Immunohistochemistry
One set of randomly chosen vein grafts (5 grafts per time point)
was used for these experiments. Transverse 5-µm sections of
formalin-fixed, paraffin-embedded control and graft tissues were cut at
500-µm intervals and placed on coated slides. Serial sections from
the proximal region (displaying the earliest IH) were chosen for
staining. Specimens were deparaffinized extensively and rehydrated in
graded ethanol solutions. Sections were stained with hematoxylin/eosin
and Verhoeff–van Gieson's elastin stains for
histological and morphometric analyses. For
immunostaining, nonspecific binding was blocked with
2% BSA in PBS. Slides were incubated with polyclonal rabbit antibody
to rat MCP-1 (a generous gift of Dr Jeffrey Warren, University of
Michigan, Ann Arbor; 10 µg/mL) at 4°C overnight. Quenching
of endogenous peroxidase with 1%
H2O2 in PBS was followed by incubation with
biotinylated anti-rabbit secondary antibody (Dako) at room temperature
for 1 hour. Serial sections were stained with monoclonal antibodies ED1
(5 µg/mL, Harlan Bioproducts for Science), which
recognizes >95% of all monocytes and macrophages, and ED2 (10
µg/mL, Harlan Bioproducts for Science, which recognizes
resident macrophages only, followed by biotinylated anti-mouse
secondary antibody. Other antibodies included asm-1 (anti–
-actin,
20 µg/mL; Boehringer Mannheim) and polyclonal rabbit
anti–factor VIII (Dako). Incubation with streptavidin-peroxidase was
followed by the addition of the substrate 3'3'-diaminobenzidine (Vector
Labs). Some specimens were counterstained lightly with hematoxylin. All
washes were done in PBS at pH 7.5. To ensure specificity of the
antibody, parallel staining with either mouse IgG1, mouse
IgG2A, or rabbit IgG at the same concentration as the test
antibody was performed. Tissues from rat spleen and cervical lymph
nodes were used as positive controls.
TEM
A separate set of grafts at 1 day and 1, 2, and 8 weeks (n=2 per
time point) was used for TEM. Two nongrafted epigastric veins were also
analyzed. Tissue was fixed in 2.5%
glutaraldehyde buffered in 0.1 mol/L sodium
cacodylate, pH 7.2, and postfixed in 1% OsO4. After
dehydration in graded alcohol solutions, the specimens were embedded in
Epon-Araldite. Thick (1 µm) sections were cut and stained with
toluidine blue. Thin (90 nm) sections were cut, placed on copper grids,
and stained with uranyl acetate and lead citrate. Three separate
sections from each segment were examined by one of the
authors (T.W.) using a Hitachi H500 TEM at various
magnifications.
RNA Extraction, Reverse Transcription, Semiquantitative PCR, and
Southern Blot Hybridization
A separate set of vein grafts (4 grafts per time point) was
randomly chosen for PCR analysis. Tissue was processed
according to previously published methods with
modifications.5 6 In brief, each patent graft was excised,
placed into Trizol denaturing solution (GIBCO BRL), and
homogenized. Chloroform extractions, washes, and
precipitations were performed. Purity and yields were determined by
spectrophotometry. RNA was reverse transcribed using Superscript II
(GIBCO BRL) according to the manufacturer's instructions. Controls
included transcription of a known amount of spleen RNA and omission of
the enzyme. DNA template (100 ng of input reverse-transcribed RNA) was
combined with sense and antisense primers (Table 1
) specific for MCP-1 or G3PDH,
[-32P]dCTP (5 µCi per reaction), dNTPs, buffer, and
Taq polymerase (Pharmacia). To ensure that amplification was
performed in the linear range, optimal cycle numbers and annealing
temperatures were determined (data not shown). Samples were subjected
to 28 (G3PDH) or 30 (MCP-1) cycles of amplification in a thermal cycler
(Stratagene). One cycle was defined as 94°C for 1 minute, 66°C for
1 minute, and 72°C for 2 minutes. Rat spleen cDNA served as the
positive control. Negative controls included omission of the template
and enzyme. PCR fragments were run on 1.8% agarose gels, which were
stained with ethidium bromide, photographed, and subjected to
confirmatory Southern hybridization. The DNA was denatured,
transferred, and immobilized on a Zeta-Probe blotting
membrane (Bio-Rad). Hybridization proceeded according to the
manufacturer's instructions. The DNA was hybridized to a
32P 5' end–labeled specific probe at 55°C overnight.
Oligonucleotide probes internal to the original PCR
primers were used (Table 1). After extensive washing, the filter was
dried and autoradiography performed. In addition, the
PCR fragments were electrophoresed on 7% polyacrylamide gels,
after which autoradiography and scintillation counting
of relevant bands were performed. Confirmatory densitometry was done
using computerized image analysis. Primers and probes were
either derived from the published cDNA sequences of rat
MCP-18 and G3PDH9 or purchased from
Clontech.
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Image and Statistical Analyses
Image analysis to quantify IH was performed as
previously described5 with modifications. All tissue
sections were imaged using a videomicroscope and analyzed using
Image-1 image analysis software (Fryer Co). Analysis
was done in a blinded fashion. Total neointimal areas were
calculated by using the internal elastic lamina as the line of
demarcation between the intima and the media-adventitia. A mean area
for each section was derived from three measurements; all the means per
time point were averaged to derive an overall mean. Total and
neointimal cells as well as the number of ED1+ and ED2+
cells per cross section were counted. Results were expressed as
mean±SEM. To determine whether values represented
significant differences from nonsurgical controls, a one-way ANOVA was
performed followed by Fisher's protected least significant difference
procedure to compare the means of the treatments. The relative
abundance of MCP-1 protein as detected by
immunostaining was scored subjectively on a graded
scale in a blinded fashion.
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Results |
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IH Is Induced in Grafts
Animal survival and graft patency rates were 100%. Predictably, IH was induced in all grafts, with neointimal areas increasing progressively throughout all time points (Fig 1A
). Total cell numbers increased until 4
weeks and then began to decline (Fig 1B). In contrast, the numbers of
cells in the neointima continued to increase. Morphometric
and histological changes observed in the vein wall were
consistent with our previously reported
results.5 6 Early endothelial denudation
was accompanied by platelet and leukocyte adherence to the
subendothelial space. The degeneration of medial cells
and marked mononuclear cell infiltration were detected by 1 day.
Transmural mononuclear cells were visible by 1 week (Fig 2A). By 2 weeks, a regenerated
endothelium and an eccentric neointima were
clearly discernible in all grafts (Fig 2B). Neointimal
areas and graft cellularity had increased significantly by 4 weeks (Fig 2C).
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TEM confirmed and extended all histological findings.
Medial smooth muscle cell degenerative changes and extensive cell death
were notable. Infiltrating mononuclear leukocytes were present
luminal and abluminal to the internal elastic membrane and were
surrounded by cell debris (Fig 3A); this
zone of necrosis persisted throughout all later time points. At 2
weeks, the majority of neointimal cells were identified as
mononuclear leukocytes (Fig 3B). Also present were smooth
muscle–like cells with ultrastructural characteristics
consistent with those of myofibroblasts: irregular outlines,
disorganized microfilaments, and abundant, rough endoplasmic reticulum.
These cells were the major component of the neointima at 4
and 8 weeks.
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ED1+ and ED2+ Macrophages Infiltrate and Persist in Healing
Vein Grafts
Grafts were further analyzed immunohistochemically for the
presence of monocytes and macrophages.
Immunostaining was performed using the monoclonal
antibodies ED1, which recognizes >95% of all rat monocytes and
macrophages, and ED2, which recognizes resident
macrophages only. Nongrafted epigastric veins contained no ED1+
cells. ED1+ monocytes were detected at the luminal surface by 1 day
after grafting and were seen transmurally by 1 week (Fig 4A). ED1+ cell infiltration was maximal
at 2 weeks. These cells were detected within the developing
neointima, at the shoulders of developing lesions, and in
the medial-adventitial layer. After 4 weeks, ED1+ macrophages
were seen near the internal elastic lamina at the base of the
neointima (Fig 4B). ED2+ resident macrophages were
detected in small numbers in the adventitia of the normal vein. They
were no longer detectable immediately after grafting but were detected
by 1 week in the adventitia and increased steadily until 4 weeks (Fig 4C), after which their numbers remained significantly higher than in
the normal epigastric vein. They were rarely seen outside the
adventitia. The results of ED1+ and ED2+ cell counting are
presented in Fig 5.
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ED1+ Cells Predominate in the Developing Neointima
As shown in Table 2, ED1+
monocytes/macrophages predominated in the neointima
at 1 day and 2 weeks after grafting. By 2 weeks, the
neointima had enlarged and become morphologically well
distinguished from the other wall layers. As the neointima
continued to develop, monocytes and macrophages became
progressively less numerous as other cell types, such as
myofibroblasts, smooth muscle cells, and endothelial
cells, populated the neointima. Nevertheless, the number of
ED1+ cells remained significantly higher than in control veins.
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MCP-1 mRNA Is Bimodally Upregulated in Vein Bypass Grafts
To investigate the most likely chemoattractant for
graft-infiltrating monocytes and macrophages, semiquantitative
reverse transcription-PCR was used to assess relative MCP-1 mRNA levels
in vein grafts. MCP-1 mRNA levels were normalized against those of
G3PDH, a constitutively expressed gene that is present in all
cells. In normal epigastric veins, there was a low level of MCP-1
expression (Fig 6). After grafting,
levels were increased variably by 1 hour and consistently by 4
hours, at 28-fold above controls. There was another increase at 1 week
(117-fold above baseline) prior to the peak in macrophage
number. Levels decreased substantially by 4 and 8 weeks but remained
elevated 7-fold over control levels. The results of densitometry
confirmed scintillation counting (data not shown).
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Immunoreactive MCP-1 Is Increased After Vein Grafting
To detect MCP-1 protein in vein grafts,
immunostaining with a specific antibody was performed
on paraffin sections. Stained sections were scored in a blinded
fashion; the temporal profile of MCP-1 localization is
presented in Table 3. The pattern
of protein expression agreed with reverse transcription-PCR results. In
the normal epigastric vein, weak cytoplasmic and extracellular staining
was seen in the intimal endothelium, with some diffuse
staining throughout the medial and adventitial layers. Throughout all
time points after grafting, marked staining was seen in the adventitia.
At 1 hour after grafting, some focal luminal and medial staining
associated with degenerating endothelial cells and
smooth muscle cells remained but was absent by 4 hours. By 1 to 4 days,
patchy luminal staining was detectable near adherent mononuclear cells
and the remaining endothelium. Adventitial staining
surrounding resident fibroblasts and infiltrating cells had increased,
but medial staining was conspicuously absent. We did not detect any
MCP-1–positive polymorphonuclear leukocytes. At 1 to 2 weeks,
immunoreactive MCP-1 was seen in the adventitia, at the luminal edge,
and in the developing neointima, often within the fibrin
matrix and surrounding the infiltrating mononuclear cells. After 4
weeks, staining was confined mainly to the area around the internal
elastic lamina at the base of the neointima, coincident
with ED1+ monocytes/macrophages (Fig 7), as well as the luminal surface.
Staining in the adventitia, though slightly weaker than at earlier time
points overall, was also seen occasionally in the vasa vasorum.
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Discussion |
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IH in vein bypass grafts, a condition often leading to obliterate stenosis and subsequent graft failure, is characterized by a thickened neointima composed of mesenchymal cells and extracellular matrix. It is thought that IH begins as a wound healing response to vascular injury that evolves into a chronic condition of unchecked proliferation.2 The development of IH in vein grafts may be regulated by mediators of wound healing and inflammation, such as activated monocytes and macrophages.10 These mononuclear leukocytes possess multiple functions, including phagocytosis; antigen presentation; and secretion of mitogenic, fibrogenic, angiogenic, and chemotactic factors.3 4 11 12 Their importance in atherosclerosis is well documented,13 and their presence has been demonstrated in human vein grafts and in animal models of vein graft IH.5 14 15 16 17 18
The factors that recruit monocytes and macrophages to vein grafts have not yet been identified. One likely chemokine is MCP-1, a potent monocyte chemotactic and activating factor belonging to the C-C family of intercrine cytokines.7 MCP-1 is synthesized by endothelial cells19 20 21 , smooth muscle cells,22 fibroblasts,19 23 24 25 and monocytes/macrophages,24 26 27 28 all of which are present in vein grafts. MCP-1 is constitutively expressed in vascular tissues21 ; this expression can be further stimulated by various factors. MCP-1 has been localized within macrophage-rich atherosclerotic lesions and abdominal aortic aneurysms.29 30 31 In a rabbit arterial injury model, antibodies against MCP-1 have been shown to decrease IH,32 lending further credence to our hypothesis. Upregulation of this factor has been demonstrated in other disease processes involving macrophages, eg, rheumatoid arthritis,33 34 pulmonary disorders,35 36 hepatitis,37 chronic tissue rejection,38 and tumor development.39 40 In addition, MCP-1 upregulation has been correlated with macrophage infiltration in normal dermal wound repair.41 These observations strongly suggest a role for MCP-1 in IH development. In an effort to elucidate monocyte/macrophage recruitment in healing vein grafts, we examined MCP-1 gene expression in rat vein bypass grafts. This semiquantitative study reports biphasic MCP-1 upregulation at both the mRNA and protein levels in vein grafts that precedes maximal macrophage infiltration and IH development.
In the normal rat epigastric vein, there is weakly detectable MCP-1
mRNA expression, consistent with the low basal level of MCP-1
mRNA found in normal vessels.21 There are
macrophages, albeit in low numbers, detectable in the
adventitia. Early after surgery, MCP-1 gene expression increases in
vein grafts. Various factors are candidates for affecting MCP-1 mRNA
expression in these grafts. Thrombin, present as part of the
coagulation cascade, is known to induce MCP-1
expression.42 The proinflammatory cytokines
IL-1 and TNF-, expressed early in healing vein
grafts5 (J.R.H., unpublished observations, 19
), have
been shown in vitro to increase MCP-1 gene
expression.19 20 TGF-ß, a fibrogenic cytokine
with pleiotropic effects, and PDGF, a smooth muscle cell mitogen, also
influence MCP-1 expression33 43 ; both are increased in
hyperplastic vein grafts and restenotic
arteries.6 44 45 46 Other possible mediators of MCP-1
upregulation in healing vein grafts include MCSF47 and
IFN-
.28 It is known that transcription of MCP-1, as an
early-response gene, is induced by fluid shear stress via a
shear-inducible element in the promoter48 49 ; thus, it is
conceivable that other hemodynamic factors also
affecting vein grafts, such as compliance mismatch and pulsatile flow,
may influence MCP-1 gene expression in vascular cells. Many of these
proteins and hemodynamic factors have been associated
with IH development.2 5 6 44 45 46 50 51
In our model, the levels of MCP-1 mRNA fluctuated in a biphasic manner,
with peaks at 4 hours and 1 week. These peaks were followed by
detectable MCP-1 immunoreactivity and immediately preceded maximal
monocyte/macrophage infiltration peaks at 1 day and 2 weeks. It
is notable that MCP-1 transcript levels did not return to baseline
after acute inflammation had subsided (
4 weeks). Instead, MCP-1 mRNA
levels remained elevated 7-fold above control levels and
macrophages persisted, suggesting a state of chronic
inflammation. This finding contrasts with the disappearance of MCP-1
mRNA expression and macrophage infiltration at 2 weeks in
healing dermal wounds41 and perhaps reflects the
pathological consequences of vein grafting. Our findings suggest that
this chemokine continuously recruits monocytes and macrophages
to the healing grafts during the development of IH.
There is very weak MCP-1 protein expression as detected by
immunohistochemical staining in the normal epigastric vein.
Coincidentally, few macrophages are seen. Early after grafting,
staining is reduced, corresponding to the partial loss of
endothelial cells. Medial staining is attenuated,
possibly as a result of a decrease in resident medial cells.
Ultrastructural examination of vein graft tissue has shown that the
majority of medial smooth muscle cells degenerate and die within hours
after grafting (V.K.S., unpublished data, 19). However, MCP-1
protein remains detectable in the fibroblast-rich adventitia. MCP-1
immunoreactivity reappears at the luminal surface, concomitant with
infiltrating cells. One to 2 weeks after grafting,
immunostaining is augmented on the luminal surface, in
the developing neointima, and in the adventitia. Possible
sources of MCP-1 protein in vein grafts are regenerated
endothelial cells, lymphocytes, and adventitial
myofibroblasts. Medial immunostaining is conspicuously
absent, reflecting the paucity of cells in this layer. At later time
points, MCP-1 staining is seen occasionally at the luminal surface in
the endothelium and most frequently in the necrotic
zone surrounding the internal elastic lamina, an area where
macrophages reside in the vein graft wall. Resident
macrophages, which do not stain strongly for MCP-1, appear to
be a population normally present in vessels and thus, may not be
important in IH development.
MCP-1 may not be the sole chemoattractant for monocytes and macrophages in vein grafts; in light of the complex cytokine milieu of vein grafts, the potential for additive or synergistic effects of MCP-1 and other factors is great. In addition, MCP-1 may be recruiting other leukocytes such as T cells,52 which are present in hyperplastic rat vein grafts.5 Our results show that elevated levels of MCP-1 mRNA and protein correlate with transmural macrophage infiltration during early neointimal development. Overall, the evidence suggests an integral role for monocytes/macrophages in the development of IH in healing vein grafts. The persistence of both MCP-1 expression and macrophage infiltration in grafted veins further supports the idea that IH is a prolonged healing response. The relationship between MCP-1 expression and neointimal development merits further investigation, possibly highlighting clinical therapeutic strategies for the prevention of vein graft IH.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grant No. 94-Gb-42 of the American Heart Association.
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Footnotes |
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Reprint requests to John R. Hoch, MD, Department of Surgery—H4/736 CSC, University of Wisconsin, 600 Highland Ave, Madison, WI 53792.
Received August 26, 1996; accepted October 28, 1996.
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