Published online before print October 14, 2004, doi: 10.1161/01.ATV.0000147766.68987.0d
© 2004 American Heart Association, Inc.
Vascular Biology |
Vein Graft Neointimal Hyperplasia Is Exacerbated by Tumor Necrosis Factor Receptor-1 Signaling in Graft-Intrinsic Cells
From Duke University Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC.
Correspondence to Karsten Peppel or Neil J. Freedman, Box 3187, Duke University Medical Center, Durham, NC 27710. E-mail karsten.peppel{at}duke.edu or neil.freedman@duke.edu
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Abstract |
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Objective— Vein graft remodeling and neointimal hyperplasia involve inflammation, graft-intrinsic cells, and recruitment of vascular progenitor cells. We sought to examine if the inflammatory cytokine tumor necrosis factor (TNF) affects vein graft remodeling via its p55 TNF receptor-1 (p55).
Methods and Results— Inferior vena cava-to-carotid artery interposition grafting was performed between p55–/– and congenic (C57Bl/6) wild-type (WT) mice. Immunofluorescence revealed TNF in early (2-week) vein grafts. Six weeks postoperatively, luminal and medial areas were indistinguishable among all vein graft groups. However, neointimal area was reduced in p55–/– grafts: by 40% in p55–/– grafts placed in p55–/– recipients, and by 21% in p55–/– grafts placed in WT recipients, compared with WT grafts in WT recipients (P<0.05). In 2-week-old vein grafts, p55 deficiency reduced intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 expression by 50% to 60%, and increased the extent of graft endothelialization. In vitro, TNF promoted chemokine expression and [3H]thymidine incorporation in vascular smooth muscle cells (SMCs) from WT, but not from p55–/– mice. However, responses of WT and p55–/– SMCs to other growth factors were equivalent.
Conclusions— Signaling via p55, in vein graft-intrinsic cells, contributes to the pathogenesis of vein graft neointimal hyperplasia.
In surgical mouse chimeras, TNF receptor-1 (p55)-deficient vein grafts (compared with WT grafts) demonstrated less ICAM-1, VCAM-1, and MCP-1 expression, accelerated endothelialization, and reduced neointimal hyperplasia. However, vein graft medial thickness was unaffected. SMC chemokine expression and DNA synthesis in response to TNF, but not PDGF, was abrogated by p55 deficiency.
Key Words: vascular remodeling • inflammation • mouse models • smooth muscle cells • tumor necrosis factor
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Introduction |
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Virtually all vein grafts develop neointimal hyperplasia within the first year after implantation.1 Vein graft neointimal hyperplasia is characterized by smooth muscle cell (SMC) accumulation and extracellular matrix deposition in the intima, a process that may reduce lumen area by as much as 25%.1 Although thickening of the vein graft media is required to decrease wall stress, development of neointimal hyperplasia serves as a nidus for accelerated atherosclerosis, which leads to vein graft failure within 10 years in >40% of grafts.1
Immediately after autologous vein grafting, a number of early events are believed to contribute to the pathogenesis of neointimal hyperplasia: endothelial damage, the expression in vein graft cells of inflammatory proteins and adhesion molecules, the adherence of platelets and leukocytes to the graft luminal surface, and, ultimately, the wound repair response that includes proliferation of SMCs2 and recruitment of graft-extrinsic cells into the arterializing graft.3 In this complex process, evidence supporting a role for pro-inflammatory cytokines is emerging.4–6
Among several pro-inflammatory cytokines with possible roles in vein graft neointimal hyperplasia, tumor necrosis factor-
(TNF) has diverse effects on different target cells7 and has been implicated in the pathogenesis of arterial vascular disease.8,9 It promotes the expression of cellular adhesion molecules on both vascular smooth muscle cells (SMCs) and endothelial cells,10,11 and engenders production of chemoattractant molecules by SMCs.12 In addition, TNF promotes SMC proliferation13 and endothelial cell apoptosis.14
TNF exerts its cellular effects through 2 known cell surface receptors: p55 (CD120a; TNF receptor-1) and p75 (CD120b; TNF receptor-2). Through these 2 receptors, TNF can elicit proliferative, survival, or apoptotic signaling in target cells.15,16 A variety of models have been used to suggest a role for TNF and its p55 receptor in neointimal hyperplasia. When neointimal hyperplasia was induced in mice by arterial constriction and consequent low shear stress, the neointimal hyperplasia was reduced by TNF deficiency and augmented by TNF overexpression.9 When neointimal hyperplasia was induced in mice by wire injury to the carotid artery, deficiency of p55, but not p75, reduced the neointimal hyperplasia.8,17 In the context of these useful (but unphysiologic) models, TNF appeared to contribute to neointimal hyperplasia through its p55 receptor. However, whether results with these models can be generalized to the neointimal hyperplasia encountered in vein grafts remains to be determined. Moreover, the use of mutant mice to investigate the role of TNF receptors in neointimal hyperplasia does not permit us to know at what locus the p55 acts: in cells of the vascular wall, in cells of the immune system, or both?
To address these questions, we used a murine interposition vein graft model that mimics early human vein graft disease.18 We have recently shown in this model that the majority of cells constituting the mature vein graft are "graft-extrinsic" cells, which originate from outside the vein graft at the time of its implantation.3 To determine whether p55 expression either in the vein graft itself or in graft-extrinsic cells affects vein graft neointimal hyperplasia, we used C57Bl/6 wild-type (WT) and histocompatible, congenic, p55–/– mice in a cross-transplantation design.
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Methods |
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Mice
Adult male C57Bl/6 (WT) mice, and congenic p55-deficient (p55–/–) mice were purchased from Jackson Labs (Bar Harbor, Me). All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee and complied with the Guide for the Care and Use of Laboratory Animals.
Vein Graft Surgery
Interposition vein graft surgery was performed as described previously.18 Inferior vena cavae from C57Bl/6 or p55–/– donor mice were anastomosed to the right common carotid artery of recipient mice, in 3 different donor/recipient combinations, as follows: (1) WT/WT; (2) p55–/–/WT; and (3) p55–/–/p55–/–. All mice were age-matched and between 12 and 20 weeks old.
Histology
Grafts were harvested 2 to 6 weeks postoperatively and prepared for histochemical and immunofluorescent analysis as we described previously.18 Morphometry was performed on vein grafts as described.18 Goat anti-TNF, anti-monocyte chemoattractant protein (MCP)-1, rabbit anti–intercellular adhesion molecule (ICAM)-1, anti–vascular cell adhesion molecule (VCAM)-1, anti–proliferating cell nuclear antigen (PCNA) (Santa Cruz Biotech, Inc), and rabbit anti-factor VIII (DAKO Inc) were used to detect vein graft protein expression. Negative control sections were incubated with nonimmune goat or rabbit IgG in lieu of primary antibody. Cyanine 3-conjugated 1A4 IgG (Sigma) was used to detect SMC actin, as described.19 The DNA-binding dye Hoechst 33342 (10 µg/mL) was added to secondary antibody incubations. Single microscopic fields were imaged for multiple fluorophores, as described.19
To quantitate protein expression within vein grafts, specimens from vein graft groups 1, 2, and 3 (see previous) were stained and imaged simultaneously, batch-wise. Identical exposure times and incident light intensities were used to visualize each specimen; images were captured with a SPOT RT charge-coupled device camera (Diagnostic Instruments). Four orthogonal clock hours of each specimen were analyzed using NIH ImageJ software and averaged. Specific staining was obtained by subtracting mean fluorescence values of negative control specimens from those incubated with the relevant first antibody. Intensities thus derived were normalized to cognate fluorescence intensities obtained from nuclear fluorescent (Hoechst) staining of the same vein graft section. These ratios were averaged among all vein grafts within each group. Thus, adhesion molecule and MCP-1 immunofluorescence were compared across groups in a manner that accounted for the cellularity of each specimen.
SMC Culture
Primary murine SMCs were derived from inferior vena cavae or aortas of C57BL/6 or congenic p55–/– mice by explant outgrowth and rendered quiescent by incubation in serum-free medium for 36 hours as described.19
Extracellular Signal-Regulated Kinase Activation
Quiescent WT or p55–/– SMCs were treated with human TNF (hTNF) or murine TNF (mTNF) (10 ng/mL), platelet-derived growth factor (PDGF) (5 ng/mL), or epidermal growth factor (EGF) (1 ng/mL) for 10 minutes and then processed for immunoblotting phospho-extracellular signal-regulated kinase (ERK)1/2 (p-ERK) as described.2 Parallel blots were probed for total ERK1/2 content to ascertain equal lane loading.
[3H]Thymidine Incorporation
Agonist-induced SMC [3H]thymidine incorporation was assessed as described.19
Transcriptional Profiling
Quiescent WT SMCs were treated with mTNF for the time indicated. mRNA was extracted using RNAzol II (TelTest), reverse-transcribed, and used to probe Affymetrix MU6400 gene chips. The relative abundance of specific mRNA species was calculated according to the algorithms developed by Affymetrix.
Cytokine Immunoassay
Quiescent aortic or venous SMCs of WT or p55–/– mice were incubated with murine TNF (10 ng/mL) for 36 hours in serum-free medium. Conditioned media were then assayed for chemokines using anti-cytokine antibody array membranes (Panomics, Calif). Chemiluminescent signals were quantitated with densitometry and NIH ImageJ software.
Statistical Analysis
One-way ANOVA with Tukey post-hoc test for multiple comparisons was used to analyze morphometric data and protein expression levels.
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Results |
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TNF Expression in Vein Grafts
If it plays an important role in vein graft remodeling, TNF should be expressed during the early phases of vein graft remodeling. To assess this possibility, we examined the time course of TNF expression in our murine vein grafts. Whereas TNF was undetectable in ungrafted veins or uninjured aortas (data not shown), it was easily demonstrated in vein grafts as early as 2 weeks after implantation (Figure 1A). By double-staining vein grafts for TNF and SMC actin, we found that SMCs and non-SMCs expressed TNF (Figure 1B). Moreover, serial vein graft sections demonstrated abundant proliferating cell nuclear antigen in areas expressing TNF (Figure 1C). Taken together, these observations suggested that TNF could promote SMC proliferation in the arterializing vein graft.
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3 grafts. Original magnification x440.
The Role of p55 in Vein Graft Neointimal Hyperplasia
To determine whether TNF contributes to vein graft remodeling, we examined vein grafts from WT as well as p55-deficient mice, and used WT as well as p55–/– mice as congenic vein isograft recipients. Vein grafts were implanted into the common carotid of recipient mice. In the case of p55–/– grafts implanted into WT recipients, this procedure created p55-chimeric mice. With these chimeras and their nonchimeric counterparts, we intended to dissect apart the roles in neointimal hyperplasia played by p55 in 2 distinct populations of cells: those residing within the vein graft at the time of its implantation ("graft-intrinsic cells"), and those residing outside the vein graft at the time of its implantation ("graft-extrinsic cells"), which ultimately constitute most of the vein graft neointimal cells.3 Vein grafts were harvested 6 weeks after surgery, after neointimal hyperplasia in WT grafts reaches steady state.18
WT vein grafts implanted into WT recipient mice demonstrated the kind of neointimal hyperplasia that characterizes many animal models of vein graft disease,18 as well as the early, pre-atherosclerotic stages of human vein graft disease1: multiple (
14) layers of -SMC actin-expressing cells that do not cause significant luminal stenosis (Figure 2 and data not shown). In contrast to these control vein grafts, p55–/– vein grafts placed into p55–/– recipients showed 40% less neointimal area, and p55–/– vein grafts placed into WT recipients showed 21% less neointimal area (P<0.05, Figure 2). However, neither medial area (Figure 2B) nor luminal area (not shown) differed among the 3 vein graft groups. When WT grafts were placed in p55–/– recipients, however, medial thickness was 47% greater than in control grafts, and medial hypercellularity suggested alloimmunity to the p55 expressed in the graft (Figure I, available online at http://atvb.ahajournals.org). Because neointimal hyperplasia in p55–/– grafts tended to decrease further when these grafts were implanted into p55–/– recipients, these data suggested that neointimal hyperplasia is affected by signaling through p55 expressed on not only graft-intrinsic cells but also, perhaps, graft-extrinsic cells.
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Pronounced endothelial cell loss ensues after vein graft implantation and contributes to neointimal hyperplasia.3,21,38 Because vein graft endothelium derives from graft-intrinsic as well as graft-extrinsic cells,3,38 and because TNF induces endothelial cell apoptosis,14 we tested whether p55 deficiency could accelerate vein graft endothelialization and thereby possibly reduce neointimal hyperplasia. In 2-week-old grafts, we found that the extent of endothelialization correlated inversely with the extent of endothelial cell p55 expression: least in WT grafts implanted into WT recipients, and most in p55–/– grafts implanted into p55–/– recipients (Figure 3). Thus, TNF-promoted endothelial toxicity mediated by p55 could contribute to vein graft neointimal hyperplasia.
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Because 60% of neointimal cells derive from the recipient in this vein graft model,3 the neointimal hyperplasia decrement observed in p55–/– grafts suggested 2 additional mechanistic possibilities, which are not mutually exclusive: that p55 in graft-intrinsic cells is important for the proliferation of graft-intrinsic cells, or/and that p55 in graft-intrinsic cells is important for the recruitment of graft-extrinsic cells to the remodeling vein graft, perhaps by triggering chemokine secretion known to be promoted by TNF.20 To test these possibilities in vitro, we studied TNF-mediated mitogenic signaling and chemokine expression in WT and p55–/– SMCs, because of the importance of SMCs and SMC-like cells in the pathogenesis of neointimal hyperplasia.21 To determine the importance of p55 to TNF-promoted mitogenic signaling in SMCs, we assessed TNF-promoted activation of ERK1 and ERK2 and TNF-promoted [3H]thymidine incorporation.
p55 Mediates TNF-Induced Mitogenic Signaling and Chemokine Production in SMCs
TNF activated ERK to a degree comparable to that achieved by PDGF or EGF in WT SMCs (Figure 4A). Moreover, human TNF (which binds only to the p55 TNF receptor-1 on murine cells22) activated ERK to a degree equivalent to murine TNF, which binds to both the p55 and p75 receptors (Figure 4A)—an observation that suggested an exclusive role for p55 in mediating TNF-induced ERK activation in SMCs. Congruent with this observation, TNF failed to activate ERK in p55–/– SMCs, even though PDGF and EGF activated ERK to a degree comparable to that observed in WT SMCs (Figure 4A). Thus, promitogenic TNF signaling appeared to occur via p55, but not p75, in murine SMCs.
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In accord with these ERK activation data, SMC [3H]thymidine incorporation in response to murine TNF did not exceed basal levels in p55–/– SMCs, whereas [3H]thymidine incorporation in response to PDGF was indistinguishable from that in WT SMCs (Figure 4B). To increase the sensitivity of our assay for detecting possible small-magnitude p75-mediated [3H]thymidine incorporation, we exploited the synergistic [3H]thymidine incorporation elicited by the combination of TNF and PDGF (Figure 4B). However, even under these conditions, which model in vivo conditions by providing a combination of growth factors, p55–/– SMCs demonstrated no detectable response to TNF (Figure 4B).
To assess the possibility that p55 mediates TNF-evoked SMC chemokine expression that, in turn, might affect the recruitment of vascular progenitor cells to the vein graft, we first used transcriptional profiling to characterize WT SMC chemokine expression in response to TNF (Figure 5A). TNF induced both C-C (RANTES, MCP-1) and C-X-C (KC and IP-10, data not shown) chemokine transcription in WT SMCs. To assess TNF-induced chemokine secretion by SMCs, and to determine the role of p55 in this process, we assayed medium from TNF-stimulated WT and p55–/– SMCs (Figure 5B). Consonant with our mRNA analysis, growth medium immunoassay demonstrated TNF-induced secretion of RANTES and IP-10 by WT SMCs. In addition, WT SMCs secreted IL-6 in response to TNF. However, none of these chemo/cytokines was secreted by p55–/– SMCs in response to TNF. Thus, as was the case with SMC mitogenic responses to TNF, important SMC chemokine secretory responses to TNF were mediated via the p55, and not the p75, TNF receptor.
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p55 Promotes Vein Graft MCP-1 and Adhesion Molecule Expression
Because the p55 of SMCs mediates TNF-evoked chemo/cytokine secretion, deficiency of p55 in graft-intrinsic cells might reduce recruitment of graft-extrinsic cells to p55–/– grafts. Supporting this possibility in vivo, we found that p55 deficiency reduced vein graft MCP-1 levels to 54±16% of those observed in WT grafts (P<0.05; Figure 6).
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The process of retaining graft-extrinsic cells recruited to the vein graft involves integrin-binding cell adhesion molecules (CAMs) on the surface of graft-intrinsic cells,23 and TNF promotes CAM expression on endothelial cells and SMCs.10,11 We therefore asked whether remodeling p55–/– vein grafts would demonstrate reduced expression of either ICAM-1 or VCAM-1. In 2-week-old vein grafts, we found that p55 deficiency in the graft alone reduced ICAM-1 and VCAM-1 expression by 62% and 52%, respectively, and that p55 deficiency in the graft and recipient reduced CAM expression only insignificantly further (Figure 6). Thus, attenuation of neointimal hyperplasia in p55–/– vein grafts likely is caused by a lack of direct mitogenic stimulation from TNF, as well as an attenuated cell-recruiting chemokine and adhesion molecule expression.
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Discussion |
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This study demonstrates for the first time to our knowledge that TNF signaling, via p55, contributes significantly to vein graft neointimal hyperplasia. By showing reduction in neointimal hyperplasia with p55 deficiency in the vein graft alone, this study provides the first evidence that p55 signaling specifically in graft-intrinsic cells promotes vein graft neointimal hyperplasia. Signaling through graft-intrinsic cell p55 engenders a variety of activities integral to neointimal hyperplasia: SMC proliferative activity and chemokine secretion, demonstrated by our in vitro data, and vein graft wall VCAM-1, ICAM-1, and MCP-1 expression, demonstrated by our in vivo data.
It appears that p55 is required for the majority of VCAM-1 and ICAM-1 expression in experimental vein grafts. This novel insight is surprising. Whereas TNF is known to promote VCAM-1 expression in vascular cells, the same is true for IL-1,24 angiotensin II,25 thrombin,26 and the combination of IL-6 and endothelin-1.27 In a distinct mouse vein graft model,28 ICAM-1 deficiency has been shown to reduce combined neointimal plus medial area by 30% to 50%; however, graft-intrinsic and graft-extrinsic cell contribution to this ICAM-1 effect could not be evaluated, because both the inferior vena cavae donor and recipient were ICAM-1–deficient. Nevertheless, together with the data presented in our current study, this report supports the possibility that the overall reduction in neointimal hyperplasia by p55 deficiency may significantly derive from its effects on adhesion molecule expression.
What part do TNF-induced chemokines play in vein graft remodeling? Our finding that vein graft MCP-1 levels parallel neointimal hyperplasia recalls similar findings with RANTES in wire-injured carotid arteries.29 It remains unknown, however, whether RANTES and MCP-1 can recruit vein graft SMC progenitors or only cells of the monocyte/macrophage lineage. Because 60% of vein graft neointimal cells are graft-extrinsic,3 our correlation of vein graft MCP-1 levels with vein graft p55 expression and neointimal hyperplasia suggests the possibility that vascular progenitor cell recruitment to vein graft neointima may be diminished in p55–/– grafts. What type or types of vascular progenitor cells could be recruited by chemo/cytokines secreted by SMCs in response to p55 signaling? The chemokines IP-10 and IL-6 have both been shown to promote SMC chemotaxis,30,31 and SMCs may enter the graft in a number of ways: from the adjacent arterial tissue by migration;32 from the bloodstream as vascular smooth muscle progenitor cells33,34 or transdifferentiating fibrocytes;35 or from the adventitia, as transdifferentiating fibroblasts36 or stem cells.37
When p55 deficiency in vein graft-intrinsic cells was complemented by p55 deficiency in graft-extrinsic cells in 2-week-old grafts, we could not detect significant further decreases in vein graft MCP-1 or CAM expression. To understand this result, it is helpful to recall that the "focal expansions" of proliferating cells in 2-week-old grafts comprise predominately either graft-intrinsic or graft-extrinsic cells.3 Thus, as a result of random sampling from a relatively small number of these expansions in our study, a true difference between p55–/–-to-p55–/– and p55–/–-to-WT grafts could easily have been obscured. Regarding neointimal hyperplasia, adding p55 deficiency of the vein graft recipient to that of the donor did cause further decrement, but with a variance that precluded statistical significance. Thus, this study can neither inculpate nor exculpate graft-extrinsic cell p55 in the process of neointimal hyperplasia.
Interestingly, p55 deficiency in donor veins significantly attenuates expansion of the SMC-rich vein graft neointima while failing to affect remodeling of the graft media, a process that includes recruitment of bone marrow-derived progenitor cells.3 This observation reveals considerable complexity in vein graft remodeling. In this regard, p55 deficiency bears similarity to E2F decoy therapy, which also reduces vein graft susceptibility to accelerated atherosclerosis.39 Recently, TNF blockade with a soluble p75–IgG fusion protein (etanercept) has been shown to accelerate endothelial recovery and reduce neointimal hyperplasia in injured rat carotid arteries,40 much as we observed with p55 deficiency in our vein grafts. Collectively, these data suggest that inhibition of TNF signaling may have therapeutic value for patients undergoing vascular bypass graft operation with venous conduits. It remains to be determined whether TNF promotes neointimal hyperplasia primarily through its effects on SMC and endothelial cell proliferation, adhesion molecule expression, chemokine secretion, or through a combination of these and other yet-unidentified mechanisms.
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Acknowledgments |
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This work was supported by grants HL63288 (N.J.F.) and HL64744 (K.P.) and American Heart Association grants-in-aid (N.J.F., K.P.).
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Footnotes |
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L.Z. and K.P. contributed equally to this work.
Received May 14, 2004; accepted October 5, 2004.
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