Published online before print November 15, 2007, doi: 10.1161/ATVBAHA.107.151613
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© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Tumor Necrosis Factor Receptor-2 Signaling Attenuates Vein Graft Neointima Formation by Promoting Endothelial Recovery
From the Departments of Medicine (Cardiology) and Cell Biology (L.Z., P.S., J.-H.W., L.B., S.T.E., M.J.F.), Duke University Medical Center, Durham, NC; and the Center for Translational Medicine (K.P.), Jefferson Medical College, Philadelphia, Pa.
Correspondence to Karsten Peppel or Neil J. Freedman, Jefferson Medical College, 1025 Walnut Street, Rm 311, Philadelphia, PA 19107. E-mail karsten.peppel{at}jefferson.edu or neil.freedman@duke.edu
Abstract
Objective— Inflammation appears intricately linked to vein graft arterialization. We have previously shown that tumor necrosis factor (TNF) receptor-1 (TNFR1, p55) signaling augments vein graft neointimal hyperplasia (NH) and remodeling through its effects on vascular smooth muscle cells (SMCs). In this study we examined the role of TNFR2 (p75) signaling in vein graft arterialization.
Methods and Results— Inferior vena cava-to-carotid artery interposition grafting was performed between p75–/– and congenic (C57B1/6J) wild-type (WT) mice. Six weeks postoperatively, neointimal and medial dimensions were greater in p75–/– grafts placed into p75–/– recipients (by 42% or 60%, respectively; P<0.05), when compared with WT veins grafted into WT recipients. Relative to WT vein grafts, p75 deficiency augmented early (2-week-old) graft vascular cell adhesion molecule (VCAM)-1 expression (by 2.4-fold, P<0.05), increased endothelial cell apoptosis (2-fold), and delayed graft re-endothelialization. Both cellular proliferation in early, and collagen I content of mature (6-week-old) vein grafts were increased (by 70% and 50%, respectively) in p75–/– grafts. P75 deficiency augmented TNF-induced apoptosis of cultured endothelial cells, but did not affect TNF-stimulated SMC proliferation or migration induced by co-cultured macrophages.
Conclusions— TNF signaling via p75 reduces vein graft neointimal hyperplasia through mechanisms involving reduction of adhesion molecule expression and endothelial cell apoptosis.
In murine IVC grafts implanted into congenic recipient mice, TNF receptor-2 deficiency significantly augmented neointimal hyperplasia, medial expansion, and adhesion molecule expression, while delaying endothelial resurfacing of the graft lumen. As opposed to TNF receptor-1 signaling, activation of TNF receptor-2 does not change SMC proliferation and chemotaxis.
Key Words: TNF • inflammation • vascular remodeling • mouse models • endothelial cells
Vein graft failure occurs largely because an atherosclerosis-prone neointima develops in the grafted vein consequent to the hyperdistension and barotrauma that accompanies placement into the arterial circuit.1 Recent evidence points to injury-induced inflammation, including macrophage infiltration and medial smooth muscle cell activation, as promoting the development of vein graft neointimal hyperplasia (NH).2 Among many different cytokines and growth factors secreted by macrophages, tumor necrosis factor (TNF) is expressed in vein grafts3 and appears to play a major role in neointimal hyperplasia of not only vein grafts but also arteries.4,5 TNF promotes expression of adhesion molecules on both vascular smooth muscle cells (SMCs) and endothelial cells (ECs),6,7 stimulates expression of cell-recruiting chemokines,8 and induces EC apoptosis,9 while simultaneously promoting SMC proliferation and migration.3,4,10 It signals via two different receptors, p55 (CD120a, TNFR1) and p75 (CD120b, TNFR2) that share ligand-binding domain homology while possessing divergent intracellular signal transduction moieties.
TNF is expressed in early vein grafts at the peak of the remodeling response in vivo4 and by activated SMCs in vitro.3 Although vein grafts lacking p55 demonstrate reduced NH,4 the role of p75 signaling has not been examined in this setting. In the present study we used cross transplantation of veins from C57Bl/6 and congenic p75–/– mice to examine the consequences of p75 signaling on vein graft arterialization.
Methods
For Supplemental Methods please see http://atvb.ahajournals.org.
Mice
Adult male C57Bl/6 wild-type (WT) and congenic p75-deficient (p75–/–) or p55-deficient (p55–/–) mice were purchased from Jackson Labs. 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.11 Inferior vena cavae from WT or congenic p75–/– or p55–/– donor mice were anastomosed to the right common carotid artery of recipient mice, in 5 different donor/recipient combinations as follows: (1) WT/WT; (2) p75–/–/WT; (3) p75–/–/p75–/–; (4) p55–/–/WT; and (5) p55–/–/p55–/–. All graft donors and recipients were age-matched and between 12 and 20 weeks old at the time of surgery. We did not place WT IVC grafts into p75–/– mice because expression of p75 on the surface of vein graft wall cells would almost certainly elicit a mild allograft rejection in p75–/– recipients, as we observed when we placed WT grafts into p55–/– recipients,4 or WT arterial grafts into apoE–/– recipients.5
Statistical Analysis
One-way ANOVA with Tukey post test for multiple comparisons was used to analyze migration, proliferation, cytotoxicity, and morphometric data as well as protein expression for VCAM-1 and factor VIII. T-test was used to analyze expression levels of cleaved caspase-3, Ki-67, and collagen. Data are presented ±SD in the text and ±SE in the figures.
Results
p75 Signaling Attenuates Vein Graft Neointimal Hyperplasia
In our murine carotid interposition vein graft model, WT vein grafts attain their final wall thickness (
14 cell layers) 4 weeks after implantation, and develop a neointima comprising predominantly SMC-like cells.11 Two different cell populations participate in the arterialization of vein grafts: (1) graft-intrinsic cells (cells that are part of the graft at the time of implantation), and (2) graft-extrinsic cells (cells that are recruited into the graft from the recipient). Graft-extrinsic cells ultimately make up the majority of the vein graft neointima and a significant portion of the vein graft endothelium.2 As in the preatherosclerotic early stage of human vein graft disease, these murine grafts do not show significant luminal stenosis.11
To determine whether p75 TNF receptor signaling affects vein graft remodeling, we placed inferior vena cava (IVC) grafts from WT or congenic p75–/– mice into the common carotid artery of WT or p75–/– recipients. In the case of p75–/– IVCs grafted into WT recipients, we thus created chimeric mice that were p75-deficient only in cells of the vein graft wall; this surgically created chimera facilitated examining the role of p75 signaling in both vein graft-extrinsic and -intrinsic cells. Compared with WT vein grafts placed in WT mice (WT/WT, "control" grafts), these p75–/– vein grafts placed into WT mice (p75–/–/WT grafts) demonstrated 27±15% greater neointimal thickness but comparable medial thickness (Figure 1). When we placed p75–/– vein grafts in p75–/– mice (p75–/–/p75–/– grafts), we observed a 42±19% increase in average neointimal thickness and a 60±26% increase in medial thickness, compared with control WT/WT grafts (P<0.05, Figure 1). Lumen area was not significantly different among the groups (data not shown). Thus, p75 expression in both vein graft-intrinsic and -extrinsic cells reduced neointimal hyperplasia, such that the total level of systemic p75 (the sum of graft-intrinsic and -extrinsic cell expression) correlated inversely with average neointimal thickness. Intriguingly, the effect of graft-intrinsic cell p75 deficiency on graft neointima formation was opposite in direction from what we found with p55 deficiency.4 In addition, vein graft medial hypertrophy was not affected by p55 deficiency in graft-intrinsic or -extrinsic cells,4 but it was enhanced significantly by p75 deficiency in graft-extrinsic cells (Figure 1B).
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5 for each group. *P<0.05 compared with WT/WT control.Increased neointimal and medial volume can result from enhanced hyperplasia of graft-intrinsic cells, recruitment or hyperplasia of graft-extrinsic cells, or a combination of these processes. To explore these possibilities, we examined 2-week-old vein grafts, which have not completed the process of arterialization.11 In grafts that lacked p75 in both graft-intrinsic and -extrinsic cells, we found evidence for both enhanced cell proliferation and cell recruitment: a 70% increase in the prevalence of proliferating cells, assessed by staining for the proliferation marker Ki-67 (supplemental Figure IA; P<0.05), and a 2.5-fold increase in the expression of VCAM-1 (P<0.05, Figure 2). In contrast, p55 deficiency substantially reduced vein graft VCAM-1 expression.
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In mature (6-week-old) vein grafts, greater neointimal and medial volume in p75–/–/p75–/– specimens corresponded to a greater number of cells in these graft layers. Nonetheless, when normalized to cell density, the prevalence of SMC-like cells among neointimal and medial cells was indistinguishable between p75–/–/p75–/– and WT/WT vein grafts, as assessed by immunofluorescence for SMC-actin. Also, we were unable to detect any change in macrophage infiltration (as assessed by staining for the F4/80 macrophage antigen, data not shown). We then quantitated the collagen I content of the vein grafts to determine whether differences in extracellular matrix or fibroblast-like cell density distinguished p75–/–/p75–/– from WT/WT specimens. Normalized to cellular density, the collagen content of the media was, indeed, 50% greater in p75–/–/p75–/– than in WT/WT vein grafts (supplemental Figure II; P<0.05).
p75 Signaling Augments Vein Graft re-endothelialization
Exposing veins to arterial pressure engenders significant graft endothelial dysfunction and cell loss,2,12,13 whereas the reestablishment of an intact endothelial cell layer limits further neointimal hyperplasia.4,14 TNF has been shown to induce EC apoptosis9 in a manner that may be attenuated by EC p75.15 If p75 signaling indeed contributes to EC survival then, by facilitating vein graft re-endothelialization, p75 could attenuate neointimal hyperplasia. To test this possibility, we examined endothelial resurfacing in vein grafts harvested at both 2 and 6 weeks postoperatively. At 2 weeks post-op, p75 deficiency in both graft-intrinsic and -extrinsic cells caused a 67% relative reduction in graft re-endothelialization (P<0.05), whereas p75 deficiency in just graft-intrinsic cells caused a much smaller, and not statistically significant, reduction in endothelialization (Figure 3). In contrast, p55 deficiency in graft-intrinsic or -extrinsic cells enhanced vein graft endothelialization. Even 6 weeks postoperatively, when endothelial resurfacing of WT or p55–/– grafts is essentially complete, p75–/– donor veins manifested incomplete re-endothelialization (Figure 3).
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To explore mechanisms by which p75 signaling contributes to endothelial recovery after vein graft placement, we examined induction of apoptosis in vein graft endothelium by immunostaining for the active (cleaved) form of the apoptosis effector caspase 3 (Figure 4).16 At 2 weeks postop, p75 deficiency more than doubled the percentage of vein graft endothelium that stained positive for cleaved caspase-3 (P<0.05, Figure 4B), indicating that p75 expression in vein graft endothelial cells greatly reduces their susceptibility to apoptosis following vein grafting.
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Role of p75 Signaling on EC and SMC Physiology
Previous work with virally transduced ECs has suggested that p75 activity protects ECs against TNF-induced apoptosis.15 To determine whether physiological expression of p75 affects EC responses to TNF, we isolated aortic ECs from WT and p75–/– mice and verified their p75 expression status (Figure 5A and 5B). When assessed for TNF-induced apoptosis, ECs lacking p75 were significantly more sensitive than WT ECs (Figure 5C). It therefore seems that activation of p75 signaling protects ECs against proapoptotic signaling mediated through p55 both in vivo and in vitro. Moreover, this p75-mediated EC antiapoptotic effect could help to explain why vein graft re-endothelialization correlates directly with the expression of p75 in both graft-intrinsic ECs and graft-extrinsic endothelial progenitor cells.
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ECs are exposed to TNF expressed by neointimal SMCs,3 which are the most abundant cell type in the developing graft neointima.2 Because both migration and proliferation of SMCs contribute to NH,17 we sought to investigate the role—if any—of p75 signaling on SMC activities. Cultured SMCs are in an activated state that is characterized by increased proliferation and migration and are thus representative of the SMCs found in vascular lesions.18 These cells demonstrably express p75 protein, which is lacking in SMCs isolated from p75–/– mice (supplemental Figure IIIA). To model the inflammatory milieu of the arterializing vein graft, we examined migration of SMCs toward co-cultured primary macrophages, because macrophages constitute an important fraction of the cells in arterializing vein grafts2,19 and secrete a plethora of cytokines and growth factors that synergistically promote SMC activation.20 In response to these macrophages or to purified TNF or PDGF, p75–/– and WT SMCs demonstrated equivalent migration (supplemental Figure IIIB). Contrastingly, p55–/– SMCs demonstrated no migration to TNF and demonstrated significantly impaired migration to activated macrophages (supplemental Figure IIIB). Just as SMC migration was unaffected by p75 activity, SMC thymidine incorporation in response to TNF, PDGF-BB, or a combination of these 2 agonists was indistinguishable between WT and p75–/– SMCs (supplemental Figure IIIC). In contrast, we have previously shown that TNF-induced proliferation is abolished in p55–/– SMCs.4 Thus, p75 does not appear to mediate changes in SMC physiology that are pertinent to neointimal hyperplasia.
Discussion
This study, for the first time, clearly demonstrates the importance of TNF receptor-2 signaling in vein graft arterialization. We have found that TNF signaling via p75 promotes vein graft re-endothelialization and reduces neontimal hyperplasia—in striking contrast to TNF signaling via p55, which inhibits vein graft reendothelization and augments neointimal hyperplasia.
Although undetectable in uninjured veins and arteries, TNF is expressed in grafted veins as early as 4 days postop.3 TNF expression precedes the onset of neointimal development and remains elevated throughout the duration of graft remodeling. Although predominantly recognized as a growth inhibitory factor produced by macrophages, in vein grafts TNF is also expressed by SMCs and it colocalizes with markers of proliferation in areas of rapid SMC growth.4 This TNF, produced by both SMCs and graft infiltrating macrophages, promotes SMC proliferation and migration via p55.3,4 In addition, TNF enhances recruitment of extrinsic cells into the graft via upregulation of graft chemokines such as MCP-1 and enhanced expression of cell-retaining adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and VCAM-1 in SMCs.2,21 The latter TNF-promoted change in vein graft biology is under opposing control by the 2 TNF receptors, because it is reduced in vein grafts taken from p55–/– and increased in grafts from p75–/– mice.4
Several signaling pathways important to vascular repair appear oppositely regulated in endothelial and vascular smooth muscle cells. A recent report by Chandrasekharan22 has shown ICAM-1 expression to be induced by p75 and attenuated by p55 in endothelial cells, whereas in cultured SMCs, and in proliferative foci of early vein grafts, ICAM-1 is induced by p55.4 Likewise, VCAM-1 expression in early vein grafts is induced by p55 and antagonized by p75, whereas elaboration of this adhesion molecule in ECs appears dependent on p55 and p75 cooperativity.22 Finally, whereas SMCs are stimulated to proliferate by TNF in a p55 dependent manner, this cytokine profoundly retards growth and migration of cultured murine EC,15 induces apoptosis of microvascular,23 cerebrovascular,24 and dermal ECs,25 and is responsible for disseminated endothelial apoptosis observed after administration of lipopolysaccharide (LPS) in vivo.26
Because a significant fraction of the endothelium undergoes apoptosis after vein grafting, and is subsequently being replaced by recipient-derived endothelial progenitor cells,13 we found that the TNF receptor status of the recipient greatly influences the speed of endothelial recovery. Thus endothelial progenitor cells that lack p75 are increasingly likely to undergo apoptosis when adherent to the TNF-expressing SMCs of early vein graft lesions.4 In contrast, vein graft re-endothelialization proceeds faster in p55–/– recipients.
To understand reciprocal effects of TNF receptors on vein graft re-endothelialization, it is important to consider TNF receptor–specific signaling pathways. Even though it elicits proliferative signals in SMCs, the death domain–containing p55 can induce apoptosis in ECs through activation of the RIP1-ASK1-JNK/p38 pathway.27 In WT ECs, however, proapoptotic p55 activity is mollified by p75-mediated activation of antiapoptotic signaling: the EC-specific Etk/BMX kinase pathway,28,29 and possibly the cIAP-induced ASK1 ubiquitination and degradation.30 Thus, in the context of vein graft hyperdistension injury and TNF elaboration from graft infiltrating leukocytes and activated SMCs, either lack of proapoptotic p55 signaling or activation of antiapoptotic p75 signaling will accelerate EC recovery and limit graft NH.
The contribution of p75 signaling to vascular lesion development appears to be specific to the type of vascular injury induced and may depend on the balance between p55- and p75-evoked signaling in ECs. This balance may be shifted toward p75 under certain pathological conditions such as ischemia15 or inflammation,31 which increase EC p75 expression relative to that of p55.
Thus, results obtained in our vein graft model accord with those generated in the mouse hind limb ischemia model of angiogenesis.15,32 In that model, p75 activity accelerates angiogenesis, which, like vein graft re-endothelialization,2 involves proliferation and migration of local ECs as well as immigration of bone marrow–derived endothelial progenitor cells. In contrast, whereas p75 signaling protects against neointimal hyperplasia in our vein graft model, it appears to have no affect on neointimal hyperplasia induced by wire injury to the carotid artery.33 The apparent discord may result from the relative importance of SMC and EC hyperplasia in these 2 different injury models, or may be attributable to the variable but generally small neointimal hyperplastic response produced by carotid wire injury in the C57BL/6 mouse.34,35
In contrast to neointimal hyperplasia, medial dimension is increased only in p75–/– graft recipients (Figure 1). We have demonstrated significant infiltration of bone marrow–derived cells of the monocyte/macrophage lineage into the media of arterializing vein grafts.2 However, there was no change in the overall cellular density in the vein graft media of p75–/– recipients and we were unable to detect an altered ratio of macrophage to non-macrophage cells. Possibly, an increase in the retention of graft infiltrating macrophages might be accompanied by an increase in the proliferation of nonmacrophage-like cells.
In the course of vein graft arterialization, we have observed that the balance between what is regarded as beneficial medial hypertrophy and deleterious neointimal hyperplasia36 appears to be controlled substantially by the extent of vein graft re-endothelialization. This complex process, in turn, appears to be regulated significantly by TNF, through opposing actions of its p55 and p75 receptors. Whether p75 can be targeted productively to treat nonatherosclerotic vein graft neointimal hyperplasia remains to be determined.
Acknowledgments
Sources of Funding
This work was supported by grants HL072842 (to K.P.), HL73005 and AG025462 (to N.J.F.), and a grant from the Pennsylvania Department of Health (to K.P.). The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions.
Disclosures
None.
Footnotes
Original received July 12, 2007; final version accepted November 2, 2007.
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