Published online before print September 25, 2008, doi: 10.1161/ATVBAHA.107.161224
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© 2008 American Heart Association, Inc.
Brief Reviews |
Chemokines in Vascular Dysfunction and Remodeling
From the Cardiology Unit, Medical Policlinic-City Center Campus, University of Munich, Germany.
Correspondence to Dr Andreas Schober, Cardiology Unit, Medizinische Poliklinik, University of Munich, Pettenkoferstraße 8a, 80336 Munich, Germany. E-mail andreas.schober{at}med.uni-muenchen.de
Series Editor: Christian Weber
ATVB In Focus
Chemokines in Atherosclerosis, Thrombosis, and Vascular Biology
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Abstract |
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Top
Abstract
IntroductionVascular remodeling stands for structural changes of the vessel wall in response to various noxious stimuli, which results in reorganization of the vessel wall architecture. Luminal narrowing because of neointima formation and constrictive remodeling leading to hypoperfusion is the most relevant clinical effect. Smooth muscle cell (SMC) accumulation, inflammatory cell recruitment, and endothelial regeneration are the critical parts in obstructive vascular remodeling. Chemokines and chemokine receptors have a great impact on initiating and progressing neointimal formation by controlling each step of the remodeling process. SDF-1
regulates vascular repair by CXCR4-dependent smooth muscle progenitor cell recruitment, which contributes to the maladaptive response to injury. The three distinct chemokine-chemokine receptor pairs MCP-1/CCR2, RANTES/CCR5, and Fractalkine/CX3CR1 direct lesional leukocyte infiltration. In addition MCP-1/CCR2 and Fractalkine/CX3CR1 increase neointimal SMC expansion. In contrast, KC/Gro- supports endothelial recovery through CXCR2, which attenuates neointima formation. These findings highlight the importance to characterize specific functions of the chemokine network to enable therapeutic intervention. |
Introduction |
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Vascular remodeling denotes morphological changes of the vessel wall in response to various noxious stimuli inducing reorganization of the vessel wall structure. This impacts the cross-sectional vessel diameter and the thickness of the arterial wall in every direction; however, luminal narrowing and resulting hypoperfusion are the most detrimental sequelae of vascular remodeling. Hemodynamic stress, mechanical injury, inflammation, or hypoxia are only some of the clinically met triggers for adaptive remodeling of the vessel wall, for instance after percutaneous interventions, heart transplantation, or vein grafting.1 Morphologically, all three layers of the arterial wall are concurrently affected by neointimal hyperplasia, medial thickening, and adventitial fibrosis attributable to the interaction of leukocyte recruitment, smooth muscle cell (SMC) accumulation, and endothelial recovery.2,3 Molecularly, chemokines play an ever-emerging role in vascular repair through guidance of circulating mononuclear cells to the injury site and activation of resident vascular cells.4,5 Considering the cell-type specific expression of chemokine receptors and the substantial overlap in ligand-receptor specificity, an interactive network of chemokines and chemokine receptors emerges with enormous plasticity in different types of vascular injury. However, a growing number of chemokine-chemokine receptor pairs with confined effects in vascular diseases have been described.6,7 To modulate the maladaptive response in arterial remodeling, it is essential to identify specific therapeutic targets in the chemokine network. The contribution of the chemokine system to arteriosclerotic diseases has been previously reviewed in-depth.8–10 This review focuses on most recent findings in regulation and function of distinct chemokine axes constituting specific repair events in the injured artery.
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Vascular Remodeling by SDF-1–Mediated Recruitment of Progenitor Cells
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An instant effect of mechanical vascular injury with endothelial denudation and distension of the media is the apoptosis of up to 70% of the medial SMCs.11 This occurs as early as 30 minutes after balloon injury with a marked decrease of the vessel wall cellularity, correlates with the intensity of the injury, and precedes the proliferative peak in the media.12,13 Inhibition of the early medial SMC apoptosis attenuates neointima formation, suggesting apoptosis as a signal for an increased demand in vascular repair to overcome the cellular deficit.14,15 In this context, replacement by resident SMCs is impaired requiring a backup repair system by circulating progenitor cells.16 In fact, smooth muscle progenitor cell (SPC) recruitment is increased in injury models with prominent medial cell apoptosis17 and contributes to intimal thickening after mechanical injury and transplant vasculopathy.18 Bone marrow (BM)–derived SPCs in the circulation are a major source for neointimal SMCs in vascular repair.19–22 In addition, the adventitial tissue harbors SPCs23; however, the impact of endogenous adventitial cells to neointimal hyperplasia may vary according to the disease model.24
The CXC-chemokine stromal cell-derived factor (SDF)-1 (also known as CXCL12) has been originally purified from the supernatant of BM stromal cells,25,26 but is constitutively expressed in various tissues.27 Compared with other chemokines, SDF-1 selectively induces the migration of BM-derived progenitor cells.28 The high SDF-1 level in the BM creates a concentration gradient, which retains hematopoietic progenitor cells,29 and disruption of this SDF-1 gradient causes mobilization of stem cells into the circulation.29–31 In contrast to other chemokines, SDF-1 signaling was thought to occur exclusively by the G protein–coupled seven transmembrane receptor (GPCR) CXCR4, because targeted deletion of SDF-1 or CXCR4 in mice results in similar phenotypes, including embryonic lethality.32 However, CXCR7 (RDC1/Cmkor1) has been identified as another SDF-1 receptor, which forms a heterodimer with CXCR4, thereby regulating GPCR activity.33 Furthermore, the chemokine-like cytokine macrophage migration inhibitory factor (MIF) is a noncognate ligand for CXCR4 and CXCR2,34,35 which stimulates neointimal macrophage infiltration after carotid wire-injury most likely through CXCR2.36
After different types of vascular injury, increased SDF-1 expression particularly in SMCs accompanied by a transient rise in SDF-1 plasma levels has been reported.17,37–42 Notably, wire-induced carotid injury in mice causes prominent SDF-1 expression in the media within 24 hours, which remains elevated throughout the vessel wall during neointima formation.38 In addition, activated platelets release and subsequently present SDF-1 on the surface after vascular injury.39,43 The increase in circulating SDF-1 affects the gradient of SDF-1 between the blood and the BM, thus mobilizing Sca-1+/Lin– SPC.38 In addition, neointimal recruitment of circulating SPCs critically depends on SDF-1.38 Further characterization of SPCs revealed that SDF-1 preferentially mobilizes and recruits c-kit–/Sca-1+/Lin– cells to the neointima, which lack the long-term repopulating potential of hematopoietic stem cells44 and express the PDGF receptor β19,39 (Figure 1).
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The implication of SDF-1 on intimal hyperplasia after wire-injury has been demonstrated in hyperlipidemic ApoE–/– mice. Treatment with a neutralizing SDF-1 antibody reduces the neointimal area and SMC content through inhibition of BM-derived SPC accumulation without affecting macrophage infiltration.38,39 Local SDF-1 expression in the injured artery is critical for vascular remodeling, because local gene transfer of a SDF-1 antagonist peptide inhibits neointima formation.39 ApoE–/– mice after BM reconstitution with fetal hematopoietic stem cells from CXCR4–/– mice show also decreased neointima formation and SMC accumulation, suggesting SDF-1–dependent SPC recruitment by CXCR439 (Figure 1). Recent evidence indicates that the A2b adenosine receptor (A2bAR) regulates CXCR4 expression in SPCs, because genetic deficiency of A2bAR increases CXCR4 on BM cells and exacerbates neointimal growth after femoral wire injury.45
Chronic pharmacological blockade of CXCR4 using the small molecule antagonist AMD3465 reduces neointima size by 59% and prevents Sca-1+/Lin– cell mobilization after carotid wire injury.46 In contrast, AMD3465 application for 12 weeks in diet-induced atherosclerosis clearly promotes plaque progression and increases lesional neutrophil infiltration.47 There are two reasons to explain this discrepancy. First, the role of SPCs in diet-induced atherosclerosis appears to be vasculoprotective by limiting plaque growth and promoting a stable plaque phenotype.48 Therefore, a decreased lesional SMC content in AMD3465-treated ApoE–/– mice on high cholesterol diet represents an inflammatory plaque type with accelerated growth.47 Second, a deranged neutrophil hemostasis with an increased number of circulating neutrophils is crucial for the proatherogenic effect AMD3465 treatment. In contrast to diet-induced atherosclerosis, neutrophils are only involved in the very early phase of neointima formation after endothelial denudation.49 Thus, neutrophilic leukocytosis induced by chronic CXCR4 inhibition may not contribute significantly to neointimal growth after arterial wire injury.47 CXCR4 inhibition may therefore be a reasonable approach to limit restenosis after percutaneous interventions through systemic (short term) or local (via drug-eluting stents) application. Long term treatment with CXCR4 antagonists, however, may have detrimental sequelae in patients with atherosclerosis.
The role of CXCR7 in neointimal SPC recruitment after vascular injury is unclear; however, CXCR7 and CXCR4 regulate different steps in the therapeutic homing of progenitor cells in mice with acute renal failure.50 Furthermore, MIF may interact with SDF-1 on CXCR4 signaling in vascular remodeling.34,36
Apoptosis of medial SMCs triggers the SPC-mediated vascular repair by the SDF-1/CXCR4 axis.39 In vitro, microvesicles released from apoptotic SMCs are sufficient to induce SDF-1 secretion from uninjured SMCs.39 Accordingly, wire-induced arterial injury, which causes more extensive apoptosis of medial cells as compared to carotid ligation and periarterial cuff placement, induces the highest neointimal SDF-1 levels.17 Therefore, a high degree of apoptosis signals the demand for vascular repair by circulating progenitor cells via up-regulation of SDF-1 (Figure 1). The molecular mechanism of apoptosis-induced SDF-1 expression remains to be determined. Unlike most other CXC chemokines, the SDF-1 promoter does not include active binding sites for proinflammatory transcription factors, such as nuclear factor (NF)-
B or NF-IL6, and shows a cell-specific regulation pattern.51 The SDF-1 promoter contains two binding sites for the hypoxia-inducible factor-1 (HIF), which control SDF-1 expression in hypoxic endothelial cells through binding to HIF-1.52 Although the HIF-1 transcriptional system mainly regulates the cellular adaptation to low oxygen supply, nonhypoxic transcriptional and translational upregulation of HIF-1 occurs in SMCs, for instance by thrombin or platelet-derived growth factor (PDGF)-AB.53–55 After wire-induced carotid injury, HIF-1 is rapidly and persistently induced in SMCs and mediates SDF-1 expression in the injured vessel wall.56 Inhibition of HIF-1 upregulation by RNA interference reduces injury-induced neointima formation.56 The tumor suppressor and PI3K/Akt antagonist PTEN (phosphatase and tensin homolog), which decreases neointimal hyperplasia after gene transfer,57 is an important mediator of HIF-1 activity. Mice with a SMC-specific deletion of PTEN show increased HIF-1–dependent SDF-1 expression with medial hyperplasia through recruiting vascular progenitor cells.58 Treatment with macrophage colony stimulating factor (CSF), a known inducer of HIF-1, also enhances wire-induced SDF-1 expression in the neointima.40 However, the signaling events connecting SMC apoptosis and HIF-1 activation are not defined (Figure 1).
In experimental models of graft vasculopathy, the alloreactive immune response by T-cells and antibodies causes massive apoptosis of the medial SMCs, and promotes host-derived SPC recruitment in the first weeks after transplantation.2,59 In analogy to wire injury–induced vascular remodeling, restraint of caspase 3-mediated apoptosis abates neointima formation in transplant arteriosclerosis.60 Although direct evidence for apoptosis-induced SDF-1 expression in graft vasculopathy is lacking, SDF-1 is upregulated in the adventitia and subsequently in the media and neointima of aortic allografts and provokes mobilization and neointimal recruitment of SPCs.42 Furthermore, inhibition of SDF-1 with a blocking antibody reduces intimal thickening and the number of neointimal CXCR4-positive cells.42 In transplanted human hearts, the extent of peritransplant ischemic injury, an important risk factor for cardiac allograft vasculopathy (CAV),61 correlates with increased SDF-1 expression and with the recruitment of recipient-derived SPCs to cardiac blood vessels.62
In summary, vascular injury-induced medial SMC apoptosis activates a universal repair mechanism through SDF-1–dependent recruitment of SPCs to meet the increased demand for SMC replacement. Thus, the SDF-1/CXCR4 axis contributes to vascular remodeling, which may be excessive depending on the extent of the injury and then fosters the progression to arterial stenosis.
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Chemokines Regulate Inflammatory Cell Infiltration in Vascular Remodeling |
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Apart from reorganization of SMCs in the injured artery, inflammatory cell recruitment of mainly monocytes and T-cells, owing to an injury-specific cellular immune response, constitutes a general feature in vascular remodeling and promotes disease progression.61,63–65 Chemokines control leukocyte trafficking in various inflammatory diseases including atherosclerosis.4,10 In vascular remodeling, many chemokines, such as MCP-1 (CCL2), RANTES (CCL5), or Fractalkine (CX3CL1), are upregulated in vascular wall cells and cooperate in leukocyte recruitment to the injured artery.8 The proinflammatory phenotype of neointimal SMCs, characterized by increased expression of adhesion molecules and chemokines driven by persistent NF-
B activation, plays a central role in preserving this inflammatory response.37,66 Although the contribution of these chemokines appears redundant, individual chemokine-receptor pairs have been identified, which regulate distinct steps of leukocyte recruitment in vascular remodeling.10 |
RANTES-Dependent Leukocyte Recruitment |
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The CC-chemokine RANTES (Regulated on activation, normally T-expressed, and presumably secreted, also known as CCL5) recruits leukocytes, including T-cells and monocytes, through different chemokine receptors (eg, CCR 1, -3, and -5). RANTES receptors on the other hand bind to several other chemokines, such as MIP-1
/CCL3 (CCR1, CCR5) or eotaxin/CCL11 (CCR3).5 However, functional specialization of CCR1 and CCR5 in RANTES-induced leukocyte recruitment depending on the oligomerization of RANTES and its heterophilic interaction with PF4 has been described.67–69
In neointimal lesions after wire-induced carotid injury of ApoE–/– mice, RANTES has been primarily detected on endothelial cells, where RANTES is deposited after release from activated platelets,70,71 and in neointimal SMCs72 (Figure 2). Treatment with the selective CCR1- and CCR5 antagonist Met-RANTES clearly reduces neointima formation and macrophage infiltration.71,72 The transcriptional regulator Y-box binding protein (YB)-1 regulates RANTES expression in neointimal SMCs, which increases monocyte adhesion on SMCs under flow.72 In vivo knockdown of YB-1 in carotid arteries inhibits RANTES expression in SMCs and impairs neointima formation via reduced macrophage infiltration, similarly to Met-RANTES treatment72 (Figure 2). Furthermore, YB-1 knockdown in CCR5-deficient mice does not result in reduced neointimal tissue, confirming RANTES as the crucial ligand in CCR5-mediated intimal hyperplasia. Using genetically targeted mice, CCR5 but not CCR1 appears to be responsible for RANTES-mediated neointimal growth and macrophage infiltration.73 In addition, CCR5 deficiency diminishes T-cell recruitment and induces a shift toward a Th2-type immune response with increased neointimal interleukin (IL)-10 expression.73 Inhibition of IL-10 reverses the effect of CCR5 deficiency on intimal thickening and macrophage infiltration,73 implying a protective role of T-cell-derived IL-10 in vascular remodeling. In CCR1–/–/ApoE–/– mice, however, Th1-immune response prevails with increased neointimal interferon (IFN)-
expression.73 Because IFN- inhibition more effectively reduces lesional macrophage content in CCR1–/– as compared to wild-type mice, Th1-related proinflammatory mechanisms may counteract the inhibitory effect of CCR1 deficiency on monocyte recruitment in transgenic mice.73 Besides, these results indicate an important role of the Th1/Th2 balance in vascular repair after mechanical injury at least in the context of hyperlipidemia, similar to native atherosclerosis.74,75
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Platelets contain significant amounts of chemokines, which are released on activation.76,77 Platelet-derived RANTES can be immobilized on activated endothelial cells via platelet P-selectin (Figure 2); thus, inducing monocyte arrest and promoting atherogenesis.70,71,78 After wire-injury, RANTES deposition on regenerating endothelial cells covering neointimal lesions is reduced in mice with P-selectin–deficient BM, demonstrating that endothelial immobilization of platelet-derived RANTES occurs in vascular repair70 (Figure 2). Furthermore, junctional adhesion molecule (JAM)-A has been implicated in endothelial RANTES deposition. JAM-A belongs to the IgG superfamily and is a part of endothelial and epithelial tight junctions.79 Endothelial JAM-A regulates the transendothelial migration of leukocytes by binding to the β2 integrin lymphocyte function-associated antigen-1.80,81 In hyperlipidemic ApoE–/– mice, JAM-A expression is increased in endothelial cells and supports atherogenic leukocyte recruitment.82 Platelet JAM-A mediates the adhesion of platelet to activated endothelial cells by homophilic interaction with endothelial JAM-A.83 Interestingly, JAM-A deficiency results in decreased luminal RANTES deposition after wire-induced carotid injury indicating an important role of JAM-A in endothelial deposition of platelet-derived RANTES84 (Figure 2). Disrupted endothelial RANTES deposition may contribute to the impaired neointima formation and reduced neointimal macrophage content in JAM-A–/– mice84 (Figure 2).
In allograft vasculopathy, increased RANTES and CCR5 expression have been reported in infiltrating leukocytes, endothelial cells, and intimal SMCs.85–88 Treatment with Met-RANTES causes reduced neointimal growth through inhibition of T-cell and monocyte infiltration in a mouse model of CAV.89 This closely resembles findings in CCR5–/–/ApoE–/– mice after carotid wire injury and diet-induced atherosclerosis.73,75 Therefore, it can be assumed that the RANTES/CCR5 axis crucially affects T-cell mediated immunity in transplant vasculopathy,89 characterized by the prevalence of memory Th1 cells,87,90 for example by regulating IL-10 synthesis.91
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MCP-1/CCR2 Is Important in Monocyte Homing |
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The role of the CC-chemokine monocyte chemotactic protein (MCP)-1 (CCL2) and its receptor CCR2 in neointima formation have been extensively studied in experimental models of mechanical vascular injury (Table 1).3 MCP-1 expression in the injured artery is induced within hours in SMCs with a subsequent increase in the circulation.92–94 Because the upregulation of MCP-1 is transiently, its contribution to neointima formation is mainly confined to the early phase.92,93 Inhibition of the MCP-1/CCR2 axis quite uniformly reduced intimal hyperplasia in different animal models of arterial injury. However, injury models with a prominent inflammatory response, for example periarterial cuff placement, stent implantation, or endothelial denudation in hyperlipidemic animals, appear to favor MCP-1/CCR2-mediated leukocyte infiltration94–100 (Table 1). In contrast, inflammatory cell infiltrates in neointimal tissue are much less in normolipidemic animals. In this regard, inhibition of the MCP-1/CCR2 axis reduces the accumulation and proliferation of neointimal SMCs.93,101,102
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MCP-1 induces transendothelial migration, but not shear-resistant arrest of monocytes on activated endothelial cells. This difference arises from the lack of surface immobilization of MCP-1 on endothelial cells, a prerequisite for chemokine-induced stable adhesion.103 In contrast, MCP-1 released from medial SMCs is effectively immobilized on platelets adhering to injured arteries.94 In ex vivo perfusion studies of denuded carotid arteries, MCP-1 induced firm monocyte adhesion early after injury, thus contributing to neointimal macrophage infiltration.94
Gene transfer of a CCR2 antagonist (N-terminal deletion mutant of MCP-1, 7ND) greatly reduces vein graft thickening in different animal models,104,105 where infiltrating macrophages express high levels of MCP-1.104 Although the mechanism of neointima reduction in vein grafts remains equivocal, monocyte recruitment and neointimal cell proliferation are significantly suppressed by inhibition of the MCP-1/CCR2 axis105 (Table 1). In CAV, MCP-1 is upregulated in arterioles106,107 and infiltrating monocytes.106 Gene transfer of 7ND reduces intimal hyperplasia and the recruitment of CCR2-positive macrophages into graft coronary arteries107 (Table 1).
Vascular obstruction of pulmonary arterioles through medial and adventitial thickening and a hypoxia-induced inflammatory response within the vessel wall characterizes vascular remodeling in pulmonary hypertension (PH).63 In patients with idiopathic PH, MCP-1 is upregulated in pulmonary endothelial cells and perivascular leukocytes.108 Blocking MCP-1 or CCR2 in animal models of PH abates medial thickening and improves right ventricular pressures.109,110
Vascular remodeling contributing to systemic arterial hypertension consists of reduced vessel diameters and medial thickening accelerated by macrophage infiltration.65,111 MCP-1 is upregulated in the vessel wall of hypertensive animals by angiotensin II and mechanical stress.112–116 In CCR2-deficient mice, hypertension-induced macrophage infiltration and vascular hypertrophy are significantly reduced. Similarly, mice with CCR2-deficient leukocytes display a blunted response to angiotensin II regarding vascular inflammation and aortic wall thickening117,118 (Table 1).
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Fractalkine/CX3CR1 Axis Induce Inflammation and SMC Proliferation |
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Fractalkine (CX3CL1) is a structurally distinct chemokine, which exists in a membrane-bound or soluble form after shedding from the cell surface.119 The transmembrane protein supports integrin-independent leukocyte adhesion, whereas the soluble form of fractalkine has a potent chemoattractant activity. Both effects are mediated through CX3CR1, which is involved in atherogenic monocyte recruitment independently of CCR2.6 In vitro, fractalkine is upregulated on activated SMCs via NF-
B and triggers monocyte adhesion to SMCs.37,120 After arterial injury, fractalkine is delayed expressed predominantly in endothelial cells and neointimal SMCs.121 Because of incomplete reendothelialization after mechanical injury, fractalkine-expressing neointimal SMCs exposed to the blood stream may enhance chronic monocyte recruitment.64 Indeed, monocyte adhesion was severely reduced in CXC3CR1-deficient mice 5 days after wire-induced endothelial denudation, which may be responsible for the inhibition of neointima formation.121 However, fractalkine-dependent SMC proliferation may also contribute to neointimal hyperplasia.120,121 Of note, the CX3CR1 polymorphism V249I is associated with enhanced monocyte adhesiveness122 and an increased risk for restenosis after coronary stent implantation.123 |
Endothelial Recovery Is Mediated by Chemokines |
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The CXC chemokine keratinocyte-derived chemokine (KC)/growth-regulated oncogene (GRO)-
(CXCL1) affects vascular wound healing entirely different than diet-induced atherosclerosis. Whereas KC/GRO- promotes atherogenesis through increased monocyte recruitment most likely via CXCR2,124,125 it appears to enhance endothelial recovery.126 Neointimal macrophages were identified as the major source of KC in injured vessels of ApoE–/– mice and treatment with a blocking KC antibody resulted in exacerbated neointimal growth.126 Although the neointimal macrophage and the SMC content were unaffected, inhibition of KC clearly impaired endothelial recovery.126 The effect of KC on reendothelialization is most likely attributable to CXCR2, because regenerating endothelial cells in vivo express CXCR2 and KC-dependent endothelial wound healing in vitro is mediated by CXCR2.126 KC/GRO- is so far the only chemokine with a vasculoprotective effect after denuding injury through enhanced vascular healing.
Reendothelialization partly depends on BM-derived recruitment of circulating endothelial progenitor cells (EPCs). Mobilization of EPCs by pharmacological interventions inhibits neointima formation by accelerated endothelial recovery.127 In addition to CXCR4, CXCR2 is critically involved in EPC arrest to injured carotid arteries and inhibition of CXCR2 abolished enhanced endothelial recovery after injection of EPCs.128 Recruitment of endogenous EPCs is not evident earlier than 2 weeks after injury,129,130 which parallels the time response of neointimal KC/GRO- expression.126 Other CXCR2 ligands, such as CXCL7, CXCL8, or MIF, are expressed early in neointima formation and may participate in CXCR2-dependent EPC recruitment.34,36,128 The functional significance of CXCR4-mediated EPC adhesion to endothelial recovery is currently unresolved. However, treatment with a CXCR4 antagonist does not inhibit reendothelialization after endothelial denudation, suggesting a minor role in EPC recruitment.46
Ex vivo activation by MCP-1 stimulates stable adhesion of BM-derived monocyte-like cells (BM-MLC) to injured arteries, which enhances reendothelialization and reduces neointima formation.131 In fact, blocking CCR2 after stent implantation had no effect on re-endothelialization,98 indicating that MCP-1–dependent activation of injected EPCs is primarily a therapeutic approach.
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Summary and Conclusions |
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In summary, chemokines functionally regulate every part of arterial remodeling with a highly elaborate specialization and in cooperation of multiple chemokines (Table 2). It is also intriguing that chemokine functions vary considerably between native atherogenesis and nonatherogenic arterial remodeling. This is a major caveat for using available chemokine receptor antagonists in clinical trials. Taking this into account, certain vascular disease entities, such as restenosis after stent implantation or cardiac allograft vasculopathy, may be most approachable for therapeutic antichemokine strategies, because of the relatively defined onset and risk for disease and the possibility for site directed therapy via drug-eluting stents. In addition, other strategies to inhibit chemokine activity or expression, such as transcription factor decoys, inhibitors of signal transduction, or siRNAs, may be feasible by locally confined delivery.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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Original received May 12, 2008; final version accepted September 15, 2008.
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References |
|---|
1. Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med. 1994; 330: 1431–1438.
2. Mitchell RN, Libby P. Vascular remodeling in transplant vasculopathy. Circ Res. 2007; 100: 967–978.
3. Schober A, Zernecke A. Chemokines in vascular remodeling. Thromb Haemost. 2007; 97: 730–737.[Medline] [Order article via Infotrieve]
4. Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol. 2001; 2: 108–115.[CrossRef][Medline] [Order article via Infotrieve]
5. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006; 354: 610–621.
6. Saederup N, Chan L, Lira SA, Charo IF. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2–/– mice: evidence for independent chemokine functions in atherogenesis. Circulation. 2008; 117: 1642–1648.
7. Veillard NR, Steffens S, Pelli G, Lu B, Kwak BR, Gerard C, Charo IF, Mach F. Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo. Circulation. 2005; 112: 870–878.
8. Raines EW, Ferri N. Thematic review series: The immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J Lipid Res. 2005; 46: 1081–1092.
9. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006; 86: 515–581.
10. Weber C, Schober A, Zernecke A. Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease. Arterioscler Thromb Vasc Biol. 2004; 24: 1997–2008.
11. Perlman H, Maillard L, Krasinski K, Walsh K. Evidence for the rapid onset of apoptosis in medial smooth muscle cells after balloon injury. Circulation. 1997; 95: 981–987.
12. Malik N, Francis SE, Holt CM, Gunn J, Thomas GL, Shepherd L, Chamberlain J, Newman CM, Cumberland DC, Crossman DC. Apoptosis and cell proliferation after porcine coronary angioplasty. Circulation. 1998; 98: 1657–1665.
13. Rivard A, Luo Z, Perlman H, Fabre JE, Nguyen T, Maillard L, Walsh K. Early cell loss after angioplasty results in a disproportionate decrease in percutaneous gene transfer to the vessel wall. Hum Gene Ther. 1999; 10: 711–721.[CrossRef][Medline] [Order article via Infotrieve]
14. Walsh K, Smith RC, Kim HS. Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res. 2000; 87: 184–188.
15. Beohar N, Flaherty JD, Davidson CJ, Maynard RC, Robbins JD, Shah AP, Choi JW, MacDonald LA, Jorgensen JP, Pinto JV, Chandra S, Klaus HM, Wang NC, Harris KR, Decker R, Bonow RO. Antirestenotic effects of a locally delivered caspase inhibitor in a balloon injury model. Circulation. 2004; 109: 108–113.
16. Korbling M, Estrov Z. Adult stem cells for tissue repair - a new therapeutic concept? N Engl J Med. 2003; 349: 570–582.
17. Tanaka K, Sata M, Hirata Y, Nagai R. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res. 2003; 93: 783–790.
18. Hirschi KK, Majesky MW. Smooth muscle stem cells. Anat Rec A Discov Mol Cell Evol Biol. 2004; 276: 22–33.[CrossRef][Medline] [Order article via Infotrieve]
19. Kashiwakura Y, Katoh Y, Tamayose K, Konishi H, Takaya N, Yuhara S, Yamada M, Sugimoto K, Daida H. Isolation of bone marrow stromal cell-derived smooth muscle cells by a human SM22alpha promoter: in vitro differentiation of putative smooth muscle progenitor cells of bone marrow. Circulation. 2003; 107: 2078–2081.
20. Ross JJ, Hong Z, Willenbring B, Zeng L, Isenberg B, Lee EH, Reyes M, Keirstead SA, Weir EK, Tranquillo RT, Verfaillie CM. Cytokine-induced differentiation of multipotent adult progenitor cells into functional smooth muscle cells. J Clin Invest. 2006; 116: 3139–3149.[CrossRef][Medline] [Order article via Infotrieve]
21. Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy. Nat Med. 2001; 7: 738–741.[CrossRef][Medline] [Order article via Infotrieve]
22. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002; 8: 403–409.[CrossRef][Medline] [Order article via Infotrieve]
23. Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest. 2004; 113: 1258–1265.[CrossRef][Medline] [Order article via Infotrieve]
24. De Leon H, Ollerenshaw JD, Griendling KK, Wilcox JN. Adventitial cells do not contribute to neointimal mass after balloon angioplasty of the rat common carotid artery. Circulation. 2001; 104: 1591–1593.
25. Nagasawa T, Kikutani H, Kishimoto T. Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc Natl Acad Sci U S A. 1994; 91: 2305–2309.
26. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996; 184: 1101–1109.
27. Shirozu M, Nakano T, Inazawa J, Tashiro K, Tada H, Shinohara T, Honjo T. Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene. Genomics. 1995; 28: 495–500.[CrossRef][Medline] [Order article via Infotrieve]
28. Wright DE, Bowman EP, Wagers AJ, Butcher EC, Weissman IL. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med. 2002; 195: 1145–1154.
29. Sweeney EA, Lortat-Jacob H, Priestley GV, Nakamoto B, Papayannopoulou T. Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood. 2002; 99: 44–51.
30. Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh JH, Hackett NR, Quitoriano MS, Crystal RG, Rafii S, Moore MA. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood. 2001; 97: 3354–3360.
31. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002; 3: 687–694.[CrossRef][Medline] [Order article via Infotrieve]
32. Schober A, Karshovska E, Zernecke A, Weber C. SDF-1alpha-mediated tissue repair by stem cells: a promising tool in cardiovascular medicine? Trends Cardiovasc Med. 2006; 16: 103–108.[CrossRef][Medline] [Order article via Infotrieve]
33. Sierro F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, Harvey RP, Martinez AC, Mackay CR, Mackay F. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci U S A. 2007; 104: 14759–14764.
34. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007; 13: 587–596.[CrossRef][Medline] [Order article via Infotrieve]
35. Schober A, Bernhagen J, Weber C. Chemokine-like functions of MIF in atherosclerosis. J Mol Med. 2008; 86: 761–770.[CrossRef][Medline] [Order article via Infotrieve]
36. Schober A, Bernhagen J, Thiele M, Zeiffer U, Knarren S, Roller M, Bucala R, Weber C. Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein e-deficient mice. Circulation. 2004; 109: 380–385.
37. Zeiffer U, Schober A, Lietz M, Liehn EA, Erl W, Emans N, Yan ZQ, Weber C. Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines. Circ Res. 2004; 94: 776–784.
38. Schober A, Knarren S, Lietz M, Lin EA, Weber C. Crucial role of stromal cell-derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice. Circulation. 2003; 108: 2491–2497.
39. Zernecke A, Schober A, Bot I, von Hundelshausen P, Liehn EA, Mopps B, Mericskay M, Gierschik P, Biessen EA, Weber C. SDF-1alpha/CXCR4 axis is instrumental in neointimal hyperplasia and recruitment of smooth muscle progenitor cells. Circ Res. 2005; 96: 784–791.
40. Shiba Y, Takahashi M, Yoshioka T, Yajima N, Morimoto H, Izawa A, Ise H, Hatake K, Motoyoshi K, Ikeda U. M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1-CXCR4 system. Arterioscler Thromb Vasc Biol. 2007; 27: 283–289.
41. Zhang LN, Wilson DW, da Cunha V, Sullivan ME, Vergona R, Rutledge JC, Wang YX. Endothelial NO synthase deficiency promotes smooth muscle progenitor cells in association with upregulation of stromal cell-derived factor-1alpha in a mouse model of carotid artery ligation. Arterioscler Thromb Vasc Biol. 2006; 26: 765–772.
42. Sakihama H, Masunaga T, Yamashita K, Hashimoto T, Inobe M, Todo S, Uede T. Stromal cell-derived factor-1 and CXCR4 interaction is critical for development of transplant arteriosclerosis. Circulation. 2004; 110: 2924–2930.
43. Massberg S, Konrad I, Schurzinger K, Lorenz M, Schneider S, Zohlnhoefer D, Hoppe K, Schiemann M, Kennerknecht E, Sauer S, Schulz C, Kerstan S, Rudelius M, Seidl S, Sorge F, Langer H, Peluso M, Goyal P, Vestweber D, Emambokus NR, Busch DH, Frampton J, Gawaz M. Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med. 2006; 203: 1221–1233.
44. Randall TD, Weissman IL. Characterization of a population of cells in the bone marrow that phenotypically mimics hematopoietic stem cells: resting stem cells or mystery population? Stem Cells. 1998; 16: 38–48.[Medline] [Order article via Infotrieve]
45. Yang D, Koupenova M, McCrann DJ, Kopeikina KJ, Kagan HM, Schreiber BM, Ravid K. The A2b adenosine receptor protects against vascular injury. Proc Natl Acad Sci U S A. 2008; 105: 792–796.
46. Karshovska E, Zagorac D, Zernecke A, Weber C, Schober A. A small molecule CXCR4 antagonist inhibits neointima formation and smooth muscle progenitor cell mobilization after arterial injury. J Thromb Haemost. In press.
47. Zernecke A, Bot I, Djalali-Talab Y, Shagdarsuren E, Bidzhekov K, Meiler S, Krohn R, Schober A, Sperandio M, Soehnlein O, Bornemann J, Tacke F, Biessen EA, Weber C. Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res. 2008; 102: 209–217.
48. Zoll J, Fontaine V, Gourdy P, Barateau V, Vilar J, Leroyer A, Lopes-Kam I, Mallat Z, Arnal JF, Henry P, Tobelem G, Tedgui A. Role of human smooth muscle cell progenitors in atherosclerotic plaque development and composition. Cardiovasc Res. 2008; 77: 471–480.
49. Roque M, Fallon JT, Badimon JJ, Zhang WX, Taubman MB, Reis ED. Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecules on the luminal surface and recruitment of neutrophils. Arterioscler Thromb Vasc Biol. 2000; 20: 335–342.
50. Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, Parente E, Mancina R, Netti GS, Becherucci F, Gacci M, Carini M, Gesualdo L, Rotondi M, Maggi E, Lasagni L, Serio M, Romagnani S, Romagnani P. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med. 2008; 205: 479–490.
51. Garcia-Moruja C, Alonso-Lobo JM, Rueda P, Torres C, Gonzalez N, Bermejo M, Luque F, Arenzana-Seisdedos F, Alcami J, Caruz A. Functional characterization of SDF-1 proximal promoter. J Mol Biol. 2005; 348: 43–62.[CrossRef][Medline] [Order article via Infotrieve]
52. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004; 10: 858–864.[CrossRef][Medline] [Order article via Infotrieve]
53. Gorlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R. Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res. 2001; 89: 47–54.
54. Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem. 2000; 275: 26765–26771.
55. Page EL, Robitaille GA, Pouyssegur J, Richard DE. Induction of hypoxia-inducible factor-1alpha by transcriptional and translational mechanisms. J Biol Chem. 2002; 277: 48403–48409.
56. Karshovska E, Zernecke A, Sevilmis G, Millet A, Hristov M, Cohen CD, Schmid H, Krotz F, Sohn HY, Klauss V, Weber C, Schober A. Expression of HIF-1alpha in injured arteries controls SDF-1alpha mediated neointima formation in apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol. 2007; 27: 2540–2547.
57. Koide S, Okazaki M, Tamura M, Ozumi K, Takatsu H, Kamezaki F, Tanimoto A, Tasaki H, Sasaguri Y, Nakashima Y, Otsuji Y. PTEN reduces cuff-induced neointima formation and proinflammatory cytokines. Am J Physiol Heart Circ Physiol. 2007; 292: H2824–H2831.
58. Nemenoff RA, Simpson PA, Furgeson SB, Kaplan-Albuquerque N, Crossno J, Garl PJ, Cooper J, Weiser-Evans MC. Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1alpha. Circ Res. 2008; 102: 1036–1045.
59. Religa P, Bojakowski K, Bojakowska M, Gaciong Z, Thyberg J, Hedin U. Allogenic immune response promotes the accumulation of host-derived smooth muscle cells in transplant arteriosclerosis. Cardiovasc Res. 2005; 65: 535–545.
60. Balsam LB, Mokhtari GK, Jones S, Peterson S, Hoyt EG, Kofidis T, Tanaka M, Cooke DT, Robbins RC. Early inhibition of caspase-3 activity lessens the development of graft coronary artery disease. J Heart Lung Transplant. 2005; 24: 827–832.[CrossRef][Medline] [Order article via Infotrieve]
61. Schmauss D, Weis M. Cardiac allograft vasculopathy: recent developments. Circulation. 2008; 117: 2131–2141.
62. Yamani MH, Ratliff NB, Cook DJ, Tuzcu EM, Yu Y, Hobbs R, Rincon G, Bott-Silverman C, Young JB, Smedira N, Starling RC. Peritransplant ischemic injury is associated with up-regulation of stromal cell-derived factor-1. J Am Coll Cardiol. 2005; 46: 1029–1035.
63. Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res. 2006; 99: 675–691.
64. Schober A, Weber C. Mechanisms of monocyte recruitment in vascular repair after injury. Antioxid Redox Signal. 2005; 7: 1249–1257.[CrossRef][Medline] [Order article via Infotrieve]
65. Savoia C, Schiffrin EL. Inflammation in hypertension. Curr Opin Nephrol Hypertens. 2006; 15: 152–158.[Medline] [Order article via Infotrieve]
66. Landry DB, Couper LL, Bryant SR, Lindner V. Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Am J Pathol. 1997; 151: 1085–1095.[Abstract]
67. Weber C, Weber KS, Klier C, Gu S, Wank R, Horuk R, Nelson PJ. Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells. Blood. 2001; 97: 1144–1146.
68. Baltus T, Weber KS, Johnson Z, Proudfoot AE, Weber C. Oligomerization of RANTES is required for CCR1-mediated arrest but not CCR5-mediated transmigration of leukocytes on inflamed endothelium. Blood. 2003; 102: 1985–1988.
69. von Hundelshausen P, Koenen RR, Sack M, Mause SF, Adriaens W, Proudfoot AE, Hackeng TM, Weber C. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood. 2005; 105: 924–930.
70. von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation. 2001; 103: 1772–1777.
71. Schober A, Manka D, von Hundelshausen P, Huo Y, Hanrath P, Sarembock IJ, Ley K, Weber C. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation. 2002; 106: 1523–1529.
72. Krohn R, Raffetseder U, Bot I, Zernecke A, Shagdarsuren E, Liehn EA, van Santbrink PJ, Nelson PJ, Biessen EA, Mertens PR, Weber C. Y-box binding protein-1 controls CC chemokine ligand-5 (CCL5) expression in smooth muscle cells and contributes to neointima formation in atherosclerosis-prone mice. Circulation. 2007; 116: 1812–1820.
73. Zernecke A, Liehn EA, Gao JL, Kuziel WA, Murphy PM, Weber C. Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10. Blood. 2006; 107: 4240–4243.
74. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
75. Braunersreuther V, Zernecke A, Arnaud C, Liehn EA, Steffens S, Shagdarsuren E, Bidzhekov K, Burger F, Pelli G, Luckow B, Mach F, Weber C. Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2007; 27: 373–379.
76. von Hundelshausen P, Petersen F, Brandt E. Platelet-derived chemokines in vascular biology. Thromb Haemost. 2007; 97: 704–713.[Medline] [Order article via Infotrieve]
77. Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res. 2005; 96: 612–616.
78. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003; 9: 61–67.[CrossRef][Medline] [Order article via Infotrieve]
79. Weber C, Fraemohs L, Dejana E. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol. 2007; 7: 467–477.[CrossRef][Medline] [Order article via Infotrieve]
80. Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3: 151–158.[CrossRef][Medline] [Order article via Infotrieve]
81. Fraemohs L, Koenen RR, Ostermann G, Heinemann B, Weber C. The functional interaction of the beta 2 integrin lymphocyte function-associated antigen-1 with junctional adhesion molecule-A is mediated by the I domain. J Immunol. 2004; 173: 6259–6264.
82. Ostermann G, Fraemohs L, Baltus T, Schober A, Lietz M, Zernecke A, Liehn EA, Weber C. Involvement of JAM-A in mononuclear cell recruitment on inflamed or atherosclerotic endothelium: inhibition by soluble JAM-A. Arterioscler Thromb Vasc Biol. 2005; 25: 729–735.
83. Babinska A, Kedees MH, Athar H, Ahmed T, Batuman O, Ehrlich YH, Hussain MM, Kornecki E. F11-receptor (F11R/JAM) mediates platelet adhesion to endothelial cells: role in inflammatory thrombosis. Thromb Haemost. 2002; 88: 843–850.[Medline] [Order article via Infotrieve]
84. Zernecke A, Liehn EA, Fraemohs L, von Hundelshausen P, Koenen RR, Corada M, Dejana E, Weber C. Importance of junctional adhesion molecule-A for neointimal lesion formation and infiltration in atherosclerosis-prone mice. Arterioscler Thromb Vasc Biol. 2006; 26: e10–e13.
85. Pattison JM, Nelson PJ, Huie P, Sibley RK, Krensky AM. RANTES chemokine expression in transplant-associated accelerated atherosclerosis. J Heart Lung Transplant. 1996; 15: 1194–1199.[Medline] [Order article via Infotrieve]
86. Yun JJ, Fischbein MP, Laks H, Irie Y, Espejo ML, Fishbein MC, Berliner JA, Ardehali A. Rantes production during development of cardiac allograft vasculopathy. Transplantation. 2001; 71: 1649–1656.[CrossRef][Medline] [Order article via Infotrieve]
87. van Loosdregt J, van Oosterhout MF, Bruggink AH, van Wichen DF, van Kuik J, de Koning E, Baan CC, de Jonge N, Gmelig-Meyling FH, de Weger RA. The chemokine and chemokine receptor profile of infiltrating cells in the wall of arteries with cardiac allograft vasculopathy is indicative of a memory T-helper 1 response. Circulation. 2006; 114: 1599–1607.
88. Horiguchi K, Kitagawa-Sakakida S, Sawa Y, Li ZZ, Fukushima N, Shirakura R, Matsuda H. Selective chemokine and receptor gene expressions in allografts that develop transplant vasculopathy. J Heart Lung Transplant. 2002; 21: 1090–1100.[CrossRef][Medline] [Order article via Infotrieve]
89. Yun JJ, Whiting D, Fischbein MP, Banerji A, Irie Y, Stein D, Fishbein MC, Proudfoot AE, Laks H, Berliner JA, Ardehali A. Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection. Circulation. 2004; 109: 932–937.
90. Isobe M, Kosuge H, Suzuki J. T cell costimulation in the development of cardiac allograft vasculopathy: potential targets for therapeutic interventions. Arterioscler Thromb Vasc Biol. 2006; 26: 1447–1456.
91. Fischbein MP, Yun J, Laks H, Irie Y, Oslund-Pinderski L, Fishbein MC, Bonavida B, Ardehali A. Regulated interleukin-10 expression prevents chronic rejection of transplanted hearts. J Thorac Cardiovasc Surg. 2003; 126: 216–223.
92. Taubman MB, Rollins BJ, Poon M, Marmur J, Green RS, Berk BC, Nadal-Ginard B. JE mRNA accumulates rapidly in aortic injury and in platelet-derived growth factor-stimulated vascular smooth muscle cells. Circ Res. 1992; 70: 314–325.
93. Furukawa Y, Matsumori A, Ohashi N, Shioi T, Ono K, Harada A, Matsushima K, Sasayama S. Anti-monocyte chemoattractant protein-1/monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia in injured rat carotid arteries. Circ Res. 1999; 84: 306–314.
94. Schober A, Zernecke A, Liehn EA, von Hundelshausen P, Knarren S, Kuziel WA, Weber C. Crucial role of the CCL2/CCR2 axis in neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early monocyte recruitment and CCL2 presentation on platelets. Circ Res. 2004; 95: 1125–1133.
95. Horvath C, Welt FG, Nedelman M, Rao P, Rogers C. Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circ Res. 2002; 90: 488–494.
96. Egashira K, Zhao Q, Kataoka C, Ohtani K, Usui M, Charo IF, Nishida K, Inoue S, Katoh M, Ichiki T, Takeshita A. Importance of monocyte chemoattractant protein-1 pathway in neointimal hyperplasia after periarterial injury in mice and monkeys. Circ Res. 2002; 90: 1167–1172.
97. Mori E, Komori K, Yamaoka T, Tanii M, Kataoka C, Takeshita A, Usui M, Egashira K, Sugimachi K. Essential role of monocyte chemoattractant protein-1 in development of restenotic changes (neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits. Circulation. 2002; 105: 2905–2910.
98. Egashira K, Nakano K, Ohtani K, Funakoshi K, Zhao G, Ihara Y, Koga J, Kimura S, Tominaga R, Sunagawa K. Local delivery of anti-monocyte chemoattractant protein-1 by gene-eluting stents attenuates in-stent stenosis in rabbits and monkeys. Arterioscler Thromb Vasc Biol. 2007; 27: 2563–2568.
99. Ohtani K, Usui M, Nakano K, Kohjimoto Y, Kitajima S, Hirouchi Y, Li XH, Kitamoto S, Takeshita A, Egashira K. Antimonocyte chemoattractant protein-1 gene therapy reduces experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys. Gene Ther. 2004; 11: 1273–1282.[CrossRef][Medline] [Order article via Infotrieve]
100. Nakano K, Egashira K, Ohtani K, Zhao G, Funakoshi K, Ihara Y, Sunagawa K. Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys. Atherosclerosis. 2007; 194: 309–316.[CrossRef][Medline] [Order article via Infotrieve]
101. Roque M, Kim WJ, Gazdoin M, Malik A, Reis ED, Fallon JT, Badimon JJ, Charo IF, Taubman MB. CCR2 deficiency decreases intimal hyperplasia after arterial injury. Arterioscler Thromb Vasc Biol. 2002; 22: 554–559.
102. Selzman CH, Miller SA, Zimmerman MA, Gamboni-Robertson F, Harken AH, Banerjee A. Monocyte chemotactic protein-1 directly induces human vascular smooth muscle proliferation. Am J Physiol Heart Circ Physiol. 2002; 283: H1455–H1461.
103. Weber KS, von Hundelshausen P, Clark-Lewis I, Weber PC, Weber C. Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow. Eur J Immunol. 1999; 29: 700–712.[CrossRef][Medline] [Order article via Infotrieve]
104. Schepers A, Eefting D, Bonta PI, Grimbergen JM, de Vries MR, van Weel V, de Vries CJ, Egashira K, van Bockel JH, Quax PH. Anti-MCP-1 gene therapy inhibits vascular smooth muscle cells proliferation and attenuates vein graft thickening both in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2006; 26: 2063–2069.
105. Tatewaki H, Egashira K, Kimura S, Nishida T, Morita S, Tominaga R. Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein graft neointimal formation. J Vasc Surg. 2007; 45: 1236–1243.[CrossRef][Medline] [Order article via Infotrieve]
106. Russell ME, Adams DH, Wyner LR, Yamashita Y, Halnon NJ, Karnovsky MJ. Early and persistent induction of monocyte chemoattractant protein 1 in rat cardiac allografts. Proc Natl Acad Sci U S A. 1993; 90: 6086–6090.
107. Saiura A, Sata M, Hiasa K, Kitamoto S, Washida M, Egashira K, Nagai R, Makuuchi M. Antimonocyte chemoattractant protein-1 gene therapy attenuates graft vasculopathy. Arterioscler Thromb Vasc Biol. 2004; 24: 1886–1890.
108. Sanchez O, Marcos E, Perros F, Fadel E, Tu L, Humbert M, Dartevelle P, Simonneau G, Adnot S, Eddahibi S. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2007; 176: 1041–1047.
109. Kimura H, Kasahara Y, Kurosu K, Sugito K, Takiguchi Y, Terai M, Mikata A, Natsume M, Mukaida N, Matsushima K, Kuriyama T. Alleviation of monocrotaline-induced pulmonary hypertension by antibodies to monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. Lab Invest. 1998; 78: 571–581.[Medline] [Order article via Infotrieve]
110. Ikeda Y, Yonemitsu Y, Kataoka C, Kitamoto S, Yamaoka T, Nishida K, Takeshita A, Egashira K, Sueishi K. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol. 2002; 283: H2021–H2028.
111. De Ciuceis C, Amiri F, Brassard P, Endemann DH, Touyz RM, Schiffrin EL. Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury. Arterioscler Thromb Vasc Biol. 2005; 25: 2106–2113.
112. Abu Nabah YN, Losada M, Estelles R, Mateo T, Company C, Piqueras L, Lopez-Gines C, Sarau H, Cortijo J, Morcillo EJ, Jose PJ, Sanz MJ. CXCR2 blockade impairs angiotensin II-induced CC chemokine synthesis and mononuclear leukocyte infiltration. Arterioscler Thromb Vasc Biol. 2007; 27: 2370–2376.
113. Capers Qt, Alexander RW, Lou P, De Leon H, Wilcox JN, Ishizaka N, Howard AB, Taylor WR. Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive rats. Hypertension. 1997; 30: 1397–1402.
114. Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res. 1998; 83: 952–959.
115. Zhan Y, Brown C, Maynard E, Anshelevich A, Ni W, Ho IC, Oettgen P. Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling. J Clin Invest. 2005; 115: 2508–2516.[CrossRef][Medline] [Order article via Infotrieve]
116. Jiang MJ, Yu YJ, Chen YL, Lee YM, Hung LS. Cyclic strain stimulates monocyte chemotactic protein-1 mRNA expression in smooth muscle cells. J Cell Biochem. 1999; 76: 303–310.[Medline] [Order article via Infotrieve]
117. Bush E, Maeda N, Kuziel WA, Dawson TC, Wilcox JN, DeLeon H, Taylor WR. CC chemokine receptor 2 is required for macrophage infiltration and vascular hypertrophy in angiotensin II-induced hypertension. Hypertension. 2000; 36: 360–363.
118. Ishibashi M, Hiasa K, Zhao Q, Inoue S, Ohtani K, Kitamoto S, Tsuchihashi M, Sugaya T, Charo IF, Kura S, Tsuzuki T, Ishibashi T, Takeshita A, Egashira K. Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling. Circ Res. 2004; 94: 1203–1210.
119. Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ. A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997; 385: 640–644.[CrossRef][Medline] [Order article via Infotrieve]
120. Chandrasekar B, Mummidi S, Perla RP, Bysani S, Dulin NO, Liu F, Melby PC. Fractalkine (CX3CL1) stimulated by nuclear factor kappaB (NF-kappaB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway. Biochem J. 2003; 373: 547–558.[CrossRef][Medline] [Order article via Infotrieve]
121. Liu P, Patil S, Rojas M, Fong AM, Smyth SS, Patel DD. CX3CR1 deficiency confers protection from intimal hyperplasia after arterial injury. Arterioscler Thromb Vasc Biol. 2006; 26: 2056–2062.
122. Daoudi M, Lavergne E, Garin A, Tarantino N, Debre P, Pincet F, Combadiere C, Deterre P. Enhanced adhesive capacities of the naturally occurring Ile249-Met280 variant of the chemokine receptor CX3CR1. J Biol Chem. 2004; 279: 19649–19657.
123. Niessner A, Marculescu R, Kvakan H, Haschemi A, Endler G, Weyand CM, Maurer G, Mannhalter C, Wojta J, Wagner O, Huber K. Fractalkine receptor polymorphisms V2491 and T280M as genetic risk factors for restenosis. Thromb Haemost. 2005; 94: 1251–1256.[Medline] [Order article via Infotrieve]
124. Boisvert WA, Rose DM, Johnson KA, Fuentes ME, Lira SA, Curtiss LK, Terkeltaub RA. Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. Am J Pathol. 2006; 168: 1385–1395.
125. Huo Y, Weber C, Forlow SB, Sperandio M, Thatte J, Mack M, Jung S, Littman DR, Ley K. The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest. 2001; 108: 1307–1314.[CrossRef][Medline] [Order article via Infotrieve]
126. Liehn EA, Schober A, Weber C. Blockade of keratinocyte-derived chemokine inhibits endothelial recovery and enhances plaque formation after arterial injury in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2004; 24: 1891–1896.
127. Hristov M, Zernecke A, Schober A, Weber C. Adult progenitor cells in vascular remodeling during atherosclerosis. Biol Chem. 2008; 389: 837–844.[CrossRef][Medline] [Order article via Infotrieve]
128. Hristov M, Zernecke A, Bidzhekov K, Liehn EA, Shagdarsuren E, Ludwig A, Weber C. Importance of CXC chemokine receptor 2 in the homing of human peripheral blood endothelial progenitor cells to sites of arterial injury. Circ Res. 2007; 100: 590–597.
129. Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, Matsunaga S, Tateishi K, Nomura T, Takahashi T, Tatsumi T, Matsubara H. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res. 2006; 98: 1405–1413.
130. Takamiya M, Okigaki M, Jin D, Takai S, Nozawa Y, Adachi Y, Urao N, Tateishi K, Nomura T, Zen K, Ashihara E, Miyazaki M, Tatsumi T, Takahashi T, Matsubara H. Granulocyte colony-stimulating factor-mobilized circulating c-Kit+/Flk-1+ progenitor cells regenerate endothelium and inhibit neointimal hyperplasia after vascular injury. Arterioscler Thromb Vasc Biol. 2006; 26: 751–757.
131. Fujiyama S, Amano K, Uehira K, Yoshida M, Nishiwaki Y, Nozawa Y, Jin D, Takai S, Miyazaki M, Egashira K, Imada T, Iwasaka T, Matsubara H. Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells. Circ Res. 2003; 93: 980–989.
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  D. Strassheim, S. R. Riddle, D. L. Burke, M. W. Geraci, and K. R. Stenmark Prostacyclin Inhibits IFN-{gamma}-Stimulated Cytokine Expression by Reduced Recruitment of CBP/p300 to STAT1 in a SOCS-1-Independent Manner J. Immunol., December 1, 2009; 183(11): 6981 - 6988. [Abstract] [Full Text] [PDF]
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 G. Grassia, M. Maddaluno, A. Guglielmotti, G. Mangano, G. Biondi, P. Maffia, and A. Ialenti The anti-inflammatory agent bindarit inhibits neointima formation in both rats and hyperlipidaemic mice Cardiovasc Res, December 1, 2009; 84(3): 485 - 493. [Abstract] [Full Text] [PDF]
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 H. S. K. Potula, D. Wang, D. Van Quyen, N. K. Singh, V. Kundumani-Sridharan, M. Karpurapu, E. A. Park, W. C. Glasgow, and G. N. Rao Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration J. Biol. Chem., November 6, 2009; 284(45): 31142 - 31155. [Abstract] [Full Text] [PDF]
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 M.-L. Sung, C.-C. Wu, H.-I Chang, C.-K. Yen, H. J. Chen, J.-C. Cheng, S. Chien, and C.-N. Chen Shear Stress Inhibits Homocysteine-Induced Stromal Cell-Derived Factor-1 Expression in Endothelial Cells Circ. Res., October 9, 2009; 105(8): 755 - 763. [Abstract] [Full Text] [PDF]
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 D. L. Burke, M. G. Frid, C. L. Kunrath, V. Karoor, A. Anwar, B. D. Wagner, D. Strassheim, and K. R. Stenmark Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment Am J Physiol Lung Cell Mol Physiol, August 1, 2009; 297(2): L238 - L250. [Abstract] [Full Text] [PDF]
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