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the Departments of Molecular Cardiovascular Research and Cardiology (A.Z., A.S., P.v.H., E.A.L., C.W.), University Hospital, Rheinisch-Westflische Technische Hochschule, Aachen, Germany
Division of Biopharmaceutics (I.B., E.A.B.), Gorlaeus Laboratories, Leiden University, The Netherlands
Department of Pharmacology and Toxicology (B.M., P.G.), University of Ulm, Germany
Physiology and Physiopathology Unit (M.M.), Pierre and Marie Curie University (PARIS 6), France.
Abstract
Recent evidence infers a contribution of smooth muscle cell (SMC) progenitors and stromal cell-derived factor (SDF)-1 to neointima formation after arterial injury. Inhibition of plaque area and SMC content in apolipoprotein E-deficient mice repopulated with LacZ+ or CXCR4eC/eC BM or lentiviral transfer of an antagonist reveals a crucial involvement of local SDF-1 and its receptor CXCR4 in neointimal hyperplasia via recruitment of BM-derived SMC progenitors. After arterial injury, SDF-1 expression in medial SMCs is preceded by apoptosis and inhibited by blocking caspase-dependent apoptosis. SDF-1 binds to platelets at the site of injury, triggers CXCR4- and P-selectin-dependent arrest of progenitor cells on injured arteries or matrix-adherent platelets, preferentially mobilizes and recruits c-kiteC/plateleteCderived growth factor receptor (PDGFR)-+/lineageeC/sca-1+ progenitors for neointimal SMCs without being required for their differentiation. Hence, the SDF-1/CXCR4 axis is pivotal for vascular remodeling by recruiting a subset of SMC progenitors in response to apoptosis and in concert with platelets, epitomizing its importance for tissue repair and identifying a prime target to limit lesion development.
Key Words: chemokines atherosclerosis smooth muscle cells progenitor cells restenosis
Introduction
The multifactorial process of atherosclerotic intimal fibrous proliferation and remodeling after arterial injury constitutes the main limitation of therapeutic revascularization. Luminal injury leads to endothelial denudation and exposure of extracellular matrix (ECM), precipitating platelet activation, and adhesion, which contribute to the inflammatory recruitment of leukocytes.1,2 Within minutes of vascular injury, the rapid induction of apoptosis in medial cells results in a substantial loss of vessel wall cellularity and has been associated with pathological pathways operative in excessive repair.3 Ultimately, the gradual neointimal hyperplasia is characterized by the accumulation of phenotypically distinct smooth muscle cells (SMCs).4 Although recent evidence implies that bone marrow (BM)eCderived cells contribute to neointima formation by giving rise to neointimal SMCs after arterial injury,5,6 the subset of SMC progenitors and pathways of their recruitment have not been defined. Chemokines are instrumental in attracting leukocytes and blood-borne progenitor cells to specific target tissues and have been implicated in regulating neointimal growth.7,8 Namely, the CXC chemokine stromal celleCderived factor (SDF)-1 is essential for hematopoietic stem cell mobilization, BM engraftment, as well as vascularization during embryogenesis.6,9,10 After arterial injury, SDF-1 has been found to be expressed in SMCs and has been involved in neointimal hyperplasia and recruitment of peripheral blood progenitor cells.11 The molecular mechanisms regulating SDF-1 expression after arterial injury and its function in the recruitment and differentiation of specific BM-derived SMC progenitors in tissue repair and restenosis, however, remain to be elucidated.
Materials and Methods
Mouse Models
Transluminal arterial injury11 was induced by inserting a 0.36-mm guide wire into the left common carotid artery of female apoEeC/eC mice or apoEeC/eC mice repopulated with LacZ+, CXCR4eC/eC, or CXCR4+/+ BM. Subgroups were injected with blocking SDF-1 mAb or isotype control twice weekly. For lentiviral transfer, the artery was cannulated immediately after injury, and the biclamped artery segment was incubated with 3rd generation self-inactivating lentiviral vectors encoding GFP or SDF-1 (P2->G) antagonist.12 Male lineC/sca-1+ peripheral blood progenitor cells or sorted BM cells (c-kiteC/lin+/sca-1+ or c-kit+/lin+/sca-1+) from ROSA26 or transgenic SM22-LacZ mice were administered 30 minutes after injury by intracardial injection. Carotid arteries were harvested 24 hours or 4 weeks after injury by in situ perfusion fixation with paraformaldehyde. All other methods are detailed in the expanded Materialsand Methods in the online data supplement available at http://circres.ahajournals.org.
Results
SDF-1/CXCR4eCDependent Recruitment of BM Cells to Neointimal Lesions
To investigate the role of SDF-1 in the recruitment of BM-derived progenitor cells to neointimal lesions, atherosclerosis-prone apolipoprotein EeCdeficient (apoEeC/eC) mice were repopulated with BM from ROSA26 mice expressing the LacZ gene. Treatment with a neutralizing SDF-1 mAb for 4 weeks after wire injury of the carotid artery diminished neointimal plaque area without affecting medial area (Figure 1a through 1c). Quantitative immunofluorescence revealed that the lesional content of BM-derived -galactosidase+ SMCs positive for -SMA was reduced in SDF-1 mAbeCtreated mice, whereas the -galactosidase+/-SMAeC area was unaltered (Figure 1d through 1f).
To evaluate whether the contribution of BM-derived cells to neointima formation depends on the SDF-1 receptor CXCR4, wire-induced lesions of carotid arteries were analyzed in apoEeC/eC mice repopulated with CXCR4-deficient BM. As seen for blocking SDF-1, the neointimal plaque area was reduced in apoEeC/eC mice with CXCR4eC/eC BM 4 weeks after injury, leaving the medial area unaltered (Figure 2a and 2b). This was accompanied by a decrease in the neointimal content of SMCs but not macrophages in mice with CXCR4eC/eC versus CXCR4+/+ BM (Figure 2c). Immunofluorescence staining for luminal VE-cadherin13 failed to reveal differences in endothelial recovery between SDF-1 mAb- and isotype control-treated apoEeC/eC mice or in mice with CXCR4eC/eC versus CXCR4+/+ BM (not shown), which do not account for reduced neointima formation. Thus, SDF-1 and CXCR4 are crucial for the recruitment of BM-derived SMC progenitors during neointimal plaque development after arterial injury.
SDF-1 Expression After Arterial Injury Is Linked to Apoptosis
A rapid burst of apoptosis occurs in medial SMCs within minutes after arterial injury.3 Although apoptosis may trigger the release of cytokines enhancing SMC proliferation,3 and an induction of SDF-1 has been documented following tissue damage,10,14,15 the mechanisms regulating SDF-1 expression after arterial injury remain unclear. One day after wire injury of apoEeC/eC carotid arteries, the detection of TUNEL+ nuclei revealed the abundant presence of apoptotic cells in the media adjacent to the site of injury, which was reduced by the pan-caspase inhibitor Z-VAD-fmk (Figure 3a and 3b). After one day, SDF-1 expression was detectable in luminally exposed medial SMCs at the area of denudation, whereas the inhibition of apoptosis with Z-VAD-fmk prevented SDF-1 induction (Figure 3c and 3d). To explore the kinetics of apoptosis and SDF-1 expression after injury, medial SMCs isolated from carotid arteries were used in a scratch injury model in vitro. Staining for cleaved caspase-3 and TUNEL+ nuclei were prominently evident at the fringe of injury after 4 hours, slightly detectable at 24 hours, and reduced by Z-VAD-fmk (Figure 3e, not shown). In contrast, SDF-1 expression was increased only after 24 hours and also seen in remote SMCs not directly affected by injury (Figure 3e). ELISA analysis of SMC supernatants confirmed a delayed increase in SDF-1 secretion at 24 hours, which was inhibited by Z-VAD-fmk (Figure 3f). Cells undergoing apoptosis can form apoptotic bodies. Notably, SDF-1 secretion was triggered in medial SMCs by exposure to apoptotic bodies16 concentrated from supernatants of injured SMCs after 24 hours but not after 6 hours (Figure 3f). These data indicate that expression of SDF-1 follows apoptosis after injury and may be induced by paracrine mechanisms related to apoptosis.
SDF-1 and Platelets Act in Concert to Trigger Progenitor Cell Recruitment Early After Injury
Subendothelial ECM exposed after denudation can precipitate adhesion of activated platelets supporting leukocyte recruitment.7 Double immunofluorescence staining for P-selectin along the luminal lining of freshly denuded apoEeC/eC carotid arteries provided evidence for platelets adherent to the vessel wall and showed that SDF-1 was detectable in conjunction with platelet P-selectin early after wire-injury (Figure 4a). Binding of SDF-1 to platelets was also detected by flow cytometry (Figure 4b), revealing a slight but distinctive shift in surface SDF-1 after exposure of platelets to recombinant SDF-1 (specific mean fluorescence activity 15.6±2.7 versus 4.7±1.7 in controls; P<0.05, n=4). To define the contribution of platelets and SDF-1 to the recruitment of progenitor cells to such lesions in situ, apoEeC/eC carotid arteries were perfused ex vivo 1 day after injury. In denuded segments, we observed a striking accumulation of murine FDCP-mix progenitor cells, which was inhibited by mAb blockade of SDF-1 in injured arteries or mAb blockade of P-selectin ligand-1 on progenitor cells (Figure 4c). Combined blockade yielded additive inhibition (Figure 4c). Similar results were obtained when perfusing human CD34+ peripheral blood progenitor cells (not shown). SDF-1 can potentiate platelet activation17 and arrests CD34+ cells when immobilized on endothelium in vitro.18 The mechanisms enacted by SDF-1 and platelets in early steps of progenitor cell recruitment after injury were dissected in adhesion assays with human CD34+ cells on endothelial ECM under flow conditions (Figure 4d). Arrest of CD34+ progenitors on ECM alone was negligible but triggered by preincubation of ECM with SDF-1 and supported by ECM-adherent human platelets. Preexposure of platelets to SDF-1 enhanced the arrest of CD34+ cells, whereas rolling was reduced (Figure 4d), showing that SDF-1 converts rolling interactions into firm arrest. This may be due to an upregulation of P-selectin surface expression in response to SDF-119 (not shown). Whereas a P-selectin mAb reduced both rolling and arrest, blocking CXCR4 reduced arrest but increased platelet-mediated rolling (Figure 4d). To test whether SMC-derived SDF-1 contributes to progenitor cell recruitment after injury by triggering migration, transwell assays were performed. Compared with murine stromal-5 cells known to express SDF-1, medial SMC isolated from arteries 1 day after injury displayed an abundant expression of SDF-1 mRNA (Figure 4e). Similar to recombinant SDF-1, lesional SMCs elicited an increase in transmigration of murine peripheral blood lineage (lin)eC/sca-1+ progenitor cells, which was dependent on SDF-1 (Figure 4f). Thus, platelet P-selectin mediates rolling as a prerequisite for arrest, whereas SDF-1 triggers arrest of circulating progenitor cells on ECM or adherent platelets via CXCR4 and subsequent migration, implying that SDF-1 and platelets act in concert to recruit progenitor cells to injured arteries.
Importance of Local SDF-1 for Neointima Formation
The role of SDF-1 in progenitor cell recruitment in situ prompted us to explore interference with neointima formation by focal inhibition of SDF-1 activity by lentiviral transfer of mutant SDF-1 (P2->G), described as a functional antagonist12 immediately after injury of apoEeC/eC carotid arteries. Arteries transduced with lentiviral green fluorescent protein (GFP) displayed robust fluorescence in medial cells in comparison to mock-treated arteries, confirming high efficacy of transfection (Figure 5a). Gene transfer of mutant SDF-1 markedly reduced neointimal hyperplasia 4 weeks after injury, leaving the medial area unaffected (Figure 5b and 5c). This was associated with a reduction of neointimal SMC but not macrophage content, falling short of statistical significance (Figure 5d). These data establish that local SDF-1 expressed in the context of arterial injury is crucially involved in mediating neointimal lesion development.
SDF-1 Preferentially Mobilizes and Recruits a Subset of c-kiteC/PDGFR-+ SMC Progenitors
After injury, the expression of SDF-1 in medial SMCs has been found to precede its expression in neointimal SMCs at later stages.11 Combined immunohistochemistry for SDF-1 and primed in situ labeling of the Y-chromosomeeCspecific Sry-gene after injecting male peripheral blood lineC/sca-1+ cells at the time of injury revealed that 21.6±2.9% of SDF-1eCexpressing cells were circulating cells recruited to the neointima, whereas 78.4±2.9% were resident SMCs (Figure 6a), confirming this subset as the principal source of lesional SDF-1. After injury, SDF-1 mediates the expansion of lineC/sca-1+ cells in peripheral blood,11 whereas a recruitment of PDGFR-+ SMC progenitors has been involved in embryonic vasculogenesis and PDGFR- is expressed at early stages of in vitro differentiation triggered by a SM22 promoter in BM-derived SMC progenitors.20,21 To more distinctly define the subpopulation of SMC progenitors mobilized after injury, flow cytometry revealed that 1 day after injury, the expansion of c-kiteC/lineC/sca-1+ cells (increase by 110%) was more prominent in peripheral blood of apoEeC/eC mice than that of c-kit+/lineC/sca-1+ cells (increase by 65%) in a process dependent on SDF-1 (Figure 6b and 6c). The percentage of PDGFR-+ cells was more markedly increased among c-kiteC/lineC than among c-kit+/lineC peripheral blood cells after injury (Figure 6b and 6d). This increase in PDGFR-+ and c-kiteC cells was confirmed by immunofluorescence and resembled the pattern seen after in vitro differentiation of lineC/sca-1+ cells from SM22-LacZ mice expressing LacZ under the control of the SM22 promoter into SMCs (not shown, Figure 6e). BM lineC/sca-1+ cells from SM22-LacZ mice were sorted into c-kit+ and c-kiteC cells and injected at the time of injury. Compared with c-kit+/lineC/sca-1+ cells, c-kiteC/lineC/sca-1+ cells were preferentially recruited to form LacZ+ neointimal SMCs, and blocking SDF-1 more clearly reduced the content of SMCs derived from c-kiteC cells than that derived from c-kit+ cells (Figure 6f and 6g). Most LacZ+ SMCs expressed PDGFR- in vivo (Figure 6g), underscoring the relevance of a distinct SMC progenitor subset recruited from the circulation. In vitro, differentiation of c-kiteC/lineC/sca-1+ cells from SM22-LacZ mice into SMCs in response to PDGF-BB22 was more effective than that of c-kit+/lineC/sca-1+ cells, as evident by the number of -galactosidase+ cells, and not inhibited by blocking SDF-1 (not shown). Thus, an inhibition of differentiation does not explain the effects observed. In conclusion, the SDF-1eCdependent pathway responsible for neointimal hyperplasia may operate by triggering the mobilization and recruitment of a c-kiteC and mostly PDGFR-+ SMC progenitor subset into neointimal lesions.
Discussion
In this study, we explored the involvement of the SDF-1/CXCR4 axis in neointimal hyperplasia and recruitment of BM-derived SMC progenitors and the functional contribution and modulation of local SDF-1 expressed in response to apoptosis after arterial injury.
Tissue repair and regeneration after injury involves the selective recruitment of circulating or resident stem cell populations.23,24 Several models of atherosclerosis have demonstrated that BM-derived or blood-borne progenitors to neointimal lesion formation give rise to a substantial proportion of neointimal cells in line with the severity of vascular injury.5,6 The expression of SDF-1 has been implicated in neointima formation by mediating mobilization and recruitment of peripheral blood progenitor cells.6,11 Accordingly, our data in apoEeC/eC mice repopulated with LacZ+ BM revealed that a major portion of -SMA+ SMCs recruited to the neointima after wire-injury originate from the BM, whereas neutralizing SDF-1 diminished plaque formation and reduced the content of BM-derived -SMA+ SMCs but not -SMAeC cells, eg, macrophages. This provides the first evidence that the role of SDF-1 extends beyond triggering expansion and lesional infiltration with circulating progenitors11 to regulating the recruitment of BM-derived SMC progenitors to the neointima. Similarly, apoEeC/eC mice repopulated with CXCR4eC/eC BM displayed a reduction of neointimal hyperplasia linked to a decrease in SMC content, demonstrating the relevance of CXCR4 on BM-derived cells. Although endothelial progenitor cells can migrate toward SDF-1 and may accelerate endothelial recovery after arterial injury,25 reendothelialization was unaltered in apoEeC/eC mice treated with a blocking SDF-1 mAb or repopulated with CXCR4eC/eC BM, suggesting that other factors, eg, CXCL1,13 are more important in promoting reendothelialization. Together, our data indicate that SDF-1 and CXCR4 are crucial for arterial remodeling by mediating neointimal recruitment of SMC progenitors from the BM. It should be noted that neointima formation was attenuated in apoEeC/eC mice repopulated with LacZ+ or CXCR4eC/eC but apoE+/+ BM compared with pure apoEeC/eC mice.11 This is in accordance with data that transplantation of apoE+/+ BM protects apoEeC/eC mice from diet-induced atherosclerosis via secretion of apoE by BM-derived macrophages,26 which may also reduce plaque formation after arterial injury.
Multiple processes initiated by arterial injury may influence SDF-1 expression. SDF-1 is induced after DNA damage and has been speculated to participate in defense mechanisms counteracting processes related to cell death.10,27 The upregulation of SDF-1 mediating the recruitment of circulating CXCR4+ stem cells has been documented in infarcted myocardium and ischemic tissue (via hypoxia-inducible factor-1).14,15,28 We detected SDF-1 expression in medial cells concomitant with the abundant occurrence of apoptosis adjacent to the site of denudation in apoEeC/eC carotid arteries 1 day after injury. A direct link between the onset of apoptosis and SDF-1 induction was invoked by the reduction of SDF-1 expression after inhibiting caspase-dependent apoptosis with Z-VAD-fmk. In vitro, apoptosis of injured SMCs triggered SDF-1 expression also in SMCs not directly affected by the injury, possibly via SMC-derived apoptotic bodies. Apoptosis has been implicated in the proliferative response after vascular injury.3,6,29,30 Although late-onset apoptosis of lesional cells has been postulated to protect against hyperplastic remodeling, as illustrated by disruption of the antiapoptotic protein bcl-xL,31 inhibition of early SMC apoptosis by Z-VAD-fmk reduced neointimal inward proliferation after balloon injury.32 Our data imply that the initial burst of apoptosis in medial cells triggers paracrine counter-regulatory mechanisms, eg, signals conferred by apoptotic bodies and SDF-1 induction, which are integral in initiating an excessive repair process, ultimately resulting in neointimal hyperplasia.
The attraction of leukocytes and progenitor cells to specific target tissues is governed by adhesion molecules and chemokines.7,8 Adherent platelets and platelet products deposited on ECM exposed after denudation provide a substrate for the recruitment of mononuclear cells.33 We show that SDF-1 is colocalized with P-selectineCexpressing platelets adherent to the luminal surface 1 day after injury and acts in concert with P-selectin to mediate arrest of progenitor cells in injured carotid arteries. In vitro adhesion assays established a role of P-selectin in rolling interactions of progenitor cells on platelets bound to ECM, consistent with PSGL-1eCmediated rolling of CD34+ cells on P-selectin,34 whereas SDF-1 triggered the arrest on ECM or adherent platelets via CXCR4. Platelet activation can be potentiated by SDF-1 and results in surface expression of P-selectin.19 Accordingly, the upregulation of platelet P-selectin by SDF-1 may contribute to progenitor recruitment. Activated platelets can shed microparticles, which can bind progenitor cells via P-selectin and promote their adhesion, eg, by conferring CXCR4.35 Transfer of CXCR4 may also occur during interactions of circulating progenitor cells with adherent platelets, amplifying arrest triggered by immobilized SDF-1 in the vicinity. Platelets can bind and present MCP-1 at the site of denudation, allowing its retention in flow to trigger monocyte arrest after arterial injury.36 Likewise, the colocalization of SDF-1 with platelets and its binding to their surface imply its luminal presentation to circulating progenitor cells facilitating arrest after injury.
By analogy to chemokine-stimulated mononuclear cell adhesion on fibronectin or ECM,8 it is conceivable that the SDF-1eCinduced arrest of progenitor cells on ECM is due to increased avidity of 1 integrins, given that smooth muscle outgrowth cells exhibit preferential 1 integrin expression and adhesion to fibronectin.37 Moreover, SDF-1 can directly bind to proteoglycans, triggering the migration of progenitor cells.38,39 Because increased proteoglycan synthesis contributes to neointimal ECM after arterial injury,40 SDF-1 may be released into the circulation but also be bound to proteoglycans in the growing neointima, shifting its role from mobilization toward recruitment of progenitor cells. Indeed, SDF-1 expressed by lesional SMCs triggered transmigration of lineC/sca-1+ cells. The importance of lesional SDF-1 was underscored by the inhibition of neointima formation after local transfer of the SDF-1 antagonist P2->G, although it cannot be excluded that P2->G is released systemically or that BM SDF-1 is diminished, as seen in response to ischemia.28
With regards to defining the origin of SMC progeny, c-kit+/lineC/sca-1+ BM cells have been shown to differentiate into SMCs in coculture with primary SMCs in vitro,5 and smooth muscle outgrowth can be generated by in vitro differentiation of peripheral mononuclear cells with PDGF-BB.41 SMC progenitors expressing PDGFR-+ are involved in embryonic vasculogenesis and may constitute a unique population in BM, which can be driven to acquire SMC-specific markers including PDGFR- during in vitro differentiation.20,21 In addition, sca-1+ adventitial cells can differentiate into SMCs by PDGF-BB stimulation in vitro.22 Although peripheral lineC/sca-1+ cells are expanded and recruited to lesions giving rise to neointimal SMCs,11 distinct subsets of circulating SMC progenitors have not been defined. Although most primitive murine hematopoietic stem cells have been identified as c-kit+/lineC/sca-1+ and exhibit multi-lineage potential, c-kiteC/lineC/sca-1+ cells can be derived from c-kit+ cells but display a quiescent phenotype without lineage reconstitution capacity.42 In restenotic but not primary atherosclerotic lesions, c-kit+ cells positive for -SMA are detectable, whereas c-kiteC cells have not been analyzed.23 We show that c-kiteC/lineC/sca-1+ cells and a subset expressing PDGFR-+ preferentially expand in peripheral blood after wire-injury, differentiate into SMCs in response to PDGF-BB in vitro, and more readily undergo SDF-1eCmediated recruitment and differentiation into neointimal SMCs than c-kit+ cells in vivo. This adds to the fundamental role of the PDGF system in neointimal SMC accumulation.43 Although plasma elevation of SDF-1 or CXCR4 desensitization mobilize both c-kit+ and c-kiteC progenitors,44,45 the conditions of wire injury with moderately increased plasma SDF-1a11 may favor the recruitment of c-kiteC cells. This is consistent with the notion that c-kiteC/lineC/sca-1+ cells show a higher migratory response to SDF-1 and expression of motility proteins than c-kit+/lineC/sca-1+ cells.46 Although BM-derived cells clearly invest in neointimal SMCs, c-kiteC cells may also be mobilized from extramedullar pools. Our data support a concept of specifically committed progenitor subsets mobilized by SDF-1 after tissue damage.
Beyond its role in mobilization and homing of progenitor cells, SDF-1 contributes to establishing a microenvironment permissive for their proliferation and survival and may support early differentiation.10,27,47 Our results imply that blocking SDF-1 does not inhibit differentiation of progenitor cells into SMCs in vitro, as monitored by SM22 promotereCdependent LacZ expression. Therefore, it is conceivable that SDF-1 is not required for neointimal differentiation of SMC progenitors in vivo. In contrast, SDF-1 has been involved in the differentiation of c-kit+ cells into endothelial progenitor cells by promoting integrin-mediated adhesion, a response suppressed by mitogenic stimulation.48 Given the prevalence of mitogenic cytokines,1,2 it appears unlikely that SDF-1 elicits differentiation into an endothelial phenotype in the context of injury or that their blockade would impair endothelial recovery to exacerbate neointimal hyperplasia.
Our data reveal a crucial role of the SDF-1/CXCR4 axis in the recruitment of a BM-derived SMC progenitor subset from the circulation in response to arterial injury and apoptosis giving rise to neointimal SMCs and mediating neointimal hyperplasia. Beyond vascular remodeling, this epitomizes important mechanisms in physiological and excessive tissue repair.
Acknowledgments
This study was supported by Deutsche Forschungsgemeinschaft (grants We1913/5-1, We1913/7-1, Scho1056/2) and "IZKF Biomat" (BMBF grant 01KS9503/9). We thank M. Roller, T. Kogel, S. Knarren, and R. Krohn for expert technical assistance.
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