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Brief Reviews |
From the Departments of Genome Research and Clinical Application (H.B.), and Clinical Cell Biology (Y.S.), Chiba University Graduate School of Medicine, Japan.
Correspondence to Hideaki Bujo; Department of Genome Research and Clinical Application, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail hbujo{at}faculty.chiba-u.jp
| Abstract |
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LDL receptor family members (LRs) regulate the catabolism of membrane-associated proteins and are expressed in SMCs of atherosclerostic lesions. LRs modulate the activity of the urokinase-type plasminogen activator (uPA) receptor and possibly of the PDGF receptor. Selective modification of the LRs/membrane receptor system may be important for suppression of atherosclerosis.
Key Words: LDL receptor family smooth muscle cells migration LR11 urokinase-type plasminogen activator receptor PDGF receptor
| Introduction |
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LRs play a key role in lipoprotein metabolism, as demonstrated by the well-established actions of the LDL receptor in a variety of tissues.1 Extensive functional analyses have also revealed that LRs play an important role in the catabolism of many membrane-associated proteins such as complexes between proteinases and their receptors.13 Recent studies using receptor-deficient or -overexpressing animals and cells have suggested that certain LRs are also important as regulators of the migration (and proliferation) of various cells such as fibroblasts, neurons, and vascular smooth muscle cells (SMCs).1017
Histochemical studies have revealed that the expression of LRs, as well as scavenger receptors, is markedly induced during the development of atherosclerotic lesions.1,18 For instance, the VLDL receptor/LR8 is highly expressed by SMCs, macrophages, and endothelial cells in rabbit atherosclerotic lesions, whereas the LDL receptor is not abundant in arterial walls.18,19 LRP-1 expression is also induced in atheromatous plaques.1820 We identified strong LR11 expression inside plaques, particularly by intimal SMCs located at the interface between intima and media.21,22 In addition, LRP-1B is expressed by SMCs of the medial layer and in thickened intimal regions.23 Thus, changes in the expression of LRs by vascular cells, particularly SMCs, may play a role in the development of atherosclerosis.
The migration and proliferation of SMCs, as well as extracellular matrix (ECM) production and catabolism by these cells, are important events in the development of atherosclerosis and intimal thickening after coronary angioplasty.24 When thickening of the intima occurs, SMCs migrate from the media into the intima. During migration, SMCs acquire or lose various functions to perform the above-mentioned activities in the intima.25,26 However, the mechanisms that control the migration of intimal SMCs have not been clarified because of the complex intracellular machinery and the interactions of numerous internal or external factors and signaling pathways. There is conclusive evidence that migration of SMCs from the media into the intima contributes to the formation of stable plaque.27,28 Here, we focus on the role of LRs in regulating membrane receptor functions related to the migration of SMCs associated with atherosclerosis.
| Platelet-Derived Growth FactorMediated Migratory Activity of Intimal SMCs |
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Many factors may contribute to altering the migratory potential of SMCs in the intima, including changes of contact with the ECM and exposure to growth factors. Cultured SMCs tend to mimic these changes because primary cultured cells rapidly lose their differentiation markers and develop a synthetic phenotype. Conversely, SMCs grown in 3D cultures, such as a honeycomb structure, are able to retain the contractile phenotype.35 Thus, various cell culture models have provided information about factors that influence the migration of intimal SMCs. Among them, sensitivity to growth factors (including platelet-derived growth factor [PDGF]) is known to be important for inducing SMC migration.25 PDGF-BBmediated intracellular signals induce migration, which is commonly observed using a migration assay system such as Boydens chamber. The influence of PDGF-BB on the migration of SMCs is mediated by a specific membrane receptor: PDGF ß-receptor.36 During the process of migration of SMCs from the media into the intima, one of the strongly expressed genes is PDGF ß-receptor,37 which contributes to the migratory capacity of intimal SMCs.38,39 The PDGF ß-receptor is highly expressed even in the media of diabetic models, which show accelerated plaque formation.40,41 PDGF-BB negatively regulates the transcription of multiple genes in SMCs and thus modulates differentiation.42 Accordingly, the switch that induces PDGF ß-receptor gene expression seems to be closely related to increasing the migratory capacity of intimal SMCs.
| Urokinase and Its Receptor System Are Activated During SMC Migration |
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Both tissue-type plasminogen activator and uPA cleave plasminogen to release plasmin. Expression of tissue-type plasminogen activator and uPA is increased in atherosclerotic plaque,4547 and a study using knockout mice has revealed a role of uPA in the development of intimal hyperplasia.48 Accordingly, uPA is thought to play an important role in the target-oriented movement of SMCs because its activation can be localized via binding to its receptor (the uPA receptor) on the cell surface. The receptor-mediated potentiation of protease activity for plasminogen also causes an increase of plasmin activation around cell surface receptors. Subsequent production of plasmin leads to the degradation of ECM components and also has the potential to activate some MMPs. The essential role of this process in enhancing cell mobility has been intensively studied with regard to tumor invasion and neuronal migration.49,50
Expression of uPA by medial SMCs increases rapidly and significantly after balloon catheter injury to a vessel, corresponding with the time course of SMC migration.51 Virally mediated overexpression of uPA by the endothelial cells of the carotid arteries promotes lesion growth in cholesterol-fed rabbits.52 After arterial injury, intimal thickening is significantly reduced in uPA-deficient mice.48,53 Thus, uPA itself seems to promote intimal thickening after vascular injury. However, despite the ability of uPA to influence the migration of cultured SMCs,5456 intimal formation is unaffected in uPA receptor knockout mice.57 The specific proteolytic activity of uPA plays a role in the processes of arterial repair after injury, although the details of the mechanism regulating association with its receptor have not been clarified in the setting of atherosclerosis.
In addition to the proteolytic cascade initiated by binding of uPA to its cell surface receptor, uPA possibly facilitates cell migration by inducing intracellular signaling pathways.58 The uPA receptor is a glycosylphosphatidylinositol-anchored protein, and therefore signaling activity is mediated by its interaction with other membrane molecules. Binding of uPA to its receptor on the cell surface influences the migratory activity through the formation of a complex involving the uPA receptor, vitronectin, and integrin.50,58 These interactions at the cell membrane stimulate intracellular signaling cascades, as well as uPA receptormediated activation of extracellular proteolysis.50,58 uPA stimulates the migration of SMCs via its receptor signaling cascade containing the Janus kinase, Tyk2, and phosphatidylinositol 3-kinase. Active GTP-bound forms of small GTPases (RhoA and Rac1) are the downstream targets for Tyk2 and phosphatidylinositol 3-kinase activation. Phosphorylation of myosin light chain is one of the end points of the uPA receptormediated signaling pathways. Observations suggesting a possible role of uPA (independent of ECM degradation) in cell migration have been reported so the uPA receptor may also modulate migration/invasion in a protease-independent manner. These findings, together with the results obtained in uPA receptor knockout mice,57 have led to the conception that the uPA receptor modulates SMC migration through cooperation between extracellular proteolysis and intracellular signaling. Proteolysis of the ECM accelerates migration and is coordinated with adhesive and structural changes that promote cell motility, with both processes leading the cells to their targets in the plaques.
| LRs Are Novel Modulators of uPA Receptor Function During PDGF-Mediated Migration of SMCs |
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LRP-1 is involved in the internalization of the uPA/uPA receptor complex, in which formation is induced by plasminogen activator inhibitor-1, and this process is dependent on LRP-1.10,11,62,63 LRP-1 is a large molecule composed of 2 subunits. Two NPXY motifs exist in the intracellular domain of LRP-1, and these motifs are not only important for endocytosis but also for intracellular signaling through molecules such as Shc.6466 Inhibition of uPA receptor internalization increases cell surface uPA receptor expression and enhances cell motility.10,16,63,67
Deficiency of LRP-1 in SMCs causes atherosclerosis, which is mediated by the modulation of intracellular PDGF signaling.17 This is attributable to the influence of LRP-1 on PDGF ß-receptor signaling or metabolism, possibly because of a molecular interaction at the cell surface.17,6870 LRP-1B is the giant family member that is most similar to LRP-1; it also binds to the PDGF ß-receptor and modulates receptor-mediated signaling in SMCs.23 These findings suggest that SMC migration might be regulated by the time-restricted expression of LRs, which determines the outcome of PDGF ß-receptor and uPA receptormediated signaling. In accordance with the concept of functional interaction between LRs and membrane signaling receptors, LR11 has been identified by us and others as a negative regulator of protein catabolism for uPA receptor.71,72 Previous histochemical studies have revealed that LRs are markedly induced during the development of atherosclerotic lesions.1,18 Altered expression of LRP-1 and the uPA receptor possibly reflects the vascular response to injury. Upregulation of LRP-1 mRNA has been detected in the aortas of rabbits fed a high-cholesterol diet.1,18 Both LRP-1 mRNA and protein are expressed in normal and atherosclerotic human arteries.19,20 Increased vascular expression of the uPA receptor is observed in cholesterol-fed rabbits and human atherosclerotic arteries.73 Because LRs are able to modulate uPA receptor activity and possibly PDGF receptor activity, LRs are expected to regulate the migration of SMCs through the functional modulation of these membrane receptors (Figure 2).
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| Involvement of LRs in Regulating SMC Migration in the Intima |
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A negative regulator of receptor catabolism, LR11, controls uPA receptor localization on the plasma membrane because both the membrane-spanning and secreted forms of LR11 bind to and colocalize with the uPA receptor on the cell surface.21,74 Expression of LR11 is induced by stimulation of PDGF-BB in SMCs and is observed in intimal SMCs localized at the intima/media border in the atherosclerotic plaques of experimental animals.21 Overexpression of LR11 by SMCs enhances their migration by elevating uPA receptor expression.21 Contrarily, neutralization of LR11 reduces the intimal thickening after cuff injury in mice.21
| Modulation of the LR11/uPAR Pathway for Prevention of Atherosclerosis |
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It has not yet been clarified whether inhibition of the migration of intimal SMCs leads to the regression of atherosclerotic plaque or prevents restenosis after coronary angioplasty. Activation of pathways mediated by the uPA receptor and the PDGF receptor that increase the migration of intimal SMCs is thought to be essential for the formation of mature plaque after endothelial injury leads to the initiation of atherosclerosis. Unregulated expression of these membrane receptors may reduce the stability of plaque because the programmed migration of SMCs from the media to target regions in the intima would be disturbed. LRs are a possible candidate for modulating SMC migration to control the process of atherosclerosis. Selective modification of the LRs/uPA receptor/PDGF receptor system in SMCs, associated with the change to a dedifferentiated phenotype, appears to be important for the occurrence of intimal thickening after angioplasty as well as plaque formation in atherosclerosis.
| Acknowledgments |
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Received August 19, 2005; accepted March 2, 2006.
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