doi: 10.1161/01.RES.0000126921.29919.51
© 2004 American Heart Association, Inc.
Reviews |
Proteoglycans in Atherosclerosis and Restenosis
Key Roles for Versican
From the Department of Vascular Biology (T.N.W.), The Hope Heart Institute, Seattle, Wash; and Department of Anatomy with Radiology (M.J.M.), School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
Correspondence to Thomas N. Wight, Department of Vascular Biology, The Hope Heart Institute, 1124 Columbia St, No. 783, Seattle, WA 98104-2046. E-mail twight{at}hopeheart.org
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Abstract |
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 Top Abstract IntroductionVersican in Normal Blood...Versican in Atherosclerosis and...Regulated Synthesis of Versican...Is Versican the Culprit?References |
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The proteoglycan versican is one of several extracellular matrix (ECM) molecules that accumulate in lesions of atherosclerosis and restenosis. Its unique structural features create a highly interactive molecule that binds growth factors, enzymes, lipoproteins, and a variety of other ECM components to influence fundamental events involved in vascular disease. Versican is one of the principal genes that is upregulated after vascular injury and is a prominent component in stented and nonstented restenotic lesions. The synthesis of versican is highly regulated by specific growth factors and cytokines and the principal source of versican is the smooth muscle cell. Versican interacts with hyaluronan, a long chain glycosaminoglycan, to create expanded viscoelastic pericellular matrices that are required for arterial smooth muscle cell (ASMC) proliferation and migration. Versican is also prominent in advanced lesions of atherosclerosis, at the borders of lipid-filled necrotic cores as well as at the plaque-thrombus interface, suggesting roles in lipid accumulation, inflammation, and thrombosis. Versican influences the assembly of ECM and controls elastic fiber fibrillogenesis, which is of fundamental importance in ECM remodeling during vascular disease. Collectively, these studies highlight the critical importance of this specific ECM component in atherosclerosis and restenosis.
Key Words: proteoglycans • versican • extracellular matrix • atherosclerosis • smooth muscle cells
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Introduction |
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TopAbstractIntroductionVersican in Normal Blood...Versican in Atherosclerosis and...Regulated Synthesis of Versican...Is Versican the Culprit?References |
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Versican is a chondroitin sulfate proteoglycan (CSPG) that is present in the extracellular matrix (ECM) of normal blood vessels and increases dramatically in all forms of vascular disease.1,2 A number of reports within the last few years have documented a significant involvement of versican in lesions of atherosclerosis and restenosis and these observations, coupled to those that demonstrate that this ECM proteoglycan regulates many of the events that contribute to the formation of atherosclerotic and restenotic lesions, highlights the critical importance of versican in the pathogenesis of vascular disease.
Versican is one of many proteoglycans identified in vascular tissue or synthesized by vascular cells3 and together with biglycan, decorin, and perlecan constitute the bulk of the proteoglycans found in the interstitial space.2 Versican interacts with hyaluronan, a long chain high molecular weight glycosaminoglycan (GAG), that is also present in the extracellular matrix (ECM) of blood vessels and increases as versican in vascular disease.4
The versican gene and protein follow a domain template. The amino-terminal globular domain (G1) binds hyaluronan, and the carboxy-terminal globular domain (G3) resembles the selectin family of proteins, consisting of a C-type lectin adjacent to two epidermal growth factor (EGF) domains and a complement regulatory region. The middle region of the versican core protein is encoded by two large exons that specify the chondroitin sulfate attachment regions of versican (Figure 1). These highly interactive domains are the basis for the name given to this "versatile" molecule.5
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Versican exists in at least four different isoforms created by alternative splicing of mRNA from a single gene. RNA splicing occurs in the two large exons, 7 and 8, that encode the GAG attachment sites, giving rise to V0, V1, V2, and V3 forms of versican.6 These variants differ in the length of the core proteins and number of attached GAGs (Figure 1).7 Expression of the versican gene is regulated by a promoter that harbors a typical TATA box and potential binding sites for several transcription factors such as AP2, CCAAT enhancer protein, and cAMP-responsive elements.8 Regulation of versican core protein synthesis can be at transcriptional8 or posttranscriptional levels (J. Lemire, C. Tsoi, S. Bressler, and T. Wight, unpublished observations, 2004).
Typically, the chondroitin sulfate (CS) chains attached to the core protein differ in size and composition depending on the tissue source or culture conditions. They vary in size from 25 to 80 kDa and contain different ratios of chondroitin 6-sulfate to chondroitin 4-sulfate.9 Their length and composition are regulated and controlled by different stimuli (see following sections).
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Versican in Normal Blood Vessels |
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TopAbstractIntroductionVersican in Normal Blood...Versican in Atherosclerosis and...Regulated Synthesis of Versican...Is Versican the Culprit?References |
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Versican is the principal CSPG in blood vessels10 and immunohistochemistry reveals that versican is prominent in the intima and adventitia of most arteries and veins.11 It is likely that accumulation of versican in the normal arterial intima is mainly responsible for the proteoglycan-rich nature of this layer.12 Versican interacts with hyaluronan and link protein to form high molecular weight stable aggregates13–15 that fill the ECM space not occupied by the other fibrous proteins such as collagens and elastic fibers. These complexes create a reversibly compressive compartment and provide a swelling pressure within the ECM that is offset by collagen and elastic fibers.16,17 Early biochemical studies of bovine18,19 and human aorta20 identified a large CSPG that resembled the principal CSPG synthesized by cultured arterial smooth muscle cells (ASMCs)21,22 and later identified as versican.1,9 Recent studies identified specific cleavage products of versican in human aorta that contain the G1 domain of versican. Further studies identified the enzymes that cleaved aortic versican as members of the ADAMS-TS family.23,24 Other proteases in arteries that are known to degrade versican include matrilysin25 and plasmin.26 These findings are consistent with the presence of multiple sizes of versican and versican fragments within vascular tissue.
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Versican in Atherosclerosis and Restenosis |
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TopAbstractIntroductionVersican in Normal Blood...Versican in Atherosclerosis and...Regulated Synthesis of Versican...Is Versican the Culprit?References |
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Accumulation and Role in Lipid Retention
The bulk of information regarding involvement of versican in naturally occurring atherosclerosis in human and experimental animals comes from immunohistochemical studies.25,27–33 Versican is present in early intimal thickenings that characterize developing atherosclerotic lesions and are primarily associated with ASMCs (Figures 2A and 2B). In a gene array study of neointimal formation in graft healing, versican was one of only 13 genes selectively upregulated34 and found to accumulate in early graft lesions (R. Kenagy, J. Fischer, A. Clowes, and T. Wight, unpublished observations, 2004). Additionally, versican tends to accumulate in human vessels susceptible to atherosclerosis such as the coronary artery and saphenous veins used for grafting when compared with those resistant such as internal mammary and radial arteries.11 Whereas versican appears to contribute to intimal expansion and lesion progression, versican degradation may be part of lesion regression. In a high blood flow model of intimal atrophy in polytetrafluoroethylene (PTFE) aortoiliac grafts, extracts of 4-day high-flow intimas degraded more vascular versican than similar extracts from 4-day low-flow intimas.26 This activity was shown to be due to elevated plasmin levels.
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Versican is present throughout advanced lesions of atherosclerosis as well. A large CSPG has been isolated from atherosclerotic lesions of large hydrodynamic size with a core protein ranging in size from 160 to 245 and containing a mixture of chondroitin 6-sulfate and chondroitin 4-sulfate chains with chondroitin 6-sulfate predominating.20,35–38 Versican is prominent at the edges of the necrotic core in more advanced lesions of atherosclerosis and in close proximity to deposited lipoproteins,25,29,30 suggesting a role in the retention of lipoproteins in the vessel wall. The response to retention hypothesis of atherosclerosis,39 based on pioneering work performed in the 1970s and 1980s40–44 invokes a critical role in atherogenesis for the retention of lipoproteins by ECM proteoglycans. A number of studies have shown that versican as well as other proteoglycans such as biglycan are associated with lipoprotein deposits in human atherosclerotic lesions25,27,29,31 and in lipid induced lesions in experimental animals.30,45,46 Large chondroitin sulfate–lipoprotein complexes have been isolated from human atherosclerotic lesions47,48 and arterial CSPGs interact with lipoproteins.38,43,49,50 Analysis of binding constants of CSPGs from lesions reveals that multiple LDL particles can bind to a single CS chain.48,49,51 Thus, GAG chain length is a determining factor in lipid binding. Vascular injury produces elongated GAG chains on the large vascular CSPG promoting LDL binding.51 Conditions that promote CS chain elongation in ASMCs such as cell proliferation,52 treatment of the cells with oxidized LDL53 and transforming growth factor-ß (TGF-ß)54 also cause increased binding of versican to LDL. In addition, exposure of human ASMCs to nonesterified free fatty acids, as occurs in diabetes, increases the production of proteoglycans including versican, which then binds LDL more effectively.55 In vitro studies of versican isolated from cultured ASMCs demonstrate that this proteoglycan binds to LDL with saturable kinetics and with a binding affinity for versican of 2.3x10–8 mol/L.56,57 The composition of the CS chains of versican may effect LDL interaction as well. CS enriched in the 6-O sulfate isomer binds LDL more avidly than those enriched in the 4-O sulfate isomer.58 Furthermore, the charge density on the GAG influences LDL interactions in that the degree of sulfation affects lipoprotein interaction with proteoglycans.59
Although a number of studies indicate that versican is clearly capable of binding to LDL, versican is generally not detected in the lipid-rich center of the necrotic core nor does it colocalize with apoE or apoB epitopes in both human and mouse atherosclerotic lesions. Instead other proteoglycans such as biglycan, a DSPG, and perlecan, a HSPG, together with macrophages, tend to predominate.31,60 For example, in the murine apoE-null atherosclerotic lesion, biglycan and perlecan were found to best colocalize with lipoproteins,60 raising questions about the importance of versican in lipid retention in this animal model. Species differences do exist regarding the types and amounts of proteoglycans in the vasculature. The murine vasculature is enriched in heparan sulfate proteoglycans, whereas the human vasculature contains a large proportion of CS and DS proteoglycans.61,62 The reasons for these differences are not clear but may indicate fundamental species differences in the nature of the ECM in atherosclerotic lesions between mice and humans. What is clear is that multiple types of proteoglycans can interact with lipoproteins, and what is important is that it may not necessarily be the type of proteoglycan present but where and how much of a particular proteoglycan is found during the lipid phase of this disease.
Although the precise structure(s) in the proteoglycans responsible for LDL binding has yet to be determined, versican and biglycan binding sites in human apoprotein B of LDL have been located at residue 3363,56 whereas different binding sites exist for apoB 48.63 Furthermore, transgenic mice overexpressing a defective proteoglycan-binding apoprotein when fed a high-fat diet failed to develop atherosclerosis after 20 weeks.64 These results indicate that subendothelial retention of apoprotein B-100–containing lipoproteins by proteoglycans is a critical step in the early stages of atherosclerosis. The precise role of versican in these early phases remains to be determined. Furthermore, lipoproteins bound to proteoglycans are more sensitive to modifications such as oxidation and enzymatic hydrolysis, thereby affecting their potential atherogenecity.65–67 It should also be pointed out that lipid content of the lipoprotein also affects their interaction with proteoglycans,66,67 indicating the probability of multiple interactive sites between these two sets of molecule.
In addition to regulating the extracellular retention of lipoproteins, versican may play a role in intracellular lipid accumulation as well. Chondroitin sulfate proteoglycan-LDL complexes are taken up rapidly by macrophages65,68 and ASMCs69 and recent studies show that ASMCs internalize versican-LDL complexes through both LDL receptor and LDL receptor–related protein pathways.70 This uptake leads to accumulation of lipid and formation of foam cells which characterize lipid-filled atherosclerotic plaques. Thus, versican may play fundamental roles in both the extracellular and intracellular retention of lipoproteins in atherogenesis.
Role in Inflammation
Accumulation of a versican-hyaluronan–enriched ECM may also influence the retention of inflammatory cells that also form part of the developing atherosclerotic lesion.71 For example, hyaluronan can serve as an attachment ligand for macrophages72 and lymphocytes through CD44-mediated interactions.4 Versican, which binds to hyaluronan, can also bind to CD44,73 suggesting that both versican and hyaluronan may stabilize CD44-dependent interactions of inflammatory cells. In vitro studies show that both versican and hyaluronan support macrophage adhesion.72,74,75 Additionally, versican interacts with inflammatory chemokines and partly regulates their activity.73,76–78 It is of interest that one of the spliced variants of CD 44 that contains CS interacts with interferon 
,79 suggesting a potential role for molecules like versican to retain inflammatory cytokines at the ASMC surface.
Thrombosis and the Eroded Plaque
Versican and hyaluronan are also present at the plaque thrombus interface in advanced human atherosclerotic lesions32 (Figures 2C and 2D), suggesting a possible role in thrombosis. Recent experiments have shown that versican promotes platelet adhesion at low shear rates and cooperates with collagens to promote platelet aggregation.80 The presence of hyaluronan with versican at these sites also supports a prothrombotic role for hyaluronan because platelets can stick to hyaluronan through CD44 receptors.81 Such findings indicate that versican-hyaluronan complexes may serve as ancillary platelet ligands to the other known ligands to influence platelet deposition after rupture of the atherosclerotic plaques. In addition, versican at the plaque thrombus interface may in part regulate the water content of this region of the lesion and in turn promote coagulation because water transfer is linked to anticoagulation activity of molecules such as the CS in versican.82 Versican isolated from advanced type IV atherosclerotic lesions prone to thrombosis is undersulfated relative to versican from nondiseased aortas. Decreased sulfation of versican may predispose the lesions to thrombosis by disrupting osmotic regulation and limiting antithrombin activity.
Aneurysms
Aortic aneurysms are a frequent complication of severe atherosclerosis and constitute an important clinical problem.83 Versican V0 mRNA is decreased by 40% in human abdominal aortic aneurysms with significantly reduced immunostaining for versican.10 Some of this loss could be due to selective versican degradation as versican degradative enzymes such as plasmin increase in association with aneurysmal expansion.84,85 Thus, late phase aneurysmal development may involve selective loss of versican. Pseudoaneurysms of the temporal artery show increased immunostaining for versican in areas where there is elastic fiber interruption,86 indicating a possible early involvement of versican in remodeling involving elastogenesis (Figures 2E and 2F). Interestingly, ASMCs cultured from aneurysmal aortas synthesize elevated levels of versican.87 In addition, a recent gene mapping study of familial thoracic aortic aneurysms and dissections identified a gene locus for this disease at 5q13-14,88 which is the chromosomal segment that contains the versican gene.89 However, sequencing of versican DNA from affected individuals failed to reveal any variation that could account for the phenotype. It remains to be seen if changes in any of the versican variants could account for susceptibility to aneurysms. Although versican changes in aneurysms are well documented, it is still not clear whether these changes are causative or secondary to other ECM abnormalities. However, a connection between versican and elastic fiber assembly as discussed below supports a role for versican in maintenance of elastic fiber assembly and blood vessel wall stability.
Increase in Response to Vascular Injury and the Restenotic Lesion
Accumulation of versican typifies early lesion development in response to vascular injury. Versican increases in the intima in the early phases of response to balloon injury and in vein graft repair and contributes to intimal expansion after vascular trauma.26,45,46,90–94 Interference with versican expression either by antibodies to TGF-ß90 or antisense92 blocks intimal expansion after injury.
Versican is markedly increased in both stented and nonstented restenotic lesions in humans95–97 (Figures 2G and 2H). Accumulation occurs primarily in the ASMC hypercellular myxoid regions of the lesions that have a very low content of collagen and elastic fibers. Hyaluronan which associates with versican also accumulates in the versican-rich regions of these lesions4,98 and forms high molecular weight hydrophilic complexes that trap water and cause tissue swelling. The rapid expansion of restenotic lesions could be due, in part, to the swelling pressure brought on by accumulation of versican-hyaluronan complexes. Conversely, loss or breakdown of the hyaluronan-versican complex could lead to expulsion of water and tissue shrinkage with reduction in arterial circumference. Interestingly, collagen gels impregnated with hyaluronan show CD-44–dependent contraction when populated by ASMCs.99 The involvement of versican in regulating the ASMC’s ability to contract their matrices has not been investigated.
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Regulated Synthesis of Versican and Regulation of Vascular Cell Phenotype |
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TopAbstractIntroductionVersican in Normal Blood...Versican in Atherosclerosis and...Regulated Synthesis of Versican...Is Versican the Culprit?References |
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Arterial smooth muscle cells are the principal source of versican in both arteries and veins,9,21,22,34,92,100–106 although endothelial cells107–110 and myofibroblasts derived from adventitial fibroblasts45 also have been shown to synthesize versican. ASMCs contain mRNA transcripts for V0, V1, and V3.103 The synthesis of versican by ASMCs is regulated by specific factors that contribute to atherogenesis. PDGF, a major mitogen for these cells, upregulates versican core protein synthesis without affecting core protein synthesis of biglycan and decorin.9,101,105,111 This upregulation depends on endogenous tyrosine kinase activity because genistein completely blocks PDGF-induced synthesis of versican.101 This growth factor also affects the posttranslational processing of versican by stimulating CS chain elongation.9 This effect, however, is not restricted to versican because PDGF also causes GAG chain elongation of decorin and biglycan.111 Such observations suggest that pathways that control versican core protein synthesis and CS and DS synthesis are regulated differently. For example, inhibiting tyrosine kinase activity does not affect CS chain elongation by PDGF in ASMCs.101 An involvement of MAPKK in the regulation of versican synthesis by ASMCs has been confirmed in that angiotensin II stimulation of versican synthesis requires MAPKK.112 Other cytokines known to regulate versican synthesis include TGF-ß,9 EGF,113 and bFGF (K. Braun, S. Potter-Perigo, and T. Wight, unpublished observations, 2004). Interestingly, leukotriene, LTD4 and EGF treatment of ASMCs increases V0 versican synthesis over V1 versican,113 indicating differential regulation of versican isoforms by specific cytokines. The larger V0 form would occupy larger ECM volumes and contribute to greater ECM expansion.
Versican synthesis by ASMCs is also regulated by mechanical forces such as cell stretching. For example, low amplitude biaxial strain induces a time-dependent increase in the synthesis of versican,106 while at the same time causing decreases in the expression of decorin. Elevated versican synthesis is accompanied by increases in versican-hyaluronan aggregation, indicating a direct influence of mechanical stretch on ECM remodeling. It may be that such changes create a more malleable, deformable, hygroscopic ECM surrounding cells to accommodate the stretch on the cell so as to prevent cell damage.
Although a number of chemical and mechanical factors stimulate ASMC versican expression, a few inhibit. Interleukin (IL)-1ß decreases versican expression while increasing the synthesis of decorin.114,115 Because macrophage-derived IL-1 is capable of causing these changes, it is likely that macrophages can also regulate versican content of developing lesions. On the other hand, versican is generally absent in areas where macrophages accumulate in atherosclerotic lesions,25,27,30,31 suggesting macrophages have a role in versican degradation.
Although ASMCs are a major source of versican in vascular lesions, endothelial cells also synthesize versican in a regulated fashion. TGF-ß increases versican expression in bovine aortic endothelial cells109 and versican synthesis is downregulated when endothelial cells are stimulated to migrate.108 More recent studies suggest that a specific isoform of versican, V3, is increased by proangiogenic cytokines such as VEGF and TNF-
and associated with a neoangionic endothelial phenotype.110
Effects on Vascular Cell Adhesion, Proliferation, and Migration
The finding that mitogens such as PDGF lead to increased synthesis of versican suggests that versican may play a role in regulating ASMC proliferation7 (Figure 3). For example, molecules that associate with versican such as hyaluronan,105 CD44,116 and TSG-6117 are also upregulated during arterial ASMC proliferation. Versican interacts with hyaluronan and accumulates in the pericellular matrix when ASMCs are stimulated to proliferate and migrate104 (Figure 4). These changes create a viscoelastic coat around the cells that expands as ASMCs are stimulated to proliferate and migrate (Figure 4). Thus, versican-hyaluronan–rich ECM around the ASMCs allows the cells to change shape to prepare them for proliferation and migration (Figure 4). Blocking the formation of the versican-hyaluronan pericellular coat, either by blocking antibodies to the hyaluronan receptors such as RHAMM,118 or using short oligosaccharides of hyaluronan, blocks PDGF induced proliferation of ASMCs.104 Thus, it would appear that a versican enriched pericellular environment is needed for the proliferative phenotype (Figures 3 and 4
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Another way in which versican could promote vascular cell proliferation is by acting as a mitogen itself through the EGF sequences in the G3 domain. For example, overexpression of G3 minigenes of versican enhances cell proliferation,119,120 and this effect is due to the EGF sequences in the G3 domain. Such studies point to the potential importance of versican fragments or degradation products controlling cell phenotype. It remains to be seen if this portion of versican is mitogenic for vascular cells.
Because versican is a large hygroscopic molecule, it functions as an antiadhesive molecule121 through interactions with hyaluronan at the cell surface or with annexin 6.122 The importance of versican in controlling cell adhesion and cell shape is highlighted by studies where versican isoforms have been overexpressed. For example, overexpression of V3 versican, which lacks CS chains, by retroviral transduction in ASMCs, promotes adhesion, a flattening of the cells, an increase in close contacts, a decrease in cell detachment in response to trypsin, a reduction of pericellular coats, and inhibition of growth and migration.123 It is hypothesized that the effects of V3 expression on these phenotypic traits are the result of competition for binding sites for V1 versican on hyaluronan associated with the cell surface. Indeed, V3 overexpressing ASMCs have less CS associated with their cell surface than controls (M. Merrilees, A. Hinek, and T. Wight, unpublished observations, 2004). Although it appears that the CS chains are somehow involved in the proliferative phenotype, the mechanism(s) by which versican influences cell proliferation is still not known.
Role in ECM Assembly
ECM remodeling takes place throughout the different phases of atherosclerosis and restenosis as part of an injury and inflammatory response. Theses phases involve breakdown and disassembly of various ECM components and reassembly of particular components as part of the pathogenesis of these diseases. The sequence of changes is not unlike what is seen during wound repair in which the early ECM changes are characterized by ECM deposits that create a loose, open, and watery matrix (referred to as a "provisional ECM"124,125), which allows for cellular invasion and repair. This provisional matrix is then replaced by a more fibrous ECM enriched in collagens and assorted glycoproteins. What is conspicuously absent in this newly remodeled ECM is elastic fibers. In fact, elastic fibers are conspicuously absent from atherosclerotic and restenotic lesions. The importance of elastic fibers in regulating intimal hyperplasia is highlighted by studies of the elastin knockout mouse. Disruption of elastin synthesis by targeting the promoter and first exon of the tropoelastin gene126 leads to subendothelial proliferation of ASMCs and obstructive vascular disease. More recently, cells from the elastin knockout animals have been shown to proliferate more rapidly than their normal littermate cells in vitro but normal proliferation is restored on addition of elastin to the knockout cells.127,128 Elastin peptides have been shown also to regulate ASMC proliferation and migration.129 In fact, elastin has been used to dampen the restenotic response in experimental animals.128 Thus, factors regulating elastic fiber formation may be critical to controlling vascular lesion formation. One factor that appears to inhibit elastic fiber assembly is CS, which is part of the versican molecule.130 We have found that overexpression of the versican variant that lacks CS in ASMCs leads to changes in tropoelastin expression and accumulation of elastic fibers in long term cultures.131 Furthermore, when these transduced cells are seeded into balloon injured rat carotid arteries, a compact and highly structured neointima enriched in elastic lamellae develops.
The mechanism by which versican V3 influences tropoelastin expression and formation of elastic fibers is not known but several studies point to an important relationship between regulation of the larger parent CS containing forms of versican and elastin production and assembly. Neonatal ASMCs express little or no versican but express high levels of tropoelastin102,132 and form elastic fibers in vitro.133 Conversely, elastic fibers are depleted in tissues where versican levels are elevated such as in restenotic arterial lesions96 or in the intimal cushions of the ductus arteriosus.130 Such studies suggest that versican inhibits elastic fiber assembly. Although the mechanism(s) for this activity is not known, it is of interest that recent experiments have used V3 transduction of cells taken from patients exhibiting defective elastogenesis to reverse their phenotype and correct the impaired elastogenic phenotype, by influencing an elastin binding protein (EBP) associated with the surface of these cells.134
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Is Versican the Culprit? |
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TopAbstractIntroductionVersican in Normal Blood...Versican in Atherosclerosis and...Regulated Synthesis of Versican...Is Versican the Culprit?References |
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Versican, with its unique structure and multiple interactions, is one of several proteoglycans that contribute to the pathogenesis of vascular disease. It is well placed to play a central role in the control or modulation of key events in atherogenesis and restenosis. Although further evidence is required to confirm causative roles for versican, there is sufficient evidence to place it at the center of many key processes in vascular pathology. In moderate amounts, and in association with hyaluronan, versican provides a hydrated viscoelastic ECM able to accommodate cyclic mechanical forces imposed on vessels. Elevated levels, however, shift the balance in favor of pathological changes. Increased amounts, especially in the intima, contribute physically to increased intimal thickness and to creation of a pericellular and extracellular matrix that supports cell migration and proliferation and inflammatory cell adhesion. Concomitantly, versican enrichment of the pericellular matrix decreases residence time for cell-associated receptors involved in ECM assembly, such as EBP, thereby decreasing elastic fiber assembly and influencing arterial smooth muscle cell proliferation and the mechanical properties of the expanding intima. Most damaging, however, is alteration in the chondroitin sulfate chains of versican, caused by specific growth factors and cytokines that results in increased retention of lipoproteins and accumulation of lipoproteins. Finally, the presence of versican at the plaque thrombus interface implicates this ECM component in one of the final phases of atherosclerosis, vessel occlusion. This encompassing hypothesis has yet to be tested but accumulating evidence strongly suggests that versican is a key molecule in atherosclerosis and restenosis and a potential target for therapeutic intervention. Unfortunately, a versican knockout is lethal due to failure of heart and blood vessels to develop normally.135 Therefore, future directions will be to develop molecular genetic models in which the expression of versican and its variants can be selectively controlled so that the impact of removing this component from the developing atherosclerotic plaque can be assessed directly and the molecular mechanisms responsible for the effects on vascular cell phenotype ascertained.
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Acknowledgments |
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This review was prepared with grant support from the National Heart, Lung, and Blood Institute (HL-18645) of the National Institutes of Health, the National Science Foundation (EEC-9529161), the Marsden Fund of the Royal Society of New Zealand, and the National Heart Foundation of New Zealand. The authors would like to thank Drs Michael Kinsella and Susan Potter-Perigo for helpful discussions and assistance in construction of the figures. We would also like to thank all the members of our laboratories, past and present, who have worked so very hard to unravel the many mysteries of this fascinating molecule. The authors would also like to thank Ellen Briggs for her careful editing and preparation of this manuscript.
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Footnotes |
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Original received August 6, 2003; resubmission received January 7, 2004; second resubmission received March 15, 2004; accepted March 18, 2004.
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References |
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TopAbstractIntroductionVersican in Normal Blood...Versican in Atherosclerosis and...Regulated Synthesis of Versican...Is Versican the Culprit?References |
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1. Yao LY, Moody C, Schönherr E, Wight TN, Sandell LJ. Identification of the proteoglycan versican in aorta and smooth muscle cells by DNA sequence analysis, in situ hybridization and immunohistochemistry. Matrix Biol. 1994; 14: 213–225.[CrossRef][Medline] [Order article via Infotrieve]
2. Wight T. The vascular extracellular matrix. In: Fuster V, Topol E, Nabel E, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Pa: Lippincott Williams and Wilkins. In press.
3. Järveläinen H, Wight T. Vascular proteoglycans. In: Garg H, Roughly P, Hales P, eds. Proteoglycans in Lung Disease. New York, NY: Marcel Dekker; 2002: 291–321.
4. Toole BP, Wight TN, Tammi MI. Hyaluronan-cell interactions in cancer and vascular disease. J Biol Chem. 2002; 277: 4593–4596.
5. Zimmermann DR, Ruoslahti E. Multiple domains of the large fibroblast proteoglycan, versican. EMBO J. 1989; 8: 2975–2981.[Medline] [Order article via Infotrieve]
6. Ito K, Shinomura T, Zako M, Ujita M, Kimata K. Multiple forms of mouse PG-M, a large chondroitin sulfate proteoglycan generated by alternative splicing. J Biol Chem. 1995; 270: 958–965.
7. Wight TN. Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol. 2002; 14: 617–623.[CrossRef][Medline] [Order article via Infotrieve]
8. Naso MF, Zimmermann DR, Iozzo RV. Characterization of the complete genomic structure of the human versican gene and functional analysis of its promoter. J Biol Chem. 1994; 269: 32999–33008.
9. Schönherr E, Järveläinen HT, Sandell LJ, Wight TN. Effects of platelet-derived growth factor and transforming growth factor-ß1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells. J Biol Chem. 1991; 266: 17640–17647.
10. Theocharis AD, Tsolakis I, Hjerpe A, Karamanos NK. Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V0. Atherosclerosis. 2001; 154: 367–376.[CrossRef][Medline] [Order article via Infotrieve]
11. Merrilees MJ, Beaumont B, Scott LJ. Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries: correlation to patency. Coron Artery Dis. 2001; 12: 7–16.[CrossRef][Medline] [Order article via Infotrieve]
12. Stary HC. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J. 1990; 11 (suppl E): 3–19.
13. Radhakrishnamurthy B, Jeansonne N, Tracy RE, Berenson GS. A monoclonal antibody that recognizes hyaluronic acid binding region of aorta proteoglycans. Atherosclerosis. 1993; 98: 179–192.[CrossRef][Medline] [Order article via Infotrieve]
14. Levesque H, Girard N, Maingonnat C, Delpech A, Chauzy C, Tayot J, Courtois H, Delpech B. Localization and solubilization of hyaluronan and of the hyaluronan-binding protein hyaluronectin in human normal and arteriosclerotic arterial walls. Atherosclerosis. 1994; 105: 51–62.[CrossRef][Medline] [Order article via Infotrieve]
15. Binette F, Cravens J, Kahoussi B, Haudenschild DR, Goetinck PF. Link protein is ubiquitously expressed in non-cartilaginous tissues where it enhances and stabilizes the interaction of proteoglycans with hyaluronic acid. J Biol Chem. 1994; 269: 19116–19122.
16. Comper WD, Laurent TC. Physiological function of connective tissue polysaccharides. Physiol Rev. 1978; 58: 255–315.
17. Comper WD, Zamparo O. Hydrodynamic properties of connective-tissue polysaccharides. Biochem J. 1990; 269: 561–564.[Medline] [Order article via Infotrieve]
18. Oegema TR, Hascall VC, Eisenstein R. Characterization of bovine aorta proteoglycan extracted with guanidine hydrochloride in the presence of protease inhibitors. J Biol Chem. 1979; 254: 1312–1318.
19. Kapoor R, Phelps CF, Wight TN. Physical properties of chondroitin sulphate/dermatan sulphate proteoglycans from bovine aorta. Biochem J. 1986; 240: 575–583.[Medline] [Order article via Infotrieve]
20. Salisbury BGJ, Wagner WD. Isolation and preliminary characterization of proteoglycans dissociatively extracted form human aorta. J Biol Chem. 1981; 256: 8050–8057.
21. Wight TN, Hascall VC. Proteoglycans in primate arteries, III: characterization of the proteoglycans synthesized by arterial smooth muscle cells in culture. J Cell Biol. 1983; 96: 167–176.
22. Chang Y, Yanagishita M, Hascall VC, Wight TN. Proteoglycans synthesized by smooth muscle cells derived from monkey (Macaca nemestrina) aorta. J Biol Chem. 1983; 258: 5679–5688.
23. Sandy JD, Westling J, Kenagy RD, Iruela-Arispe ML, Verscharen C, Rodriguez-Mazaneque JC, Zimmermann DR, Lemire JM, Fischer JW, Wight TN, Clowes AW. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem. 2001; 276: 13372–13378.
24. Somerville RP, Longpre JM, Jungers KA, Engle JM, Ross M, Evanko S, Wight TN, Leduc R, Apte SS. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem. 2003; 278: 9503–9513.
25. Halpert I, Sires U, Potter-Perigo S, Wight TN, Shapiro DS, Welgus HG, Wickline SA, Parks WC. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localized to areas of versican deposits. Proc Natl Acad Sci U S A. 1996; 93: 9748–9753.
26. Kenagy RD, Fischer JW, Davies MG, Berceli SA, Hawkins SM, Wight TN, Clowes AW. Increased plasmin and serine proteinase activity during flow-induced intimal atrophy in baboon PTFE grafts. Arterioscler Thromb Vasc Biol. 2002; 22: 400–404.
27. Gutierrez P, O’Brien KD, Ferguson M, Nikkari ST, Alpers CE, Wight TN. Differences in the distribution of versican, decorin, and biglycan in atherosclerotic human coronary arteries. Cardiovasc Pathol. 1997; 6: 271–278.[CrossRef]
28. Lin H, Wilson JE, Roberts CR, Horley KJ, Winters GL, Costanzo MR, McManus BM. Biglycan, decorin and versican protein expression patterns in coronary arteriopathy of human cardiac allograft: distinctness as compared to native atherosclerosis. J Heart Lung Transplant. 1996; 15: 1233–1247.[Medline] [Order article via Infotrieve]
29. Lin H, Ignatescu M, Wilson JE, Roberts CR, Horley KJ, Winters GL, Costanzo MR, McManus BM. Prominence of apolipoproteins B, (a), and E in the intimae of coronary arteries in transplanted human hearts: geographic relationship to vessel wall proteoglycans. J Heart Lung Transplant. 1996; 15: 1223–1232.[Medline] [Order article via Infotrieve]
30. Evanko S, Raines EW, Ross R, Gold LI, Wight TN. Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics and the proximity of PDGF and TGF-ß1. Am J Pathol. 1998; 152: 533–546.[Abstract]
31. O’Brien KD, Olin KL, Alpers CE, Chiu W, Ferguson M, Hudkins K, Wight TN, Chait A. A comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: co-localization of biglycan with apolipoproteins. Circulation. 1998; 98: 519–527.
32. Kolodgie FD, Burke AP, Farb A, Weber DK, Kutys R, Wight TN, Virmani R. Differential accumulation of proteoglycans and hyaluronan in culprit lesions: insights into plaque erosion. Arterioscler Thromb Vasc Biol. 2002; 22: 1642–1648.
33. Luttun A, Lupu F, Storkebaum E, Hoylaerts MF, Moons L, Crawley J, Bono F, Poole AR, Tipping P, Herbert JM, Collen D, Carmeliet P. Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2002; 22: 499–505.
34. Geary RL, Wong JM, Rossini A, Schwartz SM, Adams LD. Expression profiling identifies 147 genes contributing to a unique primate neointimal smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol. 2002; 22: 2010–2016.
35. Wagner WD, Salisbury GJ, Rowe HA. A proposed structure of chondroitin 6-sulfate proteoglycan of human normal and adjacent atherosclerotic plaque. Arteriosclerosis. 1986; 6: 407–417.
36. Dalferes ER Jr, Radhakrishnamurthy B, Ruiz HA, Berenson GS. Composition of proteoglycans from human atherosclerotic lesions. Exp Mol Pathol. 1987; 47: 363–376.[CrossRef][Medline] [Order article via Infotrieve]
37. Cherchi GM, Coinu R, Demuro P, Formato M, Sanna G, Tidore M, Tira ME, De Luca G. Structural and functional modifications of human aorta proteoglycans in atherosclerosis. Matrix. 1990; 10: 362–372.[Medline] [Order article via Infotrieve]
38. Coinu R, Cherchi G, Formato M, Demuro P, De Luca G. LDL interaction with proteoglycans isolated from human aortas with different atherosclerotic involvement. Haematologica. 1993; 78: 270–276.[Medline] [Order article via Infotrieve]
39. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995; 15: 551–561.
40. Srinivasan SR, Lopez A, Radhakrishnamurthy B, Berenson GS. Complexing of serum pre-ß and ß-lipoproteins and acid mucopolysaccharides. Atherosclerosis. 1970; 12: 321–334.[CrossRef][Medline] [Order article via Infotrieve]
41. Berenson GS, Radhakrishnamurthy B, Dalferes ER Jr, Srinivasan SR. Carbohydrate macromolecules and atherosclerosis. Hum Pathol. 1971; 2: 57–79.[Medline] [Order article via Infotrieve]
42. Hollander W. Unified concept on the role of acid mucopolysaccharides and connective tissue proteins in the accumulation of lipids, lipoproteins, and calcium in the atherosclerotic plaque. Exp Mol Pathol. 1976; 25: 106–120.[CrossRef][Medline] [Order article via Infotrieve]
43. Camejo G, Lalaguna F, Lopez F, Starosta R. Characterization and properties of a lipoprotein-complexing proteoglycan from human aorta. Atherosclerosis. 1980; 35: 307–320.[CrossRef][Medline] [Order article via Infotrieve]
44. Vijayagopal P, Srinivasan SR, Radhakrishnamurthy B, Berenson GS. Interaction of serum lipoproteins and a proteoglycan from bovine aorta. J Biol Chem. 1981; 256: 8234–8241.
45. Shi Y, Niculescu R, Wang D, Ormont M, Magno M, San Antonio JD, Williams KJ, Zalewski A. Myofibroblast involvement in glycosaminoglycan synthesis and lipid retention during coronary repair. J Vasc Res. 2000; 37: 399–407.[CrossRef][Medline] [Order article via Infotrieve]
46. Shi Y, Patel S, Davenpeck KL, Niculescu R, Rodriguez E, Magno MG, Ormont ML, Mannion JD, Zalewski A. Oxidative stress and lipid retention in vascular grafts: comparison between venous and arterial conduits. Circulation. 2001; 103: 2408–2413.
47. Srinivasan SR, Radhakrishnamurthy B, Pargaonkar PS, Berenson GS, Dolan P. Lipoprotein-acid mucopolysaccharide complexes of human atherosclerotic lesions. Biochim Biophys Acta. 1975; 388: 58–70.[Medline] [Order article via Infotrieve]
48. Srinivasan SR, Vijayagopal P, Eberle K, Radhakrishnamurthy B, Berenson GS. Low-density lipoprotein binding affinity of arterial wall proteoglycans: characteristics of a chondroitin sulfate proteoglycan subfraction. Biochim Biophys Acta. 1989; 1006: 159–166.[Medline] [Order article via Infotrieve]
49. Vijayagopal P, Figueroa JE, Fontenot JD, Glancy DL. Isolation and characterization of a proteoglycan variant from human aorta exhibiting a marked affinity for low density lipoprotein and demonstration of its enhanced expression in atherosclerotic plaques. Atherosclerosis. 1996; 127: 195–203.[CrossRef][Medline] [Order article via Infotrieve]
50. Anber V, Griffin BA, McConnell M, Packard CJ, Shepherd J. Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans. Atherosclerosis. 1996; 124: 261–271.[CrossRef][Medline] [Order article via Infotrieve]
51. Srinivasan SR, Xu JH, Vijayagopal P, Radhakrishnamurthy B, Berenson GS. Injury to the arterial wall of rabbits produces proteoglycan variants with enhanced low-density lipoprotein-binding property. Biochim Biophys Acta. 1993; 1168: 158–166.[Medline] [Order article via Infotrieve]
52. Camejo G, Fager G, Rosengren B, Hurt-Camejo E, Bondjers G. Binding of low density lipoproteins by proteoglycans synthesized by proliferating and quiescent human arterial smooth muscle cells. J Biol Chem. 1993; 268: 14131–14137.
53. Chang MY, Potter-Perigo S, Tsoi C, Chait A, Wight TN. Oxidized low density lipoproteins regulate synthesis of monkey aortic smooth muscle cell proteoglycans that have enhanced native low density lipoprotein binding properties. J Biol Chem. 2000; 275: 4766–4773.
54. Little PJ, Tannock L, Olin KL, Chait A, Wight TN. Proteoglycans synthesized by arterial smooth muscle cells in the presence of transforming growth factor-ß1 exhibit increased binding to LDLs. Arterioscler Thromb Vasc Biol. 2002; 22: 55–60.
55. Olsson U, Bondjers G, Camejo G. Fatty acids modulate the composition of extracellular matrix in cultured human arterial smooth muscle cells by altering the expression of genes for proteoglycan core proteins. Diabetes. 1999; 48: 616–622.[Abstract]
56. Borén J, Olin K, Lee I, Chait A, Wight TN, Innerarity TL. Identification of a principal proteoglycan binding site in LDL: a single point mutation in apo B-100 severely affects proteoglycan interaction without affecting LDL receptor binding. J Clin Invest. 1998; 101: 2658–2664.[Medline] [Order article via Infotrieve]
57. Olin KL, Potter-Perigo S, Barrett PH, Wight TN, Chait A. Lipoprotein lipase enhances the binding of native and oxidized low density lipoproteins to versican and biglycan synthesized by cultured arterial smooth muscle cells. J Biol Chem. 1999; 274: 34629–34636.
58. Cardoso LEM, Mourão PAS. Glycosaminoglycan fractions from human arteries presenting diverse susceptibilities to atherosclerosis have different binding affinities to plasma LDL. Arterioscler Thromb. 1994; 14: 115–124.
59. Sambandam T, Baker JR, Christner JE, Ekborg SL. Specificity of the low density lipoprotein-glycosaminoglycan interaction. Arterioscler Thromb. 1991; 11: 561–568.
60. Kunjathoor VV, Chiu DS, O’Brien KD, LeBoeuf RC. Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis. Arterioscler Thromb Vasc Biol. 2002; 22: 462–468.
61. Stefanovich V, Akiyama K. Comparative studies of aortic acid mucopolysaccharides in fifteen species. Comp Biochem Physiol. 1970; 34: 125–130.[Medline] [Order article via Infotrieve]
62. Gardais A, Picard J, Hermelin B. Glycosaminoglycan (GAG) distribution in aortic wall from five species. Comp Biochem Physiol B. 1973; 44: 507–515.[CrossRef][Medline] [Order article via Infotrieve]
63. Flood C, Gustafsson M, Richardson PE, Harvey SC, Segrest JP, Boren J. Identification of the proteoglycan binding site in apolipoprotein B48. J Biol Chem. 2002; 277: 32228–32233.
64. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417: 750–754.[CrossRef][Medline] [Order article via Infotrieve]
65. Hurt-Camejo E, Camejo G, Rosengren B, Lopez F, Ahlstrom C, Fager G, Bondjers G. Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. Arterioscler Thromb. 1992; 12: 569–583.
66. Hurt-Camejo E, Camejo G, Peilot H, Oorni K, Kovanen P. Phospholipase A2 in vascular disease. Circ Res. 2001; 89: 298–304.
67. Camejo G, Hurt-Camejo E, Wiklund O, Bondjers G. Association of apoB lipoproteins with arterial proteoglycans: pathological significance and molecular basis. Atherosclerosis. 1998; 139: 205–222.[CrossRef][Medline] [Order article via Infotrieve]
68. Vijayagopal P. Regulation of the metabolism of lipoprotein-proteoglycan complexes in human monocyte-derived macrophages. Biochem J. 1994; 301: 675–681.[Medline] [Order article via Infotrieve]
69. Ismail NA, Alavi MZ, Moore S. Lipoprotein-proteoglycan complexes from injured rabbit aortas accelerate lipoprotein uptake by arterial smooth muscle cells. Atherosclerosis. 1994; 105: 79–87.[CrossRef][Medline] [Order article via Infotrieve]
70. Llorente-Cortes V, Otero-Vinas M, Hurt-Camejo E, Martinez-Gonzalez J, Badimon L. Human coronary smooth muscle cells internalize versican-modified LDL through LDL receptor-related protein and LDL receptors. Arterioscler Thromb Vasc Biol. 2002; 22: 387–393.
71. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
72. de la Motte CA, Hascall VC, Calabro A, Yen-Lieberman B, Strong SA. Mononuclear leukocytes preferentially bind via CD44 to hyaluronan on human intestinal mucosal smooth muscle cells after virus infection or treatment with poly(I.C). J Biol Chem. 1999; 274: 30747–30755.
73. Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas AH, Miyasaka M. Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. J Biol Chem. 2000; 275: 35448–35456.
74. de la Motte C, Hascall V, Drazba J, Strong S. Poly I:C induces mononuclear leukocyte-adhesive hyaluronan structures on colon smooth muscle cells: II and versican facilitate adhesion. In: Kennedy JF, Phillips GO, Williams PA, Hascall VC, eds. Hyaluronan. Volume 1. Chemical, Biochemical and Biological Aspects. Cambridge, UK: Woodhead Publishing Limited; 2002: 381–388.
75. de la Motte CA, Hascall VC, Drazba J, Bandyopadhyay SK, Strong SA. Mononuclear leukocytes bind to specific hyaluronan structures on colon mucosal smooth muscle cells treated with polyinosinic acid:polycytidylic acid: inter--trypsin inhibitor is crucial to structure and function. Am J Pathol. 2003; 163: 121–133.
76. Kawashima H, Li YF, Watanabe N, Hirose J, Hirose M, Miyasaka M. Identification and characterization of ligands for L-selectin in the kidney, I: versican, a large chondroitin sulfate proteoglycan, is a ligand for L-selectin. Int Immunol. 1999; 11: 393–405.
77. Kawashima H, Atarashi K, Hirose M, Hirose J, Yamada S, Sugahara K, Miyasaka M. Oversulfated chondroitin/dermatan sulfates containing GlcAß1/IdoA1–3GalNAc(4,6-O-disulfate) interact with L- and P-selectin and chemokines. J Biol Chem. 2002; 277: 12921–12930.
78. Hirose J, Kawashima H, Yoshie O, Tashiro K, Miyasaka M. Versican interacts with chemokines and modulates cellular responses. J Biol Chem. 2001; 276: 5228–5234.
79. Hurt-Camejo E, Rosengren B, Sartipy P, Elfsberg K, Camejo G, Svensson L. CD44, a cell surface chondroitin sulfate proteoglycan, mediates binding of interferon- and some of its biological effects on human vascular smooth muscle cells. J Biol Chem. 1999; 274: 18957–18964.
80. Mazzucato M, Cozzi MR, Pradella P, Perissinotto D, Malmstrom A, Morgelin M, Spessotto P, Colombatti A, De Marco L, Perris R. Vascular PG-M/versican variants promote platelet adhesion at low shear rates and cooperate with collagens to induce aggregation. FASEB J. 2002; 16: 1903–1916.
81. Koshiishi I, Shizari M, Underhill CB. CD44 can mediate the adhesion of platelets to hyaluronan. Blood. 1994; 84: 390–396.
82. McGee M, Wagner WD. Chondroitin sulfate anticoagulant activity is linked to water transfer: relevance to proteoglycan structure in atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23: 1921–1927.
83. Ernst CB. Abdominal aortic aneurysm. N Engl J Med. 1993; 328: 1167–1172.
84. Lijnen HR. Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost. 2001; 86: 324–333.[Medline] [Order article via Infotrieve]
85. Lindholt JS, Jorgensen B, Fasting H, Henneberg EW. Plasma levels of plasmin-antiplasmin-complexes are predictive for small abdominal aortic aneurysms expanding to operation-recommendable sizes. J Vasc Surg. 2001; 34: 611–615.[CrossRef][Medline] [Order article via Infotrieve]
86. Burke AP, Jarvelainen H, Kolodgie FD, Goel A, Wight TN, Virmani R. Superficial pseudoaneurysms: clinicopathologic aspects and involvement of extracellular matrix proteoglycans. Mod Pathol. 2004; 17: 482–488.[CrossRef][Medline] [Order article via Infotrieve]
87. Melrose J, Whitelock J, Xu Q, Ghosh P. Pathogenesis of abdominal aortic aneurysms: possible role of differential production of proteoglycans by smooth muscle cells. J Vasc Surg. 1998; 28: 676–686.[CrossRef][Medline] [Order article via Infotrieve]
88. Guo D, Hasham S, Kuang SQ, Vaughan CJ, Boerwinkle E, Chen H, Abuelo D, Dietz HC, Basson CT, Shete SS, Milewicz DM. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation. 2001; 103: 2461–2468.
89. Iozzo RV, Naso MF, Cannizzaro LA, Wasmuth JJ, McPherson JD. Mapping of the versican proteoglycan gene (CSPG2) to the long arm of human chromosome 5 (5q12-5q14). Genomics. 1992; 14: 845–851.[CrossRef][Medline] [Order article via Infotrieve]
90. Wolf YG, Rasmussen LM, Ruoslahti E. Antibodies against transforming growth factor-ß1 suppress intimal hyperplasia in a rat model. J Clin Invest. 1994; 93: 1172–1178.[Medline] [Order article via Infotrieve]
91. Nikkari ST, Järveläinen HT, Wight TN, Ferguson M, Clowes AW. Smooth muscle cell expression of extracellular matrix genes after arterial injury. Am J Pathol. 1994; 144: 1348–1356.[Abstract]
92. Merrilees M, Beaumont B, Scott L, Hermanutz V, Fennessy P. Effect of TGF-ß1 antisense S-oligonucleotide on synthesis and accumulation of matrix proteoglycans in balloon catheter-injured neointima of rabbit carotid arteries. J Vasc Res. 2000; 37: 50–60.[CrossRef][Medline] [Order article via Infotrieve]
93. Geary RL, Nikkari ST, Wagner WD, Williams JK, Adams MR, Dean RH. Wound healing: a paradigm for lumen narrowing after arterial reconstruction. J Vasc Surg. 1998; 27: 96–106.[CrossRef][Medline] [Order article via Infotrieve]
94. Finn AV, Gold HK, Tang A, Weber DK, Wight TN, Clermont A, Virmani R, Kolodgie FD. A novel rat model of carotid artery stenting for the understanding of restenosis in metabolic diseases. J Vasc Res. 2002; 39: 414–425.[CrossRef][Medline] [Order article via Infotrieve]
95. Matsuura R, Isaka N, Imanaka-Yoshida K, Yoshida T, Sakakura T, Nakano T. Deposition of PG-M/versican is a major cause of human coronary restenosis after percutaneous transluminal coronary angioplasty. J Pathol. 1996; 180: 311–316.[CrossRef][Medline] [Order article via Infotrieve]
96. Wight TN, Lara S, Reissen R, LeBaron R, Isner J. Selective deposits of versican in the extracellular matrix of restenotic lesions from human peripheral arteries. Am J Pathol. 1997; 151: 963–973.[Abstract]
97. Chung IM, Gold HK, Schwartz SM, Ikari Y, Reidy MA, Wight TN. Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment. J Am Coll Cardiol. 2002; 40: 2072–2081.
98. Riessen R, Wight TN, Pastore C, Henley C, Isner JM. Distribution of hyaluronan during extracellular matrix remodeling in human restenotic arteries and balloon-injured rat carotid arteries. Circulation. 1996; 93: 1141–1147.
99. Travis JA, Hughes MG, Wong JM, Wagner WD, Geary RL. Hyaluronan enhances contraction of collagen by smooth muscle cells and adventitial fibroblasts: role of CD44 and implications for constrictive remodeling. Circ Res. 2001; 88: 77–83.
100. Asundi V, Cowan K, Matzura D, Wagner W, Dreher KL. Characterization of extracellular matrix proteoglycan transcripts expressed by vascular smooth muscle cells. Eur J Cell Biol. 1990; 52: 98–104.[Medline] [Order article via Infotrieve]
101. Schönherr E, Kinsella MG, Wight TN. Genistein selectively inhibits platelet-derived growth factor stimulated versican biosynthesis in monkey arterial smooth muscle cells. Arch Biochem Biophys. 1997; 339: 353–361.[CrossRef][Medline] [Order article via Infotrieve]
102. Lemire JM, Potter-Perigo S, Hall KL, Wight TN, Schwartz SM. Distinct rat aortic smooth muscle cells differ in versican/PG-M expression. Arterioscler Thromb Vasc Biol. 1996; 16: 821–829.
103. Lemire JM, Braun KR, Maurel P, Kaplan ED, Schwartz SM, Wight TN. Versican/PG-M isoforms in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999; 19: 1630–1639.
104. Evanko SP, Angello JC, Wight TN. Formation of hyaluronan and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999; 19: 1004–1013.
105. Evanko SP, Johnson PY, Braun KR, Underhill CB, Dudhia J, Wight TN. Platelet-derived growth factor stimulates the formation of versican-hyaluronan aggregates and pericellular matrix expansion in arterial smooth muscle cells. Arch Biochem Biophys. 2001; 394: 29–38.[CrossRef][Medline] [Order article via Infotrieve]
106. Lee RT, Yamamoto C, Feng Y, Potter-Perigo S, Briggs WH, Landschulz KT, Turi TG, Thompson JF, Libby P, Wight TN. Mechanical strain induces specific changes in the synthesis and organization of proteoglycans by vascular smooth muscle cells. J Biol Chem. 2001; 276: 13847–13851.
107. Morita H, Takeuchi T, Suzuki S, Maeda K, Yamada K, Eguchi G, Kimata K. Aortic endothelial cells synthesize a large chondroitin sulfate proteoglycan capable of binding to hyaluronate. Biochem J. 1990; 265: 61–68.[Medline] [Order article via Infotrieve]
108. Kinsella MG, Tsoi CK, Järveläinen HT, Wight TN. Selective expression and processing of biglycan during migration of bovine aortic endothelial cells: the role of endogenous basic fibroblast growth factor. J Biol Chem. 1997; 272: 318–325.
109. Kaji T, Yamada A, Miyajima S, Yamamoto C, Fujiwara Y, Wight TN, Kinsella MG. Cell density-dependent regulation of proteoglycan synthesis by transforming growth factor-ß1 in cultured bovine aortic endothelial cells. J Biol Chem. 2000; 275: 1463–1470.
110. Cattaruzza S, Schiappacassi M, Ljungberg-Rose A, Spessotto P, Perissinotto D, Morgelin M, Mucignat MT, Colombatti A, Perris R. Distribution of PG-M/versican variants in human tissues and de novo expression of isoform V3 upon endothelial cell activation, migration, and neoangiogenesis in vitro. J Biol Chem. 2002; 277: 47626–47635.
111. Schönherr E, Järveläinen HT, Kinsella MG, Sandell LJ, Wight TN. Platelet-derived growth factor and transforming growth factor-ß1 differentially affect the synthesis of biglycan and decorin by monkey arterial smooth muscle cells. Arterioscler Thromb. 1993; 13: 1026–1036.
112. Shimizu-Hirota R, Sasamura H, Mifune M, Nakaya H, Kuroda M, Hayashi M, Saruta T. Regulation of vascular proteoglycan synthesis by angiotensin II type 1 and type 2 receptors. J Am Soc Nephrol. 2001; 12: 2609–2615.
113. Potter-Perigo S, Baker C, Tsoi C, Braun K, Isenhath S, Altman G, Altman L, Wight T. Regulation of proteoglycan synthesis by leukotriene D4 and EGF in bronchial smooth muscle cells. Am J Respir Cell Mol Biol. 2004; 30: 101–108.
114. Edwards IJ, Wagner WD, Owens RT. Macrophage secretory products selectively stimulate dermatan sulfate proteoglycan production in cultured arterial smooth muscle cells. Am J Pathol. 1990; 136: 609–621.[Abstract]
115. Ostberg CO, Zhu P, Wight TN, Qwarnstrom EE. Fibronectin attachment is permissive for IL-1 mediated gene regulation. FEBS Lett. 1995; 367: 93–97.[CrossRef][Medline] [Order article via Infotrieve]
116. Jain M, He Q, Lee WS, Kashiki S, Foster LC, Tsai JC, Lee ME, Haber E. Role of CD44 in the reaction of vascular smooth muscle cells to arterial wall injury. J Clin Invest. 1996; 97: 596–603[published erratum in J Clin Invest. 1996;98:877].[Medline] [Order article via Infotrieve]
117. Ye L, Mora R, Akhayani N, Haudenschild CC, Liau G. Growth factor and cytokine-regulated hyaluronan-binding protein TSG-6 is localized to the injury-induced rat neointima and confers enhanced growth in vascular smooth muscle cells. Circ Res. 1997; 81: 289–296.
118. Savani RC, Wang C, Yang B, Zhang S, Kinsella MG, Wight TN, Stern R, Nance DM, Turley EA. Migration of bovine aortic smooth muscle cells after wounding injury: the role of hyaluronan and RHAMM. J Clin Invest. 1995; 95: 1158–1168.[Medline] [Order article via Infotrieve]
119. Wu Y, Zhang Y, Cao L, Chen L, Lee V, Zheng PS, Kiani C, Adams ME, Ang LC, Paiwand F, Yang BB. Identification of the motif in versican G3 domain that plays a dominant-negative effect on astrocytoma cell proliferation through inhibiting versican secretion and binding. J Biol Chem. 2001; 276: 14178–14186.
120. Zhang Y, Cao L, Yang BL, Yang BB. The G3 domain of versican enhances cell proliferation via epidermal growth factor-like motifs. J Biol Chem. 1998; 273: 21342–21351.
121. Yamagata M, Suzuki S, Akiyama SK, Yamada KM, Kimata K. Regulation of cell-substrate adhesion by proteoglycans immobilized on extracellular substrates. J Biol Chem. 1989; 264: 8012–8018.
122. Takagi H, Asano Y, Yamakawa N, Matsumoto I, Kimata K. Annexin 6 is a putative cell surface receptor for chondroitin sulfate chains. J Cell Sci. 2002; 115: 3309–3318.
123. Lemire JM, Merrilees MJ, Braun KR, Wight TN. Overexpression of the V3 variant of versican alters arterial smooth muscle cell adhesion, migration, and proliferation in vitro. J Cell Physiol. 2002; 190: 38–45.[CrossRef][Medline] [Order article via Infotrieve]
124. Clark RAF, Henson PM. The Molecular and Cellular Biology of Wound Repair. New York, NY: Plenum Press; 1988.
125. Clark RAF, Quinn JH, Winn HJ, Lanigan JM, Dellepella P, Colvin RB. Fibronectin is produced by blood vessels in response to injury. J Exp Med. 1982; 156: 646–651.
126. Li DY, Brooke B, Davis EC, Mecham RP, Sorensen LK, Boak BB, Eichwald E, Keating MT. Elastin is an essential determinant of arterial morphogenesis. Nature. 1998; 393: 276–280.[CrossRef][Medline] [Order article via Infotrieve]
127. Brooke BS, Karnik SK, Li DY. Extracellular matrix in vascular morphogenesis and disease: structure versus signal. Trends Cell Biol. 2003; 13: 51–56.[CrossRef][Medline] [Order article via Infotrieve]
128. Karnik SK, Brooke BS, Bayes-Genis A, Sorensen L, Wythe JD, Schwartz RS, Keating MT, Li DY. A critical role for elastin signaling in vascular morphogenesis and disease. Development. 2003; 130: 411–423.
129. Mochizuki S, Brassart B, Hinek A. Signaling pathways transduced through elastin receptor facilitate proliferation and motility of arterial smooth muscle cells. J Biol Chem. 2002; 277: 44854–44863.
130. Hinek A, Mecham RP, Keeley F, Rabinovitch M. Impaired elastin fiber assembly related to reduced 67-kD elastin-binding protein in fetal lamb ductus arteriosus and in cultured aortic smooth muscle cells treated with chondroitin sulfate. J Clin Invest. 1991; 88: 2083–2094.[Medline] [Order article via Infotrieve]
131. Merrilees MJ, Lemire JM, Fischer JW, Kinsella MG, Braun KR, Clowes AW, Wight TN. Retrovirally mediated overexpression of versican V3 by arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury. Circ Res. 2002; 90: 481–487.
132. Lemire JM, Covin CW, White S, Giachelli CM, Schwartz SM. Characterization of cloned aortic smooth muscle cells from young rats. Am J Pathol. 1994; 144: 1068–1081.[Abstract]
133. Faris B, Tan OT, Toselli P, Franzblau C. Long-term neonatal rat aortic smooth muscle cell cultures: a model for the tunica media of a blood vessel. Matrix. 1992; 12: 185–188.[Medline] [Order article via Infotrieve]
134. Hinek A, Braun KR, Liu K, Wang Y, Wight T. Retrovirally mediated overexpression of versican V3 reverses impaired elastogenesis and heightened proliferation exhibited by fibroblasts from Costello syndrome and Hurler disease patients. Am J Pathol. 2004; 164: 119–131.
135. Mjaatvedt CH, Yamamura H, Capehart AA, Turner D, Markwald RR. The Cspg2 gene, disrupted in the HDF mutant, is required for right cardiac chamber and endocardial cushion formation. Dev Biol. 1998; 202: 56–66.[CrossRef][Medline] [Order article via Infotrieve]
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  J. M. Norian, M. Malik, C. Y. Parker, D. Joseph, P. C. Leppert, J. H. Segars, and W. H. Catherino Transforming Growth Factor {beta}3 Regulates the Versican Variants in the Extracellular Matrix-Rich Uterine Leiomyomas Reproductive Sciences, December 1, 2009; 16(12): 1153 - 1164. [Abstract] [PDF]
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 S. Osada, C. Hamada, T. Shimaoka, K. Kaneko, S. Horikoshi, and Y. Tomino Alterations in proteoglycan components and histopathology of the peritoneum in uraemic and peritoneal dialysis (PD) patients Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3504 - 3512. [Abstract] [Full Text] [PDF]
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 R. D. Kenagy, S.-K. Min, A. W. Clowes, and J. D. Sandy Cell Death-associated ADAMTS4 and Versican Degradation in Vascular Tissue J. Histochem. Cytochem., September 1, 2009; 57(9): 889 - 897. [Abstract] [Full Text] [PDF]
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 H. Jarvelainen, A. Sainio, M. Koulu, T. N. Wight, and R. Penttinen Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy Pharmacol. Rev., June 1, 2009; 61(2): 198 - 223. [Abstract] [Full Text] [PDF]
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 J. Zheng, Y. Chen, B. Pat, L. A. Dell'Italia, M. Tillson, A. R. Dillon, P. C. Powell, K. Shi, N. Shah, T. Denney, et al. Microarray Identifies Extensive Downregulation of Noncollagen Extracellular Matrix and Profibrotic Growth Factor Genes in Chronic Isolated Mitral Regurgitation in the Dog Circulation, April 21, 2009; 119(15): 2086 - 2095. [Abstract] [Full Text] [PDF]
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 J. M. Gitlin, J. W. Homeister, J. Bulgrien, J. Counselman, L. K. Curtiss, J. B. Lowe, and W. A. Boisvert Disruption of Tissue-Specific Fucosyltransferase VII, an Enzyme Necessary for Selectin Ligand Synthesis, Suppresses Atherosclerosis in Mice Am. J. Pathol., January 1, 2009; 174(1): 343 - 350. [Abstract] [Full Text] [PDF]
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 S. B. Seidelmann, C. Kuo, N. Pleskac, J. Molina, S. Sayers, R. Li, J. Zhou, P. Johnson, K. Braun, C. Chan, et al. Athsq1 Is an Atherosclerosis Modifier Locus With Dramatic Effects on Lesion Area and Prominent Accumulation of Versican Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2180 - 2186. [Abstract] [Full Text] [PDF]
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 J. A. Wingrove, S. E. Daniels, A. J. Sehnert, W. Tingley, M. R. Elashoff, S. Rosenberg, L. Buellesfeld, E. Grube, L. K. Newby, G. S. Ginsburg, et al. Correlation of Peripheral-Blood Gene Expression With the Extent of Coronary Artery Stenosis Circ Cardiovasc Genet, October 1, 2008; 1(1): 31 - 38. [Abstract] [Full Text] [PDF]
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 D. T. Boll, E. M. Merkle, E. K. Paulson, R. A. Mirza, and T. R. Fleiter Calcified Vascular Plaque Specimens: Assessment with Cardiac Dual-Energy Multidetector CT in Anthropomorphically Moving Heart Phantom Radiology, October 1, 2008; 249(1): 119 - 126. [Abstract] [Full Text] [PDF]
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 N. Itano Simple Primary Structure, Complex Turnover Regulation and Multiple Roles of Hyaluronan J. Biochem., August 1, 2008; 144(2): 131 - 137. [Abstract] [Full Text] [PDF]
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 K. Tran-Lundmark, P.-K. Tran, G. Paulsson-Berne, V. Friden, R. Soininen, K. Tryggvason, T. N. Wight, M. G. Kinsella, J. Boren, and U. Hedin Heparan Sulfate in Perlecan Promotes Mouse Atherosclerosis: Roles in Lipid Permeability, Lipid Retention, and Smooth Muscle Cell Proliferation Circ. Res., July 3, 2008; 103(1): 43 - 52. [Abstract] [Full Text] [PDF]
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L. Zhao, E. Lee, A. M. Zukas, M. K. Middleton, M. Kinder, P. S. Acharya, J. A. Hall, D. J. Rader, and E. Pure CD44 Expressed on Both Bone Marrow-Derived and Non-Bone Marrow-Derived Cells Promotes Atherogenesis in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1283 - 1289. [Abstract] [Full Text] [PDF]
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M. S. Sabatine, L. Ploughman, K. L. Simonsen, O. A. Iakoubova, T. G. Kirchgessner, K. Ranade, Z. Tsuchihashi, K. E. Zerba, D. U. Long, C. H. Tong, et al. Association Between ADAMTS1 Matrix Metalloproteinase Gene Variation, Coronary Heart Disease, and Benefit of Statin Therapy Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 562 - 567. [Abstract] [Full Text] [PDF]
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 J. T. Read, M. Rahmani, S. Boroomand, S. Allahverdian, B. M. McManus, and P. S. Rennie Androgen Receptor Regulation of the Versican Gene through an Androgen Response Element in the Proximal Promoter J. Biol. Chem., November 2, 2007; 282(44): 31954 - 31963. [Abstract] [Full Text] [PDF]
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 S. A. Kuznetsova, P. Issa, E. M. Perruccio, B. Zeng, J. M. Sipes, Y. Ward, N. T. Seyfried, H. L. Fielder, A. J. Day, T. N. Wight, et al. Versican-thrombospondin-1 binding in vitro and colocalization in microfibrils induced by inflammation on vascular smooth muscle cells J. Cell Sci., November 1, 2006; 119(21): 4499 - 4509. [Abstract] [Full Text] [PDF]
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 Y. Goueffic, C. Guilluy, P. Guerin, P. Patra, P. Pacaud, and G. Loirand Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation Cardiovasc Res, November 1, 2006; 72(2): 339 - 348. [Abstract] [Full Text] [PDF]
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J. S. Isenberg, D. A. Wink, and D. D. Roberts Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses Cardiovasc Res, September 1, 2006; 71(4): 785 - 793. [Abstract] [Full Text] [PDF]
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 L. Barre, N. Venkatesan, J. Magdalou, P. Netter, S. Fournel-Gigleux, and M. Ouzzine Evidence of calcium-dependent pathway in the regulation of human {beta}1,3-glucuronosyltransferase-1 (GlcAT-I) gene expression: a key enzyme in proteoglycan synthesis FASEB J, August 1, 2006; 20(10): 1692 - 1694. [Abstract] [Full Text] [PDF]
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L. Zhuo, A. Kanamori, R. Kannagi, N. Itano, J. Wu, M. Hamaguchi, N. Ishiguro, and K. Kimata SHAP Potentiates the CD44-mediated Leukocyte Adhesion to the Hyaluronan Substratum J. Biol. Chem., July 21, 2006; 281(29): 20303 - 20314. [Abstract] [Full Text] [PDF]
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 T. Wiest, S. Hyrenbach, P. Bambul, B. Erker, A. Pezzini, I. Hausser, M.-L. Arnold, J. J. Martin, S. Engelter, P. Lyrer, et al. Genetic Analysis of Familial Connective Tissue Alterations Associated With Cervical Artery Dissections Suggests Locus Heterogeneity Stroke, July 1, 2006; 37(7): 1697 - 1702. [Abstract] [Full Text] [PDF]
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 J. Nigro, N. Osman, A. M. Dart, and P. J. Little Insulin Resistance and Atherosclerosis Endocr. Rev., May 1, 2006; 27(3): 242 - 259. [Abstract] [Full Text] [PDF]
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P.-S. Zheng, M. Reis, C. Sparling, D. Y. Lee, D. P. La Pierre, C.-K. A. Wong, Z. Deng, S. Kahai, J. Wen, and B. B. Yang Versican G3 Domain Promotes Blood Coagulation through Suppressing the Activity of Tissue Factor Pathway Inhibitor-1 J. Biol. Chem., March 24, 2006; 281(12): 8175 - 8182. [Abstract] [Full Text] [PDF]
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R. Huang, M. J. Merrilees, K. Braun, B. Beaumont, J. Lemire, A. W. Clowes, A. Hinek, and T. N. Wight Inhibition of Versican Synthesis by Antisense Alters Smooth Muscle Cell Phenotype and Induces Elastic Fiber Formation In Vitro and in Neointima After Vessel Injury Circ. Res., February 17, 2006; 98(3): 370 - 377. [Abstract] [Full Text] [PDF]
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M. van den Boom, M. Sarbia, K. von Wnuck Lipinski, P. Mann, J. Meyer-Kirchrath, B.H. Rauch, K. Grabitz, B. Levkau, K. Schror, and J.W. Fischer Differential Regulation of Hyaluronic Acid Synthase Isoforms in Human Saphenous Vein Smooth Muscle Cells: Possible Implications for Vein Graft Stenosis Circ. Res., January 6, 2006; 98(1): 36 - 44. [Abstract] [Full Text] [PDF]
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M. Rodriguez-Lee, G. Ostergren-Lunden, B. Wallin, J. Moses, G. Bondjers, and G. Camejo Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 130 - 135. [Abstract] [Full Text] [PDF]
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N. Kaplan-Albuquerque, V. Van Putten, M. C. Weiser-Evans, and R. A. Nemenoff Depletion of Serum Response Factor by RNA Interference Mimics the Mitogenic Effects of Platelet Derived Growth Factor-BB in Vascular Smooth Muscle Cells Circ. Res., September 2, 2005; 97(5): 427 - 433. [Abstract] [Full Text] [PDF]
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 P. Talusan, S. Bedri, S. Yang, T. Kattapuram, N. Silva, P. J. Roughley, and J. R. Stone Analysis of Intimal Proteoglycans in Atherosclerosis-prone and Atherosclerosis-resistant Human Arteries by Mass Spectrometry Mol. Cell. Proteomics, September 1, 2005; 4(9): 1350 - 1357. [Abstract] [Full Text] [PDF]
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 J. Tian, K. Ishibashi, K. Ishibashi, K. Reiser, R. Grebe, S. Biswal, P. Gehlbach, and J. T. Handa Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response PNAS, August 16, 2005; 102(33): 11846 - 11851. [Abstract] [Full Text] [PDF]
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N. Kaplan-Albuquerque, Y. E. Bogaert, V. Van Putten, M. C. Weiser-Evans, and R. A. Nemenoff Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells: MARKERS FOR PHENOTYPIC MODULATION AND RESPONSE TO INJURY J. Biol. Chem., May 20, 2005; 280(20): 19966 - 19976. [Abstract] [Full Text] [PDF]
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C. D. Blundell, A. Almond, D. J. Mahoney, P. L. DeAngelis, I. D. Campbell, and A. J. Day Towards a Structure for a TSG-6{middle dot}Hyaluronan Complex by Modeling and NMR Spectroscopy: INSIGHTS INTO OTHER MEMBERS OF THE LINK MODULE SUPERFAMILY J. Biol. Chem., May 6, 2005; 280(18): 18189 - 18201. [Abstract] [Full Text] [PDF]
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M. Rahmani, J. T. Read, J. M. Carthy, P. C. McDonald, B. W. Wong, M. Esfandiarei, X. Si, Z. Luo, H. Luo, P. S. Rennie, et al. Regulation of the Versican Promoter by the {beta}-Catenin-T-cell Factor Complex in Vascular Smooth Muscle Cells J. Biol. Chem., April 1, 2005; 280(13): 13019 - 13028. [Abstract] [Full Text] [PDF]
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 N. T. Seyfried, C. D. Blundell, A. J. Day, and A. Almond Preparation and application of biologically active fluorescent hyaluronan oligosaccharides Glycobiology, March 1, 2005; 15(3): 303 - 312. [Abstract] [Full Text] [PDF]
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T. N. Wight The ADAMTS Proteases, Extracellular Matrix, and Vascular Disease: Waking the Sleeping Giant(s)! Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 12 - 14. [Full Text] [PDF]
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