Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular smooth muscle cells (SMCs) in the media of normal arteries express alpha 1 beta 1 integrin with no detectable alpha 2 beta 1 as determined by immunocytochemistry. In contrast, immunoprecipitation of integrins expressed by human SMCs cultured from medial explants shows strong expression of alpha 2 beta 1 and no expression of alpha 1 beta 1. The apparent reciprocal expression of these two collagen and laminin receptors was confirmed by flow cytometric analysis of fluorescent labeled cells. Freshly isolated SMCs had detectable alpha 1, alpha 3, alpha 5, and alpha v subunits with low levels of detectable beta 3 and no detectable alpha 2. Cultured SMCs expressed alpha 2, alpha 3, alpha 5 and alpha v subunits with little or no alpha 1 or beta 3. Neither alpha 4 nor alpha 6 were detectable in freshly isolated or cultured cells. Expression of alpha 2 beta 1 receptors by cultured SMCs appears to be required for the migration of these cells on type I collagen. Migration of cultured SMCs across a type I collagen-coated membrane toward two different chemotactic stimuli, platelet-derived growth factor-BB (1 nmol/L) and insulin-like growth factor-(1 nmol/L), was Mg2+ dependent and inhibited by preincubation of cells with an affinity-purified polyclonal anti-alpha 2 beta 1 antibody or by monoclonal antibodies directed against the individual alpha 2 or beta 1 subunits. Attachment to type 1 collagen membranes was not affected by antibodies under conditions where migration was significantly impeded. The combined data show that SMC expression of alpha 1 beta 1 and alpha 2 beta 1 integrin receptors for collagen and laminin is dynamic and reciprocal and may be important with respect to SMC migration on type I collagen. These findings are potentially important in understanding the pathophysiology of vascular diseases, for example, atherosclerosis and restenosis following balloon angioplasty, where SMC migration is a contributing factor.
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PMID:Dynamic expression of alpha 1 beta 1 and alpha 2 beta 1 integrin receptors by human vascular smooth muscle cells. Alpha 2 beta 1 integrin is required for chemotaxis across type I collagen-coated membranes. 797 39

The phenotypic transition of smooth muscle cells (SMC) from a contractile to a synthetic state appears to be an early event in the pathogenesis of atherosclerosis. It was found that plasma fibronectin promotes the transition of rat aortic SMC into the synthetic phenotype and that laminin delays this process. Recently, we found that type I collagen is as efficient as fibronectin in promoting the initial attachment and phenotypic transition of rabbit arterial SMC and elastin maintained the cells in the contractile phenotype, as laminin. On the other hand, laminin plus type IV collagen suggest that a partial remodulation may be possible. These findings emphasize the importance of extracellular matrix components in the control of the differentiated properties of arterial SMC and may be important for clarifying the development of atherosclerosis.
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PMID:[Regulation of differentiated properties of arterial smooth muscle cells]. 841 60

The phenotypic transition of smooth muscle cells (SMC) from a contractile to a synthetic state appears to be an early event in the pathogenesis of atherosclerosis. We examined the effects of extracellular matrix components on the phenotypic modulation of rabbit arterial SMC in primary culture by flow cytometry. The results demonstrate that freshly isolated SMC attached, spread, and started to proliferate on type I collagen as well as on fibronectin. Moreover, type I collagen was as efficient as fibronectin in promoting the transition of the cells into the synthetic phenotype without exogenous mitogens. However, unlike on fibronectin, the synthetic peptide GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro) and the peptide KDGEA (Lys-Asp-Gly-Glu-Ala), which contains the recognition sequence for alpha 2 beta 1 integrin in type I collagen, interfered little with the attachment, spreading, and phenotypic modulation of the cells on type I collagen. On the other hand, the phenotypic modulation of the cells was counteracted by the anti-beta 1 integrin antibody. These findings indicate that type I collagen promotes the phenotypic transition of the rabbit arterial SMC by interacting with a cell surface receptor (beta 1 integrin family) for a cell-binding sequence without RGD and DGEA. In contrast, elastin, a major constituent of the media, suppressed the cell attachment and spreading and maintained the cells in the contractile phenotype as laminin. These results suggest diverse roles of type I collagen and elastin as well as of fibronectin and laminin in the control of the differentiated properties of arterial SMC.
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PMID:Type I collagen promotes modulation of cultured rabbit arterial smooth muscle cells from a contractile to a synthetic phenotype. 841 90

Biochemical modification of extracellular matrix (ECM) proteins can alter the function in overlying cells. We tested the hypothesis that metal-catalyzed oxidation of native ECM and individual matrix proteins modulates the activity of inducible nitric oxide synthase (iNOS) in cultured rat mesangial cells (RMC). Oxidized modification of native ECM resulted in a 32% increase in iNOS activity (P<0.01) without influencing the response to supplemental L-arginine or to the addition of the iNOS inhibitor, L-NAME. Immunoblot analysis indicated that enhanced iNOS activity was not associated with a parallel rise in the cytosolic content of iNOS. Synthesis of type IV collagen was unaffected by growth of RMC on oxidized native ECM. Oxidation of three normal constituents of the mesangial matrix - type IV collagen, laminin, and fibronectin - also stimulated iNOS activity in overlying RMC by 18-32% (P<0.05). Growth of RMC on oxidized type I collagen or Vitrogel had no effect on NO production. We conclude that oxidized modification of the mesangial matrix promotes increased iNOS activity and NO production by mesangial cells. Further work is required to determine whether this response limits glomerular injury or promotes damage to the mesangium in oxygen free radical-mediated diseases such as chronic renal failure, atherosclerosis and diabetes.
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PMID:Growth of rat mesangial cells on oxidized extracellular matrix increases inducible nitric oxide synthase activity. 1002 60

Gangliosides, sialic acid-containing glycosphingolipids, accumulate in atherosclerotic vessels. Their role in the pathogenesis of atherosclerosis is unknown. Gangliosides isolated from tumor cells promote collagen-stimulated platelet aggregation and ATP secretion and enhance platelet adhesion to immobilized collagen. These activities are all mediated by ganglioside effects on the platelet integrin collagen receptor alpha2beta1. Therefore, we hypothesized that gangliosides isolated from atherosclerotic plaques would enhance platelet adhesion to immobilized collagen, a major component of the subendothelial matrix of blood vessels. Furthermore, we questioned whether this effect of atherosclerotic gangliosides might play a role in the pathogenesis of atherosclerosis. To test this hypothesis, we isolated the gangliosides from postmortem aortas of patients with extensive atherosclerotic disease and examined their effects on platelet adhesion. Samples of aortic tissue taken from areas involved with atherosclerotic plaque demonstrated accumulation of gangliosides (64.9+/-6.5 nmol/g wet weight) compared with gangliosides isolated from control normal aortic tissue taken from children who died of noncardiac causes (NAGs; 21.1+/-6.4 nmol/g wet weight). Interestingly, samples of tissue taken from diseased aortas but from areas not involved with gross plaque formation also demonstrated ganglioside accumulation (47.6+/-12.8 nmol/g wet weight). Next, the activity of each of these gangliosides on platelet adhesion to immobilized type I collagen was studied. Atherosclerotic aortic gangliosides (AAGs) as well as those isolated from grossly unaffected areas of the same aorta (UAGs) both increased platelet adhesion compared with control NAGs (OD570, 0. 37+/-0.11 and 0.29+/-0.14 versus 0.16+/-0.07, respectively; P<0.01 and P<0.05, respectively). These OD570 values corresponded to 9x10(5), 8x10(4), and 6x10(3) platelets per well after preincubation with 5 micromol/L AAG, UAG, and NAG, respectively. Increased adhesion was observed after preincubation with as little as 0.5 micromol/L AAG, and maximal adhesion was seen at 2.5 micromol/L, with a plateau extending to the highest concentration tested, 10 micromol/L. The effect of AAGs on platelet adhesion to collagen was abrogated by incubation of treated platelets with F-17 anti-alpha2 monoclonal antibody (OD570, 0.13+/-0.02). Finally, the effects of the major individual gangliosides isolated from atherosclerotic tissues, GM3 and GD3, were tested. GM3 increased adhesion to collagen (OD570, 0.415+/-0.06) as did GD3 (0.31+/-0.08). Similar to that of AAGs, the effect of both molecules was blocked by F-17 (0. 09+/-0.04 and 0.13+/-0.06, respectively). These experiments demonstrate that accumulated atherosclerotic gangliosides promote platelet adhesion to collagen, the major component of the subendothelial matrix. Furthermore, this activity is mediated by an effect of the gangliosides on the collagen-binding integrin alpha2beta1. This activity may provide a mechanism for the development of platelet thrombi at sites where atherosclerotic gangliosides accumulate and help to explain the role of platelets in the process of atherosclerotic disease progression.
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PMID:Atherosclerotic aortic gangliosides enhance integrin-mediated platelet adhesion to collagen. 1007 52

Active matrix metalloproteinases and degraded collagen are observed in disease states, such as atherosclerosis. To examine whether degraded collagen fragments have distinct effects on vascular smooth muscle cells (SMC), collagenase-digested type I collagen was added to cultured human arterial SMC. After addition of collagen fragments, adherent SMC lose their focal adhesion structures and round up. Analysis of components of the focal adhesion complex demonstrates rapid cleavage of the focal adhesion kinase (pp125(FAK)), paxillin, and talin. Cleavage is suppressed by inhibitors of the proteolytic enzyme, calpain I. In vitro translated pp125(FAK) is a substrate for both calpain I- and II-mediated processing. Mapping of the proteolytic cleavage fragments of pp125(FAK) predicts a dissociation of the focal adhesion targeting (FAT) sequence and second proline-rich domain from the tyrosine kinase domain and integrin-binding sequence. Coimmunoprecipitation studies confirm that the ability of pp125(FAK) to associate with paxillin, vinculin, and p130cas is significantly reduced in SMC treated with degraded collagen fragments. Further, there is a significant reduction in the association of intact pp125(FAK) with the cytoskeletal fraction, while pp125(FAK) cleavage fragments appear in the cytoplasm in SMC treated with degraded collagen fragments. Integrin-blocking studies indicate that integrin-mediated signals are involved in degraded collagen induction of pp125(FAK) cleavage. Thus, collagen fragments induce distinct integrin signals that lead to initiation of calpain-mediated cleavage of pp125(FAK), paxillin, and talin and dissolution of the focal adhesion complex.
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PMID:Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin. 1054 5

Migration of vascular smooth muscle cells (VSMC) is a key event in the formation of neointima during atherosclerosis. Fura-2 loaded VSMCs were used to investigate calcium homeostasis during cell migration. Multiple spontaneous transient increases in cytosolic free calcium [Ca(2+)](i)were observed in single human VSMCs migrating on type I collagen. Such [Ca(2+)](i)transients were dependent on the presence of serum or PDGF-BB. Removal of serum, or loading cells with BAPTA, abolished the transients and decreased cell migration speed. The transients were not affected by disruption of cell polarization by dihydrocytochalasin B. Adhesion was used to investigate the specific role of cell-substrate interactions in the generation of transients. Transients are seen in VSMCs adhering either on collagen or on poly-L-lysine, suggesting that generation of transients is not strictly dependent on integrins. Buffering [Ca(2+)](i) with BAPTA led to accumulation of (beta)1 integrins at the cellular tail, and to increased release of integrin on the extracellular matrix. These results demonstrate a role for [Ca(2+)](i) transients in the rapid, serum-dependent migration of VSMCs. These [Ca(2+)](i)transients are present in migrating VSMCs only when two simultaneous events occur: (1) substrate independent spreading and (2) stimulation of cells by serum components such as PDGF-BB.
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PMID:Migration of human vascular smooth muscle cells involves serum-dependent repeated cytosolic calcium transients. 1065 58

This study was conducted to investigate how a continuous load of hydrodynamic stresses influences the tissue architecture of a branched hybrid vessel in vitro. Tubular hybrid medial tissue of small (3 mm) and large (6 mm) diameters, prepared by thermal gelation of a cold mixed solution of bovine smooth muscle cells (SMCs) and type I collagen in glass molds, was assembled into a branched hybrid medial tissue by end-to-side anastomosis. After a 2-week culture period, bovine endothelial cells (ECs) were seeded onto the luminal surface. The branched hybrid vessel was connected to a mock circulatory loop system and tested for two modes of flow: 1) low flow rate for 24 h, 2) high flow rate for 24 or 72 h. After exposure to a low flow rate for 24 h, cobblestone appearance of the ECs was dominant. After exposure to a high flow rate, EC alignment in the direction of flow was observed in the branch region, except at the region of predicted flow separation where ECs retained their polygonal configuration. Elongation of SMCs with no preferential orientation was observed in the case of vessels exposed to a high flow rate for 24 h, and circumferential orientation was prominent in those exposed to a high flow rate for 72 h. On the other hand, collagen fibrils exhibited no preferential orientation in either case. After injection of Evans blue-albumin conjugate into the circulating medium, the luminal surface of the hybrid vessel exposed to a high flow rate for 24 h was examined by confocal laser scanning microscopy. The fluorescence intensity was low at the high shear zone in the branch region, while at the flow separation region it was very high, indicating the increased albumin permeability at the latter region. These findings reflect region-specific tissue architecture in the branch region, in response to the local flow pattern, and may provide an in vitro atherosclerosis model as well as a fundamental basis for the development of functional branched hybrid grafts.
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PMID:Branched hybrid vessel: in vitro loaded hydrodynamic forces influence the tissue architecture. 1078 71

The matrix metalloproteinase (MMP) family has been implicated in the process of a variety of diseases such as arthritis, atherosclerosis, and tumor cell metastasis. To study the mechanisms of MMP action on collagenous substrates, we have constructed homotrimeric triple-helical peptide (THP) models of the collagenase cleavage sites in types I and II collagen. The THPs incorporate either the alpha1(I)772-786 or the alpha1(II)772-783 sequence. The alpha1(I)772-786 and alpha1(II)772-783 THPs were hydrolyzed by MMP-1 at the Gly-Ile and Gly-Leu bonds, respectively, analogous to the bonds cleaved in corresponding native collagens. Thus, the THPs contained all necessary information to direct MMP-1 binding and proteolysis. Subsequent investigations using the alpha1(I)772-786 THP showed hydrolysis by MMP-2, MMP-13, and a COOH-terminal domain-deleted MMP-1 (MMP-1(Delta(243-450))) but not by MMP-3 or a COOH-terminal domain-deleted MMP-3 (MMP-3(Delta(248-460))). Kinetic analyses showed a k(cat)/K(m) value of 1,808 s(-1) m(-1) for MMP-1 hydrolysis of alpha1(I)772-786 THP, approximately 10-fold lower than for type I collagen. The effect is caused primarily by relative K(m) values. MMP-2 and MMP-13 cleaved the THP more rapidly than MMP-1, but MMP-2 cleavage occurred at distinct multiple sites. Comparison of MMP-1 and MMP-1(Delta(243-450)) hydrolysis of alpha1(I)772-786 THP showed that both can cleave a triple-helical substrate with a slightly higher K(m) value for MMP-1(Delta(243-450)). We propose that the COOH-terminal domain of MMPs is necessary for orienting whole, native collagen molecules but may not be necessary for binding to and cleaving a THP. This proposal is consistent with the large distance between the MMP-1 catalytic and COOH-terminal domains observed by three-dimensional structural analysis and supports previous suggestions that the features of the catalytic domain contribute significantly toward enzyme specificity.
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PMID:Hydrolysis of triple-helical collagen peptide models by matrix metalloproteinases. 1078 34

Focal accumulation of smooth muscle (SMC) within the arterial intima contributes to the formation of lesions of atherosclerosis. Platelet-derived growth factor (PDGF) is a potent stimulant of SMC migration and proliferation in culture that may play a role in the accumulation of SMC in atherogenesis. SMCs normally reside in the media of the artery wall surrounded by extracellular matrix (ECM), including type I collagen. In atherogenesis, the ECM is degraded, new ECM components, such as fibronectin, are synthesized and assembled, and these alterations in ECM components are associated with changes in SMC phenotype. To model the changes in ECM in normal and diseased arteries, we have analyzed SMCs cultured on different forms of type I collagen. Our studies demonstrate that integrin-mediated signals from various forms of type I collagen lead to specific and rapid modulation of the integrin signaling complex, including cytoskeletal connections, and of the responsiveness of SMC to PDGF stimulation.
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PMID:The extracellular matrix dynamically regulates smooth muscle cell responsiveness to PDGF. 1086 24


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