UMLS:C0042373 - FACTA Search

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased elastase activity and deposition of the matrix glycoprotein tenascin-C (TN), codistributing with proliferating smooth muscle cells (SMCs), are features of pulmonary vascular disease. In pulmonary artery (PA) SMC cultures, TN is regulated by matrix metalloproteinases (MMPs) and mechanical stress. On attached collagen gels, MMPs upregulate TN, leading to SMC proliferation, whereas on floating collagen, reduced MMPs suppress TN and induce SMC apoptosis. We now investigate the response of SMCs in the whole vessel by comparing attached and floating conditions using either normal PAs derived from juvenile pigs or normal or hypertrophied rat PAs that were embedded in collagen gels for 8 days. Normal porcine PAs in attached collagen gels were characterized by increasing activity of MMP-2 and MMP-9 assessed by zymography and TN deposition detected by Western immunoblotting and densitometric analysis of immunoreactivity. PAs on floating collagen showed reduced activity of both MMPs and deposition of TN. Tenascin-rich foci were associated with proliferating cell nuclear antigen immunoreactivity, and TN-poor areas with apoptosis, by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, but no difference in wall thickness was observed. Although normal rat PAs were similar to piglet vessels, hypertrophied rat PAs showed an amplified response. Increased elastase, MMP-2, TN, and elastin deposition, as well as SMC proliferating cell nuclear antigen positivity, correlated with progressive medial thickening on attached collagen, whereas reduced MMP-2, elastase, TN, and induction of SMC apoptosis accompanied regression of the thickened media on floating collagen. In showing that hypertrophied SMCs in the intact vessel can be made to apoptose and that resorption of extracellular matrix can be achieved by inhibition of elastase and MMPs, our study suggests novel strategies to reverse vascular disease.
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PMID:Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis. 1034 97

Increased levels of the physiological amino acid homocysteine (Hcy) are considered a risk factor for vascular disease. Hyperhomocysteinemia causes an intense remodelling of the extracellular matrix in arterial walls, particularly an elastolysis involving metalloproteinases. We investigated the activation of the latent elastolytic metalloproteinase proMMP-2 (72 kDa) by Hcy. Hcy was proved to exert a dual effect, activating proMMP-2 at low molar ratio (MR 10:1) and inhibiting active MMP2 at high molar ratio (MR > 1000:1). Methionine and the disulphide homocystine did not activate nor inhibit MMP-2, showing that the activation as well as the inhibition requires the thiol group to be free. The activation of proMMP-2 by Hcy is in accordance with the "cysteine-switch" mechanism, but occurs without further autoproteolysis of the enzyme molecule. In contrast with Hcy, the other physiological thiol compounds cysteine and reduced glutathione did not activate proMMP-2. These results suggest that the direct activation of proMMP2 by Hcy could be one of the mechanisms involved in the extracellular matrix deterioration in hyperhomocysteinemia-associated arteriosclerosis.
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PMID:Influence of homocysteine on matrix metalloproteinase-2: activation and activity. 1049 21

Angiotensin II (ANG II) has been etiologically linked to vascular disease; however, its role in the alterations of endothelial function that occur in vascular disorders is not completely understood. Matrix metalloproteinases (MMPs) and proinflammatory cytokines are involved in the pathological remodeling of blood vessels that occurs in vascular disease. In this study we evaluated the effects of ANG II on tumor necrosis factor (TNF)-alpha and MMP-2 production in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with ANG II (0.1-10 microM) for 24 h, in the presence or absence of antagonists of ANG II type 1 (AT(1)R) and type 2 (AT(2)R) receptors, and the production and release of TNF-alpha and MMP-2 were assessed. ANG II increased TNF-alpha mRNA and protein expression and the release of bioactive TNF-alpha. Moreover, ANG II induced MMP-2 release and reduced the secretion of tissue inhibitor of MMP (TIMP)-2 from endothelial cells. To elucidate whether endogenous TNF-alpha could mediate the effects of ANG II on MMP-2 release, cells were pretreated with anti-TNF-alpha neutralizing antibodies or pentoxifylline (an inhibitor of TNF-alpha synthesis). TNF-alpha inhibition prevented the secretion of MMP-2 induced by ANG II. Furthermore, AT(1)R antagonism with candesartan prevented the formation of MMP-2 and TNF-alpha and the reduction of TIMP-2 induced by ANG II. These results indicate that ANG II, via AT(1)R, modulates the secretion of TNF-alpha and MMP-2 from endothelial cells and that TNF-alpha mediates the effects of ANG II on MMP-2 release.
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PMID:Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-alpha. 1464 77

Widely used tetracycline antibiotics affect many cellular functions relevant to human vascular disease including cell proliferation, migration, and matrix remodeling. We examined whether minocycline inhibited human aortic smooth muscle cell (HASMC) migration induced by vascular endothelial growth factor (VEGF). After the establishment of an optimal dose, minocycline treated HASMC were exposed to VEGF. HASMC migration, matrix metalloproteinase (MMP)-2 and MMP-9 activities, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) phosphorylation were determined by smooth muscle cell (SMC) invasion assay, real-time polymerase chain reaction, zymograms, and Western blot analysis, respectively. We demonstrated that VEGF and platelet-derived growth factor (PDGF)-induced SMC migration in a dose-dependent manner. MMP-9, but not MMP-2, mRNA was increased during VEGF stimulation. MMP-9 activity was increased from 1.5- to 2.5-fold in a dose-dependent manner (P<0.05). Both ERK1/2 and PI3K/AKt pathways were activated during VEGF-induced HASMCs migration. We then demonstrated that minocycline can inhibit VEGF-induced HASMC migration (P<0.05). The effects may be through the inhibition of MMP-9 mRNA transcription, protein activities and downregulation of ERK1/2 and PI3K/Akt pathway phosphorylation. Our results indicated that minocycline exerts multiple effects on VEGF-induced SMC migration, including inhibition of MMP-9 mRNA transcription and protein activities and downregulating ERK1/2 and PI3K signal pathways, suggesting minocycline may be a potentially therapeutic approach to inhibit disease process induced angiogenesis.
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PMID:Minocycline exerts multiple inhibitory effects on vascular endothelial growth factor-induced smooth muscle cell migration: the role of ERK1/2, PI3K, and matrix metalloproteinases. 1525 78

Deregulation of matrix metalloproteinases (MMPs) is an important factor contributing to the development of vascular lesions. Plasma levels and zymographic activities of MMP-2 and MMP-9 were investigated in type II diabetics with (n = 51) or without (n = 42) peripheral artery disease (PAD) and in normal volunteers (n = 23). Plasma MMP-2 levels were higher in type II diabetics with (p < 0.01) or without (p > 0.05) PAD in comparison with normal volunteers. Similarly, type II diabetics with (p < 0.0001) or without (p > 0.05) PAD had higher plasma MMP-9 levels than normal volunteers. Plasma zymographic activities of both MMP-2 and MMP-9 were positively correlated with their plasma levels. Plasma MMP-2 zymographic activity was higher in type II diabetics with PAD than type II diabetics without PAD (p > 0.05). Plasma MMP-9 zymographic activity was higher in type II diabetics with (p < 0.0001) or without (p < 0.0001) PAD in comparision with normal volunteers. Together, these results indicate that increased plasma levels and zymographic activities of MMP-2 and MMP-9 may contribute to PAD in type II diabetics. In particular, plasma MMP-9 may be a useful marker for the development of vascular disease in type II diabetics.
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PMID:Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease. 1592 Sep 93

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.
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PMID:MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells. 1614 77

As a direct correlation between aging and the risk of onset of vascular disease has been universally accepted, we prepared an in vitro aging model consisting in sequential passages of human aortic smooth muscle cells (AoSMC) in order to evaluate the cell behavior changes during aging. Because matrix metalloproteinases (MMP) are actively involved in matrix remodeling and disease outcome, in our model we found active MMP-2 only in the conditioned medium of young AoSMCs, whereas aged cells showed only the inactive zymogen form of MMP-2 (pro-MMP-2). We ascribed the pro-MMP-2 activation in young cells to an increase in membrane type 1 matrix metalloproteinase (MT1-MMP) content. Furthermore, we found that transcripts coding for tissue inhibitor of metalloproteinases (TIMPs) were up-regulated in aged cells, and this increase of TIMPs could also prevent pro-MMP-2 activation in aged cells. Moreover, we demonstrated that young AoSMCs possess higher migratory capabilities than aged cells. The young AoSMC migration can be inhibited by adding TIMP-1 and TIMP-2 to the cells reproducing aged AoSMC migratory behavior. Finally, the role of MMP-2 and TIMP-2 in AoSMC migration was confirmed silencing MMP-2 and TIMP-2 in young and aged AoSMCs, respectively; therefore, in this study we showed that these enzymes play a pivotal role in the regulation of the AoSMC migration during in vitro aging.
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PMID:Matrix metalloproteinase 2 and tissue inhibitors of metalloproteinases regulate human aortic smooth muscle cell migration during in vitro aging. 1677 11

Hypertension is associated with vascular remodeling characterized by rearrangement of extracellular matrix proteins. To evaluate how matrix metalloproteinase (MMP)-9 contributes to the progression of hypertensive vascular disease in vivo, wild-type (wt) or MMP-9(-/-) mice were treated with angiotensin II (Ang II; 1 microg/kg per minute, by minipump) plus a 5% NaCl diet during 10 days. Baseline blood pressure was equivalent in wt and knockout mice, but Ang II treatment increased systolic blood pressure to a greater extent (P<0.05) in MMP-9(-/-) mice (94+/-6 to 134+/-6 mm Hg; P<0.001) than in wt animals (93+/-4 to 114+/-6 mm Hg; P<0.01). In wt mice, Ang II treatment increased the carotid artery pressure-diameter relationship significantly, and maximal diameter reached 981+/-19 microm (P<0.01 versus sham; 891+/-10 microm). In contrast, in MMP-9(-/-) mice, carotid artery compliance was actually reduced after Ang II (P<0.05), and maximal diameter only reached 878+/-13 microm. Ang II treatment induced MMP-2 and increased carotid media thickness equally in both phenotypes. However, MMP-9 induction and in situ gelatinase activity were only enhanced in Ang II-treated wt mice, and vessels from these mice also produced more collagen I breakdown products than their MMP-9(-/-) counterparts (P<0.05). Inversely, staining for collagen IV was particularly enhanced in vessels from MMP-9(-/-) mice treated with Ang II. These results demonstrate the following: (1) the onset of Ang II-induced hypertension is accompanied by increased MMP-9 activity in conductance vessels; (2) absence of MMP-9 activity results in vessel stiffness and increased pulse pressure; and (3) MMP-9 activation is associated with a beneficial role early on in hypertension by preserving vessel compliance and alleviating blood pressure increase.
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PMID:Role of matrix metalloproteinases in early hypertensive vascular remodeling. 1751 50

Emerging evidence now indicates that the 5-lipoxygenase (5-LO) pathway play a role in the pathogenesis of atherosclerosis and restenosis. The expression of 5-LO by activated macrophages in symptomatic plaques leads to leukotriene B(4) (LTB(4)) accumulation and enhanced synthesis and release of matrix metalloproteinases (MMPs) that can promote plaque rupture. However, the role of 5-LO pathway in diabetic vascular disease has not been previously reported. Thus, the present study was designed to analyze the expression of 5-LO in carotid plaques of diabetic patients and to investigate the possible role of 5-LO pathway in the pathogenesis and progression of diabetic atherosclerosis. Atherosclerotic plaques from 60 patients undergoing carotid endarterectomy were divided into non-diabetic and diabetic group. Plaques were analyzed for 5-LO, MMP-2 and MMP-9 by immunohistochemical, Western blot, and densitometric analyses, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+macrophages, CD3+T-lymphocytes, and HLA-DR+inflammatory cells. LTB(4) were quantified by enzyme-linked immunosorbent assay. 5-LO showed abundant immunoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage infiltrates in atherosclerotic intima. 5-LO expression was higher in diabetic compared with non-diabetic plaques and was associated with increased MMP-2 and MMP-9 expression. Follow-up analyze with zymography assay revealed MMP activity was elevated in diabetic compared with non-diabetic plaques. Notably, in contrast to non-diabetic plaques, LTB(4) levels were significantly increased in diabetic plaques by enzyme-linked immunosorbent assay. These results suggest that overexpression of 5-LO and LTB(4) in atherosclerotic plaques possibly promote MMP-induced plaque rupture in diabetes. Hence, anti-LTs may be useful, not only in reducing atherogenesis, but also in the prevention and treatment of acute atherothrombotic events in diabetic patients.
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PMID:Expanding expression of the 5-lipoxygenase/leukotriene B4 pathway in atherosclerotic lesions of diabetic patients promotes plaque instability. 1782 94

In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.
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PMID:Abeta-degrading enzymes in Alzheimer's disease. 1836 35

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