Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Production of vascular endothelial growth factor (VEGF) by cancer cells at invasive and metastatic sites is an important aspect of tumor angiogenesis. Although known primarily as a mitogen and a vascular permeability factor (VPF) for endothelial cells, VEGF/VPF has been proposed to induce the expression of procoagulant factors in endothelial cells. In this study, we have explored the ramifications of VEGF induction of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) and subsequent activation of progelatinase A. Within 3 hr of incubation with VEGF/VPF, endothelial cells accelerate TF generation as measured using chromogenic substrate assays for coagulation factors Xa and thrombin. Incubation of VEGF/VPF-pre-treated cells with prothrombin and factors X, Va, and VIIa at 37 degrees C and subsequent generation of thrombin resulted in activation of secreted endothelial progelatinase A as demonstrated by gelatin zymography. Anti-thrombin III or antibodies to TF inhibited thrombin generation and progelatinase A activation. VEGF/VPF also directly increased HUVEC secretion of interstitial collagenase, tissue inhibitor of metalloproteinases (TIMP-1) and, to a lesser extent, gelatinase A. The effect of thrombin on endothelial proliferation in serum-free media was examined. Thrombin was a growth factor for HUVECs at a lower dose than that required for progelatinase A activation. Whereas TIMP-2 abrogated thrombin-induced progelatinase A activation, it had no significant effect on thrombin-induced endothelial cell growth. We propose that an early step in tumor angiogenesis involves VEGF-induced thrombin generation and increased MMP production with subsequent activation of endothelial progelatinase A and degradation of the underlying basement membrane.
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PMID:Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. 949 49

This article describes the significance of mRNA expression of VEGF, MMP-2, MMP-9, and MT1-MMP in human colorectal cancer metastases, particularly hepatic metastases. The levels of gene expression were quantified by Northern blot hybridization in tumor and nontumor tissues obtained from 66 primary cases. Significantly higher levels of expression of VEGF mRNA were observed in patients with synchronous hepatic metastases (n = 15) and/or lymph node metastases than in those without. Patients with synchronous hepatic metastases had significantly higher levels of mRNA expression of all MMP genes than in those without, and no apparent correlation was seen between MMP mRNA expression and other clinicopathologic variables. Also in a study including 4 cases of metachronous hepatic metastases after surgery. VEGF, MMP-9, and MT1-MMP mRNA expression were significantly higher in patients with hepatic metastases than in those without, indicating that these are predictable markers for hepatic metastases. Immunohistochemical examination revealed that VEGF and MT1-MMP were localized mainly in cancer cells, whereas MMP-2 and MMP-9 were distributed throughout stromal cells such as fibroblasts and leukocytes in tumor tissues.
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PMID:[Implication of VEGF and MMPs in hepatic metastasis of human colon cancer]. 974 24

Endothelial cells expose receptors for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) at the abluminal, basal surface that work as basic regulators of tumor-induced angiogenesis. Their specific localization makes them susceptible to the activity of tumor-released stimulatory factors, like VEGF/VPF, which induce proliferation of the endothelial cell toward the extracellular matrix. At the same time, VEGF/VPF stimulates endothelial cells to expose tissue factor (TF), the high-affinity transmembrane receptor and cofactor for cellular initiation of the plasma coagulation protease cascades through the extrinsic pathway, so generating thrombin. Thrombin exerts a number of activities: it forms an extracellular fibrin barrier from the VEGF/VPF-dependent fibrinogen extravasation; it activates progelatinase-A (pro-MMP-2), which destroys the basal membrane, allowing proliferation of endothelial cells (ECs) in the novel tumoral fibrin matrix; finally, it induces EC proliferation, potentiating the VEGF effect. Another important factor exposed at the abluminal endothelial cell surface is membrane type 1 matrix metalloproteinase (MT1-MMP), a membrane-bound metalloproteinase, which also activates progelatinase-A, allowing an alternative pathway to that of thrombin to destroy the basal membrane. In addition, we will see that MT1-MMP is also engaged in a direct, cell-associated fibrinolytic activity, essential for tubulogenesis of the novel outsprouting capillary.
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PMID:Molecular polarity in endothelial cells and tumor-induced angiogenesis. 1106 39

We examined the expression level of several genes that regulate distinct steps of metastasis in 55 formalin-fixed, paraffin-embedded, archival specimens of primary human ovarian carcinoma from patients undergoing curative surgery. The expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), basic fibroblast growth factor (bFGF), E-cadherin, type IV collagenase, matrix metalloproteinase (MMP-2 and MMP-9), and interleukin 8 (IL-8) was examined by a colorimetric in situ mRNA hybridization technique. The expression level of E-cadherin, MMP-2, MMP-9, VEGF, and IL-8 mRNA correlated with disease stages. The ratio of type IV collagenase expression (mean of the expression of MMP-2 and MMP-9) to E-cadherin expression (MMP:E-cadherin ratio) increased with increasing stage of disease (p<0.0001). Death rates significantly increased with high MMP:E-cadherin ratio (p=0.0005). Multivariate analysis of overall survival showed that the MMP:E-cadherin ratio was a significant independent prognostic factor, even after adjustment for known prognostic factors, such as histology, stage, and age.
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PMID:Expression of metastasis-related genes in human epithelial ovarian tumors. 1174 36

The levels of expression of various genes were altered in cellular transformants with manipulation of expression of single genes. Vascular endothelial growth factor A (VEGF-A) is a key molecule for tumor progression, although it is unclear how VEGF-A expression regulates various genes. Multiple gene expression levels were evaluated using cDNA arrays in a human hepatocellular carcinoma cell line (HLF) with suppression of the VEGF-A gene by anti-VEGF-A ribozyme (alphaVRz). The ribozyme-mediated suppression of VEGF-A gene solely up-regulated matrix metalloproteinase 1 (MMP1) gene level in HLF/alphaVRz. Levels of expression of other members of MMP family or tissue inhibitors of MMPs did not show any alteration. These results suggested that intracellular suppression of VEGF-A gene was specifically linked to up-regulation of MMP1 in human hepatocellular carcinoma cells.
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PMID:Ribozyme mediated suppression of vascular endothelial growth factor gene expression enhances matrix metalloproteinase 1 expression in a human hepatocellular carcinoma cell line. 1206 53

Atrioventricular (AV) septal defects resulting from aberrant endocardial cushion (EC) formation are observed at increased rates in infants of diabetic mothers. EC formation occurs via an epithelial-mesenchymal transformation (EMT), involving transformation of endocardial cells into mesenchymal cells, migration, and invasion into extracellular matrix. Here, we report that elevated glucose inhibits EMT by reducing myocardial vascular endothelial growth factor A (VEGF-A). This effect is reversed with exogenous recombinant mouse VEGF-A165, whereas addition of soluble VEGF receptor-1 blocks EMT. We show that disruption of EMT is associated with persistence of platelet endothelial cell adhesion molecule-1 (PECAM-1) and decreased matrix metalloproteinase-2 (MMP-2) expression. These findings correlate with retention of a nontransformed endocardial sheet and lack of invasion. The MMP inhibitor GM6001 blocks invasion, whereas explants from PECAM-1 deficient mice exhibit MMP-2 induction and normal EMT in high glucose. PECAM-1-negative endothelial cells are highly motile and express more MMP-2 than do PECAM-1-positive endothelial cells. During EMT, loss of PECAM-1 similarly promotes single cell motility and MMP-2 expression. Our findings suggest that high glucose-induced inhibition of AV cushion morphogenesis results from decreased myocardial VEGF-A expression and is, in part, mediated by persistent endocardial cell PECAM-1 expression and failure to up-regulate MMP-2 expression.
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PMID:Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2. 1259 18

To account for reproductive failure induced by surgical deletion of paternal accessory sex glands in the golden hamster in vivo, we studied expression of vegf, FLT-1 (VEGF-R1), FLK-1 (VEGF-R2), MMP and TGF-beta in endometrium of the dam and sired embryos during 5-7 days post coitum by immunohistochemistry, in situ hybridisation, semiquantitative RT-PCR and enzyme-linked immunosorbent assay. Spatiotemporal pattern of vegf expression in the control animals was similar to that reported for intact animals by our group. Removal of paternal ampullary glands did not disturb the normal expression pattern. Removal of ventral prostate glands alone or all accessory sex glands was associated with reduction of vegf transcripts and protein levels in both the embryo and endometrium. FLT-1, FLK-1 and MMP-2 were also reduced. MMP-1 was not changed whereas TGF-beta1 expression was enhanced. There was no expression in endometrium in between implantation sites. Thus the implanted embryos had a trophic effect on growth factor production by the endometrium, and the levels of expression were determined by viability and structural integrity of the conceptus. Based on these findings we concluded that incompetent embryos sired by males without the ventral prostate gland or all accessory sex glands reduced the potential of the uterus to support pregnancy. A negative cycle of events was thus set up and eventually led to premature termination of pregnancies.
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PMID:Embryos sired by males without accessory sex glands induce failure of uterine support: a study of VEGF, MMP and TGF expression in the golden hamster. 1259 72

VEGF and MMP protein production are both required for exercise-induced capillary growth in skeletal muscle. The underlying process by which muscle activity initiates an angiogenic response is not established, but it is known that mechanical forces such as muscle stretch are involved. We hypothesized that stretch of skeletal muscle microvascular endothelial cells induces production of MMP-2 and VEGF through a common signal pathway. Endothelial cells were grown on Bioflex plates and exposed to 10% static stretch for up to 24 h. MMP-2 protein level was measured by gelatin zymography and VEGF, MMP-2, and MT1-MMP mRNA levels were quantified by real-time quantitative PCR. ERK1/2 and JNK phosphorylation and VEGF protein levels were assessed by Western blotting. Effects of mitogen-activated protein kinases (MAPKs) (ERK1/2, JNK) and reactive oxygen species (ROS) on stretch-induced expression of MMP-2 and VEGF were tested using pharmacological inhibitors. Stretching of endothelial cells for 24 h caused significant increases in MMP-2 protein and mRNA level, but no change in MT1-MMP mRNA. While MMP-2 protein production was enhanced by H(2)O(2) in unstretched cells, ROS inhibition during stretch did not diminish MMP-2 mRNA or protein production. Inhibition of JNK suppressed stretch-induced MMP-2 protein and mRNA, but inhibition of ERK had no effect. In contrast, inhibition of ERK but not JNK attenuated the stretch-induced increase in VEGF mRNA. Our results demonstrate that differential regulation of MMP-2 and VEGF by MAPK signal pathways contribute to stretch-induced activation of microvascular endothelial cells.
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PMID:Static strain stimulates expression of matrix metalloproteinase-2 and VEGF in microvascular endothelium via JNK- and ERK-dependent pathways. 1703 56

Malignant tumors and chronic inflammatory diseases induce angiogenesis by overexpressing vascular endothelial growth factor A (VEGF-A/VPF). VEGF-A-induced pathological angiogenesis can be mimicked in immunoincompetent mice with an adenoviral vector expressing VEGF-A(164) (Ad-VEGF-A(164)). The initial step is generation of greatly enlarged "mother" vessels (MV) from preexisting normal venules by a process involving degradation of their rigid basement membranes. Immunohistochemical and Western blot analyses revealed that versican, an extracellular matrix component in the basement membranes of venules, is degraded early in the course of MV formation, resulting in the appearance of a versican N-terminal DPEAAE fragment associated with MV endothelial cells. The protease ADAMTS-1, known to cleave versican near its N terminus to generate DPEAAE, is also upregulated by VEGF-A in parallel with MV formation and localizes to the endothelium of the developing MV. The authors also show that MMP-15 (MT-2 MMP), a protease that activates ADAMTS-1, is upregulated by VEGF-A in endothelial cells in vitro and in vivo. These data suggest VEGF-A initiates MV formation, in part, by inducing the expression of endothelial cell proteases such as ADAMTS-1 and MMP-15 that act in concert to degrade venular basement membrane versican. Thus, versican is actively processed during the early course of VEGF-A-induced pathological angiogenesis.
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PMID:Proteolytic cleavage of versican and involvement of ADAMTS-1 in VEGF-A/VPF-induced pathological angiogenesis. 2141 13

Exercise-induced angiogenesis in skeletal muscle involves both non-sprouting and sprouting angiogenesis and results from the integrated responses of multiple systems and stimuli. VEGF-A (vascular endothelial growth factor A) levels are increased in exercised muscle and have been demonstrated to be critical for exercise-induced capillary growth. Only limited information is available regarding the role of other angiogenic and angiostatic factors in exercise, but changes in the angiopoietin family following repetitive bouts of exercise occur in a pattern that is favourable for angiogenesis. Results from other angiogenic model systems, indicate that miRNAs (microRNAs) are important factors in the regulation of angiogenesis and thus to explore their role as regulators of exercise induced angiogenesis will be an important avenue of study in the future. ECM (extracellular matrix) remodelling and activation of MMPs (matrix metalloproteinases) are, to some extent, overlooked players in skeletal muscle adaptation. Degradation of ECM proteins liberates angiogenic factors from immobilized matrix stores and make cell migration possible. In fact, it is known that MMPs become activated by a single bout of exercise in humans, rapid interstitial changes occur long before any changes in gene transcription could result in protein synthesis and inhibition of MMP activity completely abolishes sprouting angiogenesis. A growing body of evidence suggests that circulating and resident progenitor cells, in addition to other cell types located in skeletal muscle tissue, participate in skeletal muscle angiogenesis by various mechanisms. However, more studies are needed before these can be confirmed as mechanisms of exercise-induced capillary growth.
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PMID:Vascular remodelling in human skeletal muscle. 2210 98


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