Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impaired trophoblastic invasion and proliferation have been implicated in the pathogenesis of eclampsia, pre-eclampsia, spontaneous abortions and intra-uterine growth retardation (IUGR). First trimester trophoblast cells (which do not grow in culture) and choriocarcinoma (BeWo) (which grow spontaneously, and are used as a model for proliferating trophoblast) were incubated with interleukin-1 beta (IL-1 beta). BeWo cell growth was decreased dose-dependently by exogenous IL-1 beta at concentrations of 100-1000 pg/ml. This effect was first detected after 24 h of incubation with IL-1 beta, and persisted for up to 96 h of culture. In contrast, trophoblast cells isolated from first trimester placental tissue showed no growth response when stimulated with IL-1 beta. The levels of active interstitial collagenase produced by BeWo cells were increased by IL-1 beta (100-1000 pg/ml), which paralleled the decrease in cell growth. First trimester trophoblast cells produced lower levels of collagenase and this was not affected by incubation of the cells by IL-1 beta. These results indicate that IL-1 beta may regulate placental development, but further development of culture systems for first trimester trophoblast will be needed before this result can be confirmed.
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PMID:Regulation by interleukin-1 beta of growth and collagenase production by choriocarcinoma cells. 820 67

Human pregnancy is associated with extensive growth and remodelling of the uterus and placenta, and restructuring of these tissues during specific stages of gestation likely involves the degradative activity of various matrix metalloproteinases (MMPs). In this investigation, we used in situ hybridization and immunohistochemistry to identify the sites and cell source of collagenase-1 (MMP-1), stromelysin-1 (MMP-3), matrilysin (MMP-7), and 92 kDa gelatinase (MMP-9), a subgroup of MMPs with the combined ability to degrade essentially all matrix proteins. Human tissues were recovered from uncomplicated pregnancies at various gestational ages and from pregnancies complicated by chorioamnionitis, pre-eclampsia, and placenta accreta. Our results show prominent expression of all four MMPs in specific cells of human placentae involved in trophoblast invasion and placental maturation. Collagenase-1 and stromelysin-1 were detected in cells of the amnion, decidua, and chorionic villi at all stages of pregnancy. Ninety-two kilodalton gelatinase was present in granulocytes whenever present. Matrilysin was seen in cytotrophoblasts and syncytiotrophoblasts during early pregnancy but only in cytotrophoblasts by the third trimester. In addition, we found that matrilysin is over expressed and is produced by more cell types in placentae from pregnancies complicated by pre-eclampsia suggesting that the proteolytic activity of this MMP contributes to the pathology of this condition. We conclude that certain MMPs produced by resident cells of the human placenta, and in particular trophoblasts, participate in the physiological progress human gestation and parturition.
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PMID:Collagenase-I, stromelysin-I, and matrilysin are expressed within the placenta during multiple stages of human pregnancy. 891 3

During pregnancy, the uterine artery demonstrates refractoriness to vasoconstriction by infused angiotensin II (AII). AII increases prostacyclin (PGI2) production by uterine artery endothelium from pregnant ewes, and this response is mediated via the AT1 receptor (AT1-R). This response is also unique to pregnancy because AII does not stimulate PGI2 production by uterine artery endothelium from nonpregnant ewes. We therefore hypothesize that the increase in uterine artery PGI2 production in response to AII in pregnancy is associated in part with a concomitant increase in AT1-R expression in uterine artery endothelium. Endothelium-derived protein was directly removed from the lumenal surface of freshly isolated uterine and systemic (omental) arteries from nonpregnant and pregnant ewes. AT1-R expression was then measured in both the endothelium-derived fraction and endothelium-denuded vascular smooth muscle (VSM) fraction by Western analysis. AT1-R was detected as 54- and 65-kDa proteins in all samples, as well as adrenal cortex control. AT1-R expression increased more than 8-fold in uterine artery endothelium of pregnant ewes over that in nonpregnant ewes at each of four gestational ages (P < 0.05 at 110, 120, 130, 142 days, n = 4 each vs. n = 6 nonpregnant). No significant differences were seen, however, from 110 to 142 days of gestation. In contrast, whereas the level of AT1-R staining in omental artery endothelium in nonpregnant ewes was higher than in uterine artery, AT1-R increased less in pregnant ewes (2-fold) and only reached significance over nonpregnant values at 110 and 120 days, or when data was combined irrespective of gestational age (P < 0.05). Although AT1-R was also detected in uterine and omental artery VSM, little or no change in expression was observed in pregnancy. Results were confirmed by immunohistochemical staining of arterial cross sections, and the increase in AT1-R expression in uterine artery endothelium was confirmed by RT/PCR amplification of AT1-R messenger RNA from collagenase dispersed cells (n = 4 pregnant vs. n = 4 nonpregnant, mean 20-fold increase, P < 0.028). We conclude that increased uterine artery endothelial PGI2 responsiveness to AII during pregnancy is indeed associated with a correspondingly marked and localized increase in expression of the endothelial AT1-R receptor. We believe our findings allow a more detailed understanding of the molecular mechanisms that underlie increased uterine blood flow that is so central to the normal development of the growing fetus, and on dysfunction may lead to conditions such as preeclampsia.
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PMID:Pregnancy induces an increase in angiotensin II type-1 receptor expression in uterine but not systemic artery endothelium. 897 39

Hepatocyte growth factor (HGF) is a cytokine that is produced in the placental villous core and acts in a paracrine manner on trophoblasts that express the HGF receptor Met. Because HGF stimulates the invasion of many epithelial cell types, villous core HGF could regulate placental trophoblast invasion. As preeclampsia is characterized by inadequate trophoblast invasion, we investigated the hypothesis that decreased placental HGF production is a mechanism for inadequate trophoblast invasion in this disease. Placental villous explant HGF production over 24 h was 25% lower in patients with preeclampsia (n = 5; 7.29 +/- 0.8 ng/mL) than in normal patients (n = 5; 9.76 +/- 0.5 ng/mL; P < 0.05). The human first trimester trophoblast cell line (ED27) used in subsequent invasion studies was found to express c-met messenger ribonucleic acid by RT-PCR and Met protein by Western analysis, and underwent phosphorylation of tyrosine residues on Met with HGF exposure. A Boyden chamber invasion assay using collagen type I showed that HGF caused a specific dose-response increase in trophoblast invasion first seen at 10 ng/mL (2.2-fold increase; P < 0.05). The stimulation of trophoblast invasion by HGF may in part be due to the 2-fold induction of 92-kDa collagenase as determined by zymogram analysis of the trophoblast-conditioned medium. These studies suggest that HGF has an important role in placental trophoblast invasion through the activation of Met and the subsequent induction of 92-kDa collagenase in these cells. In addition, decreased placental production of HGF in preeclampsia provides a potential mechanism for the lack of trophoblast invasion that is seen in this pregnancy disorder.
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PMID:Hepatocyte growth factor stimulates trophoblast invasion: a potential mechanism for abnormal placentation in preeclampsia. 1056 55

Edema, proteinuria, hypertension (EPH)-gestosis, known also as preeclampsia, is the most common, pregnancy-associated pathological syndrome. It is accompanied by a significant increase in collagen content in the umbilical cord arteries and premature replacement of hyaluronic acid by sulfated glycosaminoglycans both in these arteries and in Wharton's jelly. This remodelling of the umbilical cord tissues is accompanied by a distinct increase in insulin-like growth factor-I (IGF-I) concentration in the umbilical cord serum. Such a serum introduced into the culture medium of fibroblasts growing in vitro strongly stimulated the incorporation of radioactive proline into collagen (hydroxyproline-containing and collagenase-sensitive protein). Biosynthesis of noncollagenous proteins was not stimulated. Since IGF-I is known as a stimulator of collagen and sulfated glycosaminoglycan biosynthesis, the high concentration of this growth factor in the umbilical cord plasma may be an agent responsible for preeclampsia-associated remodelling of the umbilical cord, which results in dysfunction in fetal circulation.
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PMID:Stimulation of collagen biosynthesis by the umbilical cord serum of newborns delivered by mothers with EPH-gestosis (preeclampsia). 1107 61

The placenta is formed by developing trophoblast cells to facilitate fluid, gas and nutrient exchange with the mother. Inappropriate trophoblast responsiveness can lead to life threatening complications during pregnancy including intrauterine growth retardation, pre-eclampsia, spontaneous abortion and malignancy that could lead to fetal loss. Transforming growth factor beta (TGFbeta) is a multifunctional cytokine required for embryonic development and is an important regulator of human trophoblast function. Although TGFbeta is critical for placental and embryonic development, there are currently no established TGFbeta-responsive human trophoblast-derived cell lines available to study the mechanisms by which TGFbeta regulates trophoblast function. Our studies have examined the transformed human trophoblast-derived cell line, ED27, to determine if it is responsive to TGFbeta. Our data indicate that TGFbeta dose responsively and reversibly inhibits cell growth in ED27 cells and induces classic TGFbeta response genes, fibronectin and plasminogen activator inhibitor 1 (PAI-1). TGFbeta also induces an inhibitor of trophoblast invasion, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in ED27 cells. Our studies have identified a human trophoblast-derived cell line that parallels isolated primary human trophoblasts in their responses to TGFbeta. This cell line may provide us with the opportunity to determine TGFbeta-mediated responses on human trophoblast functions not previously possible.
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PMID:Characterization of a TGFbeta-responsive human trophoblast-derived cell line. 1171 79

In preeclampsia the cytotrophoblast invasion of the decidual vessels is reduced. The endothelia in the decidual vessels may influence cytotrophoblast invasion and remodeling of decidual spiral arteries. The decidual endothelial cells from preeclamptic placentas produce less matrix metalloproteinase-1 (MMP1) than those from normal placentas. MMPs form a group of enzymes that are capable of degrading components of extracellular matrix. The present study investigated the prevalence and possible association of an insertion of guanine in the promoter of the MMP1 gene in pregnancy-induced hypertension, preeclampsia and eclampsia in the Czech population. This was a case-control study. No differences were observed in genotype frequencies between cases and controls. The insertion of the guanine in the promoter of the MMP1 gene does not appear to increase the risk of development of pregnancy-induced hypertension, preeclampsia and eclampsia.
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PMID:Lack of an association of a single nucleotide polymorphism in the promoter of the matrix metalloproteinase-1 gene in Czech women with pregnancy-induced hypertension. 1158 41

Deficient trophoblast invasion is a major feature of pre-eclampsia. In vitro studies suggest that in normal pregnancy, maternal cells may play a role in controlling trophoblast invasion, although the exact nature of the regulatory interactions between these cells is not fully understood. To examine the effect of maternal-placental cell interactions on matrix metalloproteinase (MMP) secretion and endovascular cytotrophoblast migration in normal pregnancy and in pre-eclampsia, we performed co-culture experiments using cytotrophoblasts from normal pregnancies, together with decidual endothelial cells from both normal and preeclamptic pregnancies. Cells were incubated on semi-permeable membranes with or without phorbol 12-myristate 13-acetate (PMA). Results showed that third trimester cytotrophoblasts are migratory under basal conditions and display a different MMP profile from decidual endothelial cells. Co-culture did not damage either cell type and resulted in reduced latent MMP-9 secretion and reduced cytotrophoblast migration. Although PMA upregulated MMPs in decidual endothelial cells, it had no effect on cytotrophoblast MMP secretion. PMA, however, reduced cytotrophoblast migration. Pre-eclamptic decidual endothelial cells showed reduced MMP-1 secretion, but overall were not different in co-culture from normal endothelial cells. This study demonstrates the effectiveness of a bilayer co-culture model to study maternal-foetal cell interactions and provides evidence that maternal cells may contribute to the control of endovascular cytotrophoblast invasion.
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PMID:In vitro migration of cytotrophoblasts through a decidual endothelial cell monolayer: the role of matrix metalloproteinases. 1265 3

Progesterone-induced decidualized human endometrial stromal cells form a hemostatic envelope that protects against hemorrhage during invasion of endometrial capillaries by implanting blastocyst-derived cytotrophoblasts (CTs). This hemostatic milieu reflects co-upregulated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation and plasminogen activator inhibitor type 1, which inactivates tissue-type plasminogen activator, the primary fibrinolytic agent. During deep invasion of the decidua, CTs breach and remodel spiral arteries and arterioles to produce high-conductance vessels. Shallow invasion results in incomplete vascular transformation and an underperfused fetal - placental unit associated with preeclampsia and intrauterine growth restriction. Decidual hemorrhage and severe thrombophilias elicit aberrant thrombin generation from decidual cell-expressed TF. Such thrombin induces decidual cells to synthesize and secrete soluble fms-like tyrosine kinase-1 (sFlt-1), the matrix metalloproteinases MMP-1 and MMP-3, and the neutrophil chemoattractant interleukin-8. Excess sFlt-1 at the implantation site may inhibit CT invasion by altering the angiogenic factor balance. During abruptions, thrombin-enhanced MMP-1, MMP-3 by decidual cells and neutrophil-derived proteases degrade the decidual and fetal membrane extracellular matrix to promote preterm premature rupture of the membranes. In association with long-term progestin-only contraception, overexpression of decidual cell-derived thrombin promotes aberrant angiogenesis and vessel maintenance to contribute to abnormal uterine bleeding.
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PMID:The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states. 1725 97

The reduced migration/invasion of extravillous trophoblasts (EVTs) is a key feature of the genesis of preeclampsia. We and others previously reported that transcriptional factors activator protein-2 (AP-2) alpha and AP-2gamma act as suppressors of tumor invasion. The present study examined the expressions of AP-2alpha and AP-2gamma in preeclamptic placenta vs. control placenta and investigated their effect on the function of EVTs. The expressions of AP-2alpha and AP-2gamma were elevated in the preeclamptic placentas in comparison with the gestational age-matched control placentas. Their expressions also increased in EVTs of the preeclamptic placentas. Thereafter, we transfected AP-2alpha or AP-2gamma into human EVT cell line, HTR-8/SVneo. The overexpression of AP-2alpha or AP-2gamma decreased the migratory and invasive abilities in HTR-8/SVneo cells. This was followed by the reduction of protease activated receptor-1 and matrix metalloproteinases and a significant induction of plasminogen activator inhibitor-1 and the tissue inhibitor of metalloproteinase-1. AP-2alpha and AP-2gamma were weakly expressed in the cultured EVTs and HTR-8/SVneo cells, whereas they were induced by TNF-alpha, which increases in preeclamptic placenta and impairs trophoblast invasion. In the presence of TNF-alpha, the invasion of the HTR-8/SVneo cells was partially restored by a blocking of AP-2 induction using small interfering RNA of AP-2. The present data suggest that AP-2 may suppress trophoblast migration and invasion, thus leading to a shallow placentation in preeclampsia.
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PMID:Activator protein-2 impairs the invasion of a human extravillous trophoblast cell line. 1944 78


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