References of "Munaut, Carine"
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See detailTrophoblast Invasion and Placentation: Molecular Mechanisms and Regulation
van den Brule, F.; Berndt, Sarah ULg; Simon, N. et al

in Chemical Immunology and Allergy (2005), 88

Trophoblast invasion is a key process during human placentation. This event constitutes the basis of the conversion of the uterine spiral arteries, a process which allows an adequate vascular connection ... [more ▼]

Trophoblast invasion is a key process during human placentation. This event constitutes the basis of the conversion of the uterine spiral arteries, a process which allows an adequate vascular connection between the intervillous space and the maternal blood flow. Trophoblast invasion is transient, with stringent spatial and temporal control. Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is associated with decreased, shallow trophoblastic invasion. In this article, we review the molecular mechanisms of trophoblast invasion, and its mechanisms of regulation. Insights into the etiopathogenesis of preeclampsia will also be detailed. [less ▲]

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See detailSmooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension.
Lepetit, H.; Eddahibi, S.; Fadel, E. et al

in European Respiratory Journal (2005), 25(5), 834-42

Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs ... [more ▼]

Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in ECM turnover, and in smooth muscle cell (SMC) and endothelial cell migration and proliferation. MMP expression and activity are increased in experimental PAH. Therefore, this study investigated whether similar changes occur in idiopathic PAH (IPAH; formerly known as primary pulmonary hypertension). Both in situ and in vitro studies were performed on PAs from patients undergoing lung transplantation for IPAH and from patients treated by lobectomy for localised lung cancer, who served as controls. In IPAH, MMP–tissue inhibitor of metalloproteinase (TIMP) imbalance was found in cultured PASMCs, with increased TIMP-1 and decreased MMP-3. MMP-2 activity was markedly elevated as a result of increases in both total MMP-2 and proportion of active MMP-2. In situ zymography and immunolocalisation showed that MMP-2 was associated with SMCs and elastic fibres, and also confirmed the MMP-3–TIMP-1 imbalance. In conclusion, the findings of this study were consistent with a role for the matrix metalloproteinase–tissue inhibitor of metalloproteinase system in pulmonary vascular remodelling in idiopathic pulmonary arterial hypertension. The matrix metalloproteinase–tissue inhibitor of metalloproteinase imbalance may lead to matrix accumulation, and increased matrix metalloproteinase-2 activity may contribute to smooth muscle cell migration and proliferation. Whether these abnormalities are potential therapeutic targets deserves further investigation. [less ▲]

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See detailHuman chorionic gonadotropin and growth factors at the embryonic-endometrial interface control leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) secretion by human endometrial epithelium
PERRIER d'HAUTERIVE, Sophie ULg; Charlet, Jeanne de Chantal ULg; Berndt, Sarah ULg et al

in Human Reproduction (2004), 19(11), 2633-2643

BACKGROUND: The elucidation of the molecular mechanisms by which the embryo contributes to its implantation is an area of extensive research. The main objective of this study was to investigate the ... [more ▼]

BACKGROUND: The elucidation of the molecular mechanisms by which the embryo contributes to its implantation is an area of extensive research. The main objective of this study was to investigate the pattern of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) secretion by human endometrial epithelium, and their regulation by human chorionic gonadotropin (hCG) and other growth factors present at the embryonic-endometrial interface. METHODS: Endometrial epithelial cells (EEC) were isolated from biopsies collected at both proliferative and secretory phases of fertile women. RESULTS: HCG (1-50 IU/ml) increased LIF secretion by EEC cultures derived from follicular phase (up to 285+/-75%) or from secretory phase (up to 212+/-16%). In contrast, hCG reduced IL-6 secretion by EEC in both phases. The hCG/LH receptor gene was transcribed by EEC as evidenced by RT-PCR. Insulin-like growth factors 1 and 2 increased LIF secretion by EEC. Transforming growth factor beta1 stimulated LIF and reduced IL-6 secretion. CONCLUSIONS: Through hCG, the blastocyst may be involved in the control of its implantation (via an increase of proimplantatory LIF) and tolerance (via an inhibition of proinflammatory IL-6). Other growth factors present at the embryonic-endometrial interface are also involved in the control of LIF and IL-6 endometrial secretion. [less ▲]

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See detailUp-regulation of vascular endothelial growth factor-A by active membrane-type 1 matrix metalloproteinase through activation of Src-tyrosine kinases
Sounni, Nor Eddine ULg; Roghi, C.; Chabottaux, Vincent et al

in Journal of Biological Chemistry (2004), 279(14), 13564-13574

Membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor ( VEGF) are two key molecules involved in pericellular proteolysis and cell proliferation during tumor growth and ... [more ▼]

Membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor ( VEGF) are two key molecules involved in pericellular proteolysis and cell proliferation during tumor growth and angiogenesis. Our previous data showed that MT1-MMP overexpression in human breast carcinoma MCF7 cells induced an up-regulation of VEGF expression. This effect was associated in vivo with accelerated tumor growth and angiogenesis. We now provide evidence that MT1-MMP overexpression specifically affected VEGF-A production and failed to influence that of other VEGF family members ( VEGF, B, C, D, or PlGF) or their receptors. The up-regulation of VEGF-A by MT1-MMP was related to an increased transcriptional activation rather than to a modification of mRNA stability. It was blocked by synthetic MMP inhibitors, TIMP2, but not TIMP-1 and abolished by a partial deletion of the catalytic domain or the cytoplasmic tail of MT1-MMP. Analysis of the signal transduction mechanisms demonstrated that MT1-MMP acts through a signaling pathway involving Src tyrosine kinases. Thus, our results provide new insight into the mechanisms of action of MT1-MMP during angiogenesis and suggest that the full enzymatic activity of MT1-MMP is required for a specific up-regulation of VEGF-A through an activation of Src tyrosine kinase pathways. [less ▲]

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See detailMatrix metalloproteinases and tissue inhibitors of matrix metalloproteinases mRNA transcripts in the bronchial secretions of asthmatics
Cataldo, Didier ULg; Guéders, Maud ULg; Munaut, Carine ULg et al

in Laboratory Investigation : Journal of Technical Methods & Pathology (2004), 84(4), 418-424

Asthma is a chronic inflammatory disease characterized by profound extracellular matrix changes referred to as bronchial remodelling. In this study, we evaluated matrix metalloproteinases (MMPs) and ... [more ▼]

Asthma is a chronic inflammatory disease characterized by profound extracellular matrix changes referred to as bronchial remodelling. In this study, we evaluated matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) mRNA expression in bronchial secretions of asthmatics and correlated MMPs modulations with the lung function as a reflection of the bronchial extracellular matrix remodelling. Quantitative RT-PCR was performed on cell pellets obtained from induced sputum in order to detect the mRNAs for MMP-1, -2, -3, -8, -9, -12, -13 TIMP-1, -2, while semiquantitative RT-PCR was performed to assess the expression of MMP-7, monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta(1) (TGF-beta(1)). The mRNA transcripts for MMP-1, TIMP-1 and monocyte chemoattractant protein-1 (MCP-1) were increased in cell pellets of induced sputum from asthmatics when compared to controls (P<0.05), and the intensity of MMP-1 mRNA expression inversely correlated with the FEV(1) in asthmatics (r=-0.49, P<0.05). The MMP-1 mRNA/TIMP-1 mRNA ratio correlated with the levels of MCP-1 mRNA in asthmatics (r=0.47, P<0.05). There were no differences between the groups with respect to mRNA coding for MMP-2, -3, -7, -8, -9, -12, -13, -14, TIMP-2 and TGF-beta(1). We conclude that cells contained in the bronchial secretions from asthmatics express higher amounts of mRNA for MMP-1 and TIMP-1, perhaps related to an increased expression of MCP-1, which might contribute to the extracellular matrix changes observed during airway remodelling. [less ▲]

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See detailOverexpression of TIMP-1 under the MMP-9 promoter interferes with wound healing in transgenic mice
Salonurmi, T.; Parikka, M.; Kontusaari, S. et al

in Cell & Tissue Research (2004), 315(1), 27-37

We have generated transgenic mice harboring the murine matrix metalloproteinase 9 (MMP-9) promoter cloned in front of human TIMP-1 cDNA. The transgenic mice were viable and fertile and exhibited normal ... [more ▼]

We have generated transgenic mice harboring the murine matrix metalloproteinase 9 (MMP-9) promoter cloned in front of human TIMP-1 cDNA. The transgenic mice were viable and fertile and exhibited normal growth and general development. During wound healing the mice were shown to express human TIMP-1 in keratinocytes that normally express MMP-9. However, the healing of skin wounds was significantly retarded with slow migration of keratinocytes over the wound in transgenic mice. In situ zymography carried out on wound tissues revealed total blockage of gelatinolytic activity (i.e., MMP-9 and MMP-2). The results confirm studies with MMP-9 knockout mice showing that MMP-9 is not essential for general development, but they also demonstrate an important role of keratinocyte MMP-9, as well that of other keratinocyte MMPs that are inhibited by TIMP-1, in wound healing. The transgenic mice generated in this study provide a model for the role of MMPs in MMP-9-producing cells in other challenging situations such as bone fracture recovery and cancer invasion. [less ▲]

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See detailOverexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: Pathophysiological consequences
Tsatsaris, V.; Goffin, Frédéric ULg; Munaut, Carine ULg et al

in Journal of Clinical Endocrinology and Metabolism (2003), 88(11), 5555-5563

Several growth factors such as vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) are involved in the placental vascular development. We investigated whether dysregulation in ... [more ▼]

Several growth factors such as vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) are involved in the placental vascular development. We investigated whether dysregulation in the VEGF family may explain the defective uteroplacental vascularization characterizing preeclampsia. We compared pregnancies complicated by early onset severe preeclampsia or intrauterine growth retardation to normal pregnancies. Maternal plasma, placentas, and placental bed biopsies were collected. The mRNA levels of VEGF-A, PlGF, and their receptors were quantified in placentas and placental beds. Levels of VEGF-A, PlGF, and soluble VEGF receptor (VEGFR) were assessed in maternal plasma. In compromised pregnancies, elevated levels of VEGF-A and VEGFR-1 mRNAs may reflect the hypoxic status of the placenta. On contrast, the membrane-bound VEGFR-1 was decreased in the placental bed of preeclamptic patients. Preeclampsia was associated with low levels of circulating PlGF and increased levels of total VEGF-A and soluble VEGFR-1. Free VEGF-A was undetectable in maternal blood. Immunohistochemical studies revealed that VEGF-A and PlGF were localized in trophoblastic cells. Altogether, our results suggest two different pathophysiological mechanisms associated with preeclampsia. The first one is related to an overproduction of competitive soluble VEGFR-1 that may lead to suppression of VEGF-A and PlGF effects. The second one is the down-regulation of its membrane bound form (VEGFR-1) in the placental bed, which may result in the defective uteroplacental development. [less ▲]

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See detailExpression pattern of metalloproteinases and tissue inhibitors of matrix-metalloproteinases in cycling human endometrium
Goffin, Frédéric ULg; Munaut, Carine ULg; Frankenne, Francis et al

in Biology of Reproduction (2003), 69(3), 976-984

The cyclic growth, differentiation, and cell death of endometrium represents the most dynamic example of steroid-driven tissue turnover in human adults. Key effectors in these processes-matrix ... [more ▼]

The cyclic growth, differentiation, and cell death of endometrium represents the most dynamic example of steroid-driven tissue turnover in human adults. Key effectors in these processes-matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs)-are regulated by ovarian steroids and, locally, by cytokines. We used reverse transcription-polymerase chain reaction to evaluate the expression of both transcriptionally regulated molecules such as estrogen receptor-alpha, progesterone receptor, and prolactin and a large array of MMPs and TIMPs (MMP-1, -2, -3, -7, -8, -9, -11, -12, -19, -26, MT1-MMP, MT2-MMP, MT3-MMP, TIMP-1, -2, -3). Altogether, three distinct patterns of MMP and two patterns of TIMP expression were detected in cycling endometrium: 1). MMPs restricted to the menstrual period (MMPs-1, -3, -8, -9, -12); 2). MMPs and TIMPs expressed throughout the cycle (MMP-2, MT1-MMP, MT2-MMP, MMP-19, TIMP-1, and TIMP-2); 3). MMPs predominantly expressed during the proliferative phase (MMP-7, MMP-11, MMP-26, and MT3-MMP); and 4). TIMP-3, which, contrary to the other TIMPs, shows significant modulations, with maximum expression during the late secretory and menstrual phases. These specific patterns of MMP expression associated with each phase of the cycle may point to specific roles in the processes of menstruation, housekeeping activities, angiogenesis, tissue growth, and extracellular matrix remodeling. [less ▲]

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See detailEvidence of a limited contribution of feto-maternal interactions to trophoblast differentiation along the invasive pathway
Goffin, Frédéric ULg; Munaut, Carine ULg; Malassine, A. et al

in Tissue Antigens (2003), 62(2), 104-116

Trophoblast differentiation is a key event in human placental development. During extravillous trophoblast (EVT) differentiation, stem cells from the anchoring villi detach from their basement membrane ... [more ▼]

Trophoblast differentiation is a key event in human placental development. During extravillous trophoblast (EVT) differentiation, stem cells from the anchoring villi detach from their basement membrane and proliferate to form aggregates called trophoblast cell columns (TCCs). They subsequently invade the decidua and differentiate into interstitial and endovascular trophoblasts. The influence of the decidua on EVT differentiation is controversial. We therefore compared the pattern of trophoblast differentiation marker expression in viable intrauterine and tubal pregnancies, as decidual cell markers (prolactin [PRL] and insulin-like growth factor binding Protein-1 [IGFBP1]) were only expressed in endometrial implantation sites. Extravillous trophoblast differentiation in anchoring villi from uterine and ectopic pregnancies exhibited a comparable phenotypical switch: alpha6 integrin subunit, E-cadherin, EGF receptor, Ki 67 and connexin 40 were localized in the proximal part of the TCC, while alpha5beta1 and alpha1 integrins, c-erb B2, hPL and HLA-G were expressed by invasive cytotrophoblasts. The cyclin-dependent kinase inhibitors p16 and p57 were mainly detected in invasive cytotrophoblasts some distance from the columns. However, the TCC was markedly longer in tubal pregnancy than in intrauterine pregnancy. These findings suggest that the decidua is not necessary to trigger EVT invasion, but that it is likely to limit the extent of the TCC and to accelerate the onset of EVT migration. [less ▲]

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See detailPlacental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization
Rakic, Jean-Marie ULg; Lambert, Vincent ULg; Devy, Laetitia et al

in Investigative Ophthalmology & Visual Science (2003), 44(7), 3186-3193

PURPOSE. VEGF has been shown to be necessary, but not sufficient alone, for the development of subretinal pathologic angiogenesis. In the current study, the influence of placental growth factor (PIGF), a ... [more ▼]

PURPOSE. VEGF has been shown to be necessary, but not sufficient alone, for the development of subretinal pathologic angiogenesis. In the current study, the influence of placental growth factor (PIGF), a member of the VEGF family, in human and experimental choroidal neovascularization (CNV) was investigated. METHODS. The presence of VEGF family member mRNA was evaluated by RT-PCR in neovascular membranes extracted during surgery. The spatial and temporal pattern of VEGF isoforms and PIGF mRNA expression were explored by using the laser capture catapulting technique and RT-PCR in a murine laser-induced model and in vitro. PIGF expression was also studied in human donor eyes. The influence of endogenous PIGF was evaluated in deficient mice (PlGF(-/-)) and by antibody-mediated neutralization of the PIGF receptor. RESULTS. Human neovascular membranes consistently expressed VEGF-A, -B, and -C; PlGF; and VEGFR-1 and -2. The VEGF(120) isoform mRNA was primarily induced in early stages of angiogenesis in vivo and in vitro. PIGF mRNA expression was present in the intact choroid and significantly upregulated during the course of experimental CNV. Both deficient PIGF expression in PIGF(-/-) mice and PIGF receptor neutralization in wild-type mice prevented the development of choroidal neovascularization induced by laser. CONCLUSIONS. These observations demonstrate the participation of PIGF in experimental CNV. They identify therefore PIGF as an additional promising target for ocular antiangiogenic strategies. [less ▲]

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See detailDose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type 1: Implications for clinical trials
Lambert, Vincent ULg; Munaut, Carine ULg; Carmeliet, Peter et al

in Investigative Ophthalmology & Visual Science (2003), 44(6), 2791-2797

PURPOSE. To explain the conflicting reports about the influence of plasminogen activator inhibitor type (PAI-1) on pathologic angiogenesis, such as occurs during the exudative form of age-related macular ... [more ▼]

PURPOSE. To explain the conflicting reports about the influence of plasminogen activator inhibitor type (PAI-1) on pathologic angiogenesis, such as occurs during the exudative form of age-related macular degeneration. METHODS. The expression of PAI-1 mRNA was analyzed in human and murine choroidal neovascularization (CNV) by RTPCR. The influences of increasing doses of recombinant PAI-1 were evaluated by daily intraperitoneal injections in PAI-1-1-and wild-type animals with a model of laser-induced CNV. The double mechanism of action of PAI-1 (proteolytic activity inhibition versus vitronectin binding) was explored by immunohistochemical localization of fibrinogen/fibrin and by injection of recombinant PAI-1 protein defective for vitronectin binding or with adenoviral vectors bearing a mutated binding-deficient PAI-1 gene. RESULTS. PAI-1 expression was present in human CNV and strongly induced in the course of experimental subretinal neovascularization. Daily injections of recombinant PAI-1 proteins in control and PAI-1(-/-) animals demonstrated that PAI-1 could exhibit both pro- and antiangiogenic effects, dependent on the dose. PAI-1 mutants defective for vitronectin binding were used to show that PAI-1 promotes choroidal pathologic angiogenesis merely through its antiproteolytic activity. CONCLUSIONS. These observations may help to reconcile reports with opposite results regarding the effects of PAI-1 on angiogenesis and certainly warn against uncontrolled use of PAL I modulating drugs in clinical trials. [less ▲]

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See detailSevere inhibition of choroidal neovascularization in mice with a combined deficiency of MMP-2 and MMP-9 genes
Lambert, Vincent ULg; Wielockx, B.; Munaut, Carine ULg et al

in Investigative Ophthalmology & Visual Science (2003, May), 44(Suppl. 2), 410

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See detailMice without uPA, tPA, or plasminogen genes are resistant to experimental choroidal neovascularization
Rakic, Jean-Marie ULg; Lambert, Vincent ULg; Munaut, Carine ULg et al

in Investigative Ophthalmology & Visual Science (2003), 44(4), 1732-1739

PURPOSE. To evaluate the presence and potential involvement of members of the plasminogen/plasminogen activator (Plg/PA) system in the exudative form of age-related macular degeneration (AMD). METHODS ... [more ▼]

PURPOSE. To evaluate the presence and potential involvement of members of the plasminogen/plasminogen activator (Plg/PA) system in the exudative form of age-related macular degeneration (AMD). METHODS. The expression of PA members mRNA was evaluated in human and experimental choroidal neovascularization (CNV) by RT-PCR. The presence and activity of PA was studied by immunofluorescence and in situ zymography. The influence of endogenous plasminogen (Plg), urokinase (uPA), tissue type plasminogen activator (tPA), and uPA receptor (uPAR) was explored in single-gene-deficient mice in a model of laser-induced CNV. RESULTS. Members of the Plg/PA system were present both in human and murine CNV. The absence of Pig, uPA, or tPA significantly decreased the development of experimental CNV compared with wild-type or uPAR-deficient mice. This effect could be attributable, partly to a modulation of matrix metalloproteinase activity, but also to an accumulation of fibrinogen-fibrin in the laser-induced wounds. CONCLUSIONS. Together with previous work done by the authors, this study indicates that choroidal neovascularization is extremely sensitive to the modulation of Plg/PA system activity. This may provide a new strategy for the treatment of exudative AMD. [less ▲]

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See detailTIMP-2 and PAI-1 mRNA levels are lower in aneurysmal as compared to athero-occlusive abdominal aortas.
Defawe, Olivier D; Colige, Alain ULg; Lambert, Charles ULg et al

in Cardiovascular Research (2003), 60(1), 205-13

OBJECTIVE: Significant alterations of the vascular wall occurs in abdominal aortic aneurysm (AAA) and atherosclerotic occlusive disease (AOD) that ultimately may lead to either vascular rupture or ... [more ▼]

OBJECTIVE: Significant alterations of the vascular wall occurs in abdominal aortic aneurysm (AAA) and atherosclerotic occlusive disease (AOD) that ultimately may lead to either vascular rupture or obstruction. These modifications have been ascribed to one or a group of proteases, their inhibitors or to the matrix macromolecules involved in the repair process without considering the extent of the observed variations. METHODS: The mRNA steady-state level of a large spectrum of proteolytic enzymes (matrix metalloproteinases: MMP-1, -2, -3, -8, -9, -11, -12, -13, -14; urokinase plasminogen activator: u-PA), their physiological inhibitors (tissue inhibitors of MMPs: TIMP-1, -2, -3; plasminogen activator inhibitor: PAI-1) and that of structural matrix proteins (collagens type I and III, decorin, elastin, fibrillins 1 and 2) was determined by RT-PCR made quantitative by using a synthetic RNA as internal standard in each reaction mixture. The profile of expression was evaluated in AAA (n=7) and AOD (n=5) and compared to non-diseased abdominal (CAA, n=7) and thoracic aorta (CTA, n=5). RESULTS: The MMPs -8, -9, -12 and -13 mostly associated with inflammatory cells were not or barely detected in CAA and CTA while they were largely and similarly expressed in AAA and AOD. Expression of protease inhibitors or structural proteins were only slightly increased in both pathological conditions with the exception of elastin which was reduced. The main significant difference between AAA and AOD was a lower expression of TIMP-2 and PAI-1 in the aneurysmal lesions. CONCLUSIONS: The remodeling of the aortic wall in AAA and AOD involves gene activation of a large and similar spectrum of proteolytic enzymes while the expression of two physiological inhibitors, TIMP-2 and PAI-1, is significantly lower in AAA compared to AOD. The repair process in the aneurysmal disease seems similar to that of the occlusive disease. [less ▲]

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See detailVascular endothelial growth factor expression correlates with matrix metalloproteinases MT1-MMP, MMP-2 and MMP-9 in human glioblastomas.
Munaut, Carine ULg; Noël, Agnès ULg; Hougrand, Olivier ULg et al

in International Journal of Cancer = Journal International du Cancer (2003), 106(6), 848-55

Vascular endothelial growth factor (VEGF) is the major endothelial mitogen in central nervous system neoplasms and it is expressed in 64-95% of glioblastomas (GBMs). Tumour cells are the main source of ... [more ▼]

Vascular endothelial growth factor (VEGF) is the major endothelial mitogen in central nervous system neoplasms and it is expressed in 64-95% of glioblastomas (GBMs). Tumour cells are the main source of VEGF in GBMs whereas VEGF receptors (VEGFR-1, its soluble form sVEGFR-1, VEGFR-2 and neuropilin-1) are expressed predominantly by endothelial cells. Infiltrating tumour cells and newly-formed capillaries progress through the extracellular matrix by local proteolysis involving matrix metalloproteinases (MMPs). Recent studies have shown that VEGF expression and bioavailability can be modulated by MMPs. We reported previously that the expression of MT1-MMP in human breast cancer cells was associated with an enhanced VEGF expression. We used quantitative RT-PCR, Western blot, gelatin zymography and immunohistochemistry to study the expression of VEGF, VEGFR-1, VEGFR-2, sVEGFR-1, neuropilin-1, MT1-MMP, MMP-2, MMP-9 and TIMP-2 in 20 human GBMs and 5 normal brains. The expression of these MMPs was markedly increased in most GBMs with excellent correlation between mRNA and protein levels; activated forms of MMP-2 and MMP-9 were present in 8/18 and 7/18 of GBMs. A majority of GBMs (17/20) also expressed high levels of VEGF, as previously reported, with strong correlation between VEGF and MT1-MMP gene expression levels, and double immunostaining showed that VEGF and MT1-MMP peptides co-localize in tumour and endothelial cells. Our results suggest that the interplay between metalloproteinases and VEGF previously described in experimental tumours may also be operative in human GBMs. Because of its dual ability to activate MMP-2 and to up-regulate VEGF, MT1-MMP might be of central importance in the growth of GBMs and represent an interesting target for anti-cancer treatments. [less ▲]

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See detailEstrogens reduce the expression of YKL-40 in the retina: Implications for eye and joint diseases
Rakic, Jean-Marie ULg; Lambert, Vincent ULg; Deprez, Manuel ULg et al

in Investigative Ophthalmology & Visual Science (2003), 44(4), 1740-1746

PURPOSE. To identify modifications in the gene expression profile of the ocular posterior segment in ovariectomized (OVX) mice with and without substitutive estradiol therapy and to select differentially ... [more ▼]

PURPOSE. To identify modifications in the gene expression profile of the ocular posterior segment in ovariectomized (OVX) mice with and without substitutive estradiol therapy and to select differentially expressed genes that could be relevant to the natural history of human age-related macular degeneration (AMD). METHODS. Chorioretinal tissues from two groups of 25 treated and untreated OVX mice were analyzed by using cDNA array technology. The expression level of selected genes was confirmed in triplicate by RT-PCR and related to the estrogenic status of the animals. Expression of the YKL-40 gene was further investigated in intact or diseased human retinas and in a murine model of experimental choroidal neovascularization (CNV), using laser pressure catapulting. RESULTS. Of the approximately, 10,000 genes screened, only YKL-40 expression was significantly downregulated by 17-beta-estradiol. YKL-40 was expressed in intact human neural retina and in the RPE. The expression of YKL-40 was upregulated in experimental CNV and in neovascular membranes extracted from patients affected by the exudative form of AMD. CONCLUSIONS. These observations indicate that YKL-40 expression in the retina is modulated by serum levels of estradiol. This protein could be relevant to the development of AMD and is also a new mediator to take into account when evaluating the broad consequences of hormonal replacement therapy. [less ▲]

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See detailMMP-2 and MMP-9 synergize in promoting choroidal neovascularization
Lambert, Vincent ULg; Wielockx, B.; Munaut, Carine ULg et al

in FASEB Journal (2003), 17(15), 2290-2292

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but ... [more ▼]

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization. [less ▲]

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See detailMacrophage migration inhibitory factor (MIF) expression in human glioblastomas correlates with vascular endothelial growth factor (VEGF) expression
Munaut, Carine ULg; Boniver, Jacques ULg; Foidart, Jean-Michel ULg et al

in Neuropathology & Applied Neurobiology (2002), 28(6), 452-460

Macrophage migration inhibitory factor (MIF) is a peptide released upon hypothalamo-pituitary stimulation that acts as a potent endogenous antagonist of the glucocorticoid inhibition of acute inflammatory ... [more ▼]

Macrophage migration inhibitory factor (MIF) is a peptide released upon hypothalamo-pituitary stimulation that acts as a potent endogenous antagonist of the glucocorticoid inhibition of acute inflammatory response and subsequent antigen-specific response. MIF also sustains tumour growth as it promotes angiogenesis, overcomes p53-mediated cell growth arrest and inhibits tumour-specific immune responses. Using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, we studied MIF expression in 35 human glioblastomas and two normal brains. We compared these results with the expression of vascular endothelial growth factor (VEGF), the most potent angiogenic factor in glioblastomas. We detected MIF in normal cortical neurons and glial cells. All glioblastomas were positive for MIF mRNA with expression levels similar to or higher than those of normal brain. MIF immunoreactivity was seen mainly in tumour cells and less frequently in hyperplastic endothelial cells. The expressions of MIF and VEGF mRNA were strongly correlated (P < 0.0001). Our results demonstrate the expression of MIF in human glioblastomas, and indicate a close relationship with VEGF expression. This is of particular interest given the potential modulation of MIF by glucocorticosteroids. [less ▲]

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See detailPresence of alpha and beta estrogen receptors in human gingiva
Fraikin, N.; Munaut, Carine ULg; Lambert, Vincent ULg et al

in Journal of Dental Research (2002, December), 81(Sp. Iss. B), 239-239

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See detailEffect of matrigel on human extravillous trophoblasts differentiation: Modulation of protease pattern gene expression
Tarrade, A.; Goffin, Frédéric ULg; Munaut, Carine ULg et al

in Biology of Reproduction (2002), 67(5), 1628-1637

The human placenta is characterized by extensive trophoblast invasion of the uterus. Indeed, extravillous cytotrophoblast cells invade the. decidua and the upper third of uterine spiral arteries in the ... [more ▼]

The human placenta is characterized by extensive trophoblast invasion of the uterus. Indeed, extravillous cytotrophoblast cells invade the. decidua and the upper third of uterine spiral arteries in the myometrium. This invasion is reflected in situ by the expression of specific markers. In order to study this invasion process, we have established an in vitro culture model of human extravillous trophoblast isolated from first trimester chorionic villi. The aim of this study was to investigate the effect of a composite matrix, the Matrigel required for the culture of this homogenous population of extravillous trophoblasts (EVCT), on their in vitro differentiation. The effect of Matrigel was studied on different markers characterized by immunocytochemistry and by real-time polymerase chain reaction assay of transcripts. In addition, the expression of 12 different matrix metalloproteases and their inhibitors were investigated. We show that human extravillous cytotrophoblasts acquire an invasive phenotype on Matrigel associated with a specific pattern of protease gene expression. This in vitro model will be of interest to study the cellular mechanisms involved in abnormal trophoblast invasion observed in poor placentation and preeclampsia. [less ▲]

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