References of "Carmeliet, Peter"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailPAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin.
Bajou, Khalid ULg; Herkenne, Stéphanie ULg; Thijssen, Victor L. et al

in Nature Medicine (2014), sous presse

The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor ... [more ▼]

The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis. [less ▲]

Detailed reference viewed: 22 (12 ULg)
Full Text
Peer Reviewed
See detailPP2A regulatory subunit Balpha controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.
Martin, Maud ULg; Geudens, Ilse; Bruyr, Jonathan et al

in EMBO Journal (2013)

To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens ... [more ▼]

To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Balpha regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Balpha in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Balpha in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Balpha controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Balpha, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Balpha/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion. [less ▲]

Detailed reference viewed: 22 (6 ULg)
Full Text
Peer Reviewed
See detailInhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties.
Bono, Francoise; De Smet, Frederik; Herbert, Corentin et al

in Cancer Cell (2013), 23(4), 477-88

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the ... [more ▼]

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment. [less ▲]

Detailed reference viewed: 36 (14 ULg)
Full Text
Peer Reviewed
See detailMOSAIC: a multiscale model of osteogenesis and sprouting angiogenesis with lateral inhibition of endothelial cells.
Carlier, Aurélie ULg; Geris, Liesbet ULg; Bentley, Katie et al

in PLoS Computational Biology (2012), 8(10), 1002724

The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis) in the callus. During angiogenesis tip cells lead the developing sprout in response to ... [more ▼]

The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis) in the callus. During angiogenesis tip cells lead the developing sprout in response to extracellular signals, amongst which vascular endothelial growth factor (VEGF) is critical. In order to ensure a correct development of the vasculature, the balance between stalk and tip cell phenotypes must be tightly controlled, which is primarily achieved by the Dll4-Notch1 signaling pathway. This study presents a novel multiscale model of osteogenesis and sprouting angiogenesis, incorporating lateral inhibition of endothelial cells (further denoted MOSAIC model) through Dll4-Notch1 signaling, and applies it to fracture healing. The MOSAIC model correctly predicted the bone regeneration process and recapitulated many experimentally observed aspects of tip cell selection: the salt and pepper pattern seen for cell fates, an increased tip cell density due to the loss of Dll4 and an excessive number of tip cells in high VEGF environments. When VEGF concentration was even further increased, the MOSAIC model predicted the absence of a vascular network and fracture healing, thereby leading to a non-union, which is a direct consequence of the mutual inhibition of neighboring cells through Dll4-Notch1 signaling. This result was not retrieved for a more phenomenological model that only considers extracellular signals for tip cell migration, which illustrates the importance of implementing the actual signaling pathway rather than phenomenological rules. Finally, the MOSAIC model demonstrated the importance of a proper criterion for tip cell selection and the need for experimental data to further explore this. In conclusion, this study demonstrates that the MOSAIC model creates enhanced capabilities for investigating the influence of molecular mechanisms on angiogenesis and its relation to bone formation in a more mechanistic way and across different time and spatial scales. [less ▲]

Detailed reference viewed: 18 (3 ULg)
Full Text
Peer Reviewed
See detailInvolvement of placental growth factor in Wallerian degeneration
Chaballe, Linda ULg; Close, Pierre ULg; SEMPELS, Maxime ULg et al

in Glia (2011), 59(3), 379-396

Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively ... [more ▼]

Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively in successful and aborted axon regeneration. In the peripheral nervous system, Schwann cells (SCs) and macrophages, under the control of a network of cytokines and chemokines, represent the main cell types involved in this process. Within this network, the role of placental growth factor (PlGF) remains totally unknown. However, properties like monocyte activation/attraction, ability to increase expression of pro-inflammatory molecules, as well as neuroprotective effects, make it a candidate likely implicated in this process. Also, nothing is described about the expression and localization of this molecule in the peripheral nervous system. To address these original questions, we decided to study PlGF expression under physiological and degenerative conditions and to explore its role in WD, using a model of sciatic nerve transection in wild-type and Pgf(-/-) mice. Our data show dynamic changes of PlGF expression, from periaxonal in normal nerve to SCs 24h postinjury, in parallel with a p65/NF-κB recruitment on Pgf promoter. After injury, SC proliferation is reduced by 30% in absence of PlGF. Macrophage invasion is significantly delayed in Pgf(-/-) mice compared with wild-type mice, which results in worse functional recovery. MCP-1 and proMMP-9 exhibit a 3-fold reduction of their relative expressions in Pgf(-/-) injured nerves, as demonstrated by cytokine array. In conclusion, this work originally describes PlGF as a novel member of the cytokine network of WD. [less ▲]

Detailed reference viewed: 60 (21 ULg)
Full Text
See detailInvolvement of Placental growth factor in Wallerian degeneration
Chaballe, Linda ULg; Close, Pierre ULg; Sempels, Maxime ULg et al

Poster (2010, September)

Detailed reference viewed: 34 (12 ULg)
Full Text
Peer Reviewed
See detailFurther pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.
Van de Veire, Sara; Stalmans, Ingeborg; Heindryckx, Femke et al

in Cell (2010), 141(1), 178-90

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as ... [more ▼]

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies. [less ▲]

Detailed reference viewed: 124 (10 ULg)
Full Text
Peer Reviewed
See detailModeling Lymphangiogenesis in a three-dimensional culture system
Bruyere, Françoise; Melen-Lamalle, Laurence; Blacher, Silvia ULg et al

in Nature Methods (2008), 5(5), 431-437

Unraveling the molecular mechanisms of lymphangiogenesis is hampered by the lack of appropriate in vitro models of three-dimensional (3D) lymph vessel growth which can be used to exploit the potential of ... [more ▼]

Unraveling the molecular mechanisms of lymphangiogenesis is hampered by the lack of appropriate in vitro models of three-dimensional (3D) lymph vessel growth which can be used to exploit the potential of available transgenic mice. We developed a potent reproducible and quantifiable 3D-culture system of lymphatic endothelial cells, the lymphatic ring assay, bridging the gap between 2D-in vitro and in vivo models of lymphangiogenesis. Mice thoracic duct fragments are embedded in a collagen gel leading to the formation of lymphatic capillaries containing a lumen as assessed by electron microscopy and immunostaining. This assay phenocopies the different steps of lymphangiogenesis, including the spreading from a preexisting vessel, cell proliferation, migration and differentiation into capillaries. Our study provides evidence for the implication of an individual matrix metalloproteinase, MMP-2, during lymphangiogenesis. The lymphatic ring assay is a robust, quantifiable and reproducible system which offers new opportunities for rapid identification of unknown regulators of lymphangiogenesis. [less ▲]

Detailed reference viewed: 132 (25 ULg)
Full Text
Peer Reviewed
See detailDeficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism.
Aragones, Julian; Schneider, Martin; Van Geyte, Katie et al

in Nature Genetics (2008), 40

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen ... [more ▼]

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. [less ▲]

Detailed reference viewed: 43 (10 ULg)
Full Text
Peer Reviewed
See detailTumoral and choroidal vascularization: differential cellular mechanisms involving plasminogen activator inhibitor type I.
Jost, Maud; Maillard, Catherine ULg; Lecomte, Julie ULg et al

in American Journal of Pathology (2007), 171(4), 1369-80

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal ... [more ▼]

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1(-/-) mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1(-/-) BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis. [less ▲]

Detailed reference viewed: 79 (32 ULg)
Full Text
Peer Reviewed
See detailRole of Gas-6 in adipogenesis and nutritionally induced adipose tissue development in mice.
Maquoi, Erik ULg; Vörös, Gabor; Carmeliet, Peter et al

in Arteriosclerosis, Thrombosis, and Vascular Biology (2005), 25(5), 1002-1007

OBJECTIVE: A potential role of growth arrest-specific gene 6 (Gas-6) in energy storage in adipose tissue was investigated in murine models of obesity. Gas-6 is a ligand for the Axl, C-Mer, and Sky family ... [more ▼]

OBJECTIVE: A potential role of growth arrest-specific gene 6 (Gas-6) in energy storage in adipose tissue was investigated in murine models of obesity. Gas-6 is a ligand for the Axl, C-Mer, and Sky family of tyrosine kinase receptors. METHODS AND RESULTS: Whereas Gas-6, C-Mer, and Sky were expressed in mature murine adipocytes, the expression of Axl was restricted to the stromal-vascular fraction, which includes pre-adipocytes. During the in vitro conversion of adipogenic 3T3-F442A cells into mature adipocytes, the expression of Gas-6 increased in undifferentiated confluent pre-adipocytes during a transient phase of growth arrest. On treatment of these cells with an adipogenic medium, Gas-6 expression decreased sharply, coinciding with expression of early adipocytes markers. This modulation was not observed in the nonadipogenic 3T3-C2 cells. The Gas-6 mRNA level was transiently downregulated during nutritionally induced expansion of adipose tissues in vivo. When kept on a standard diet, no significant difference in either total body weight or weight of gonadal or subcutaneous fat pads was observed between Gas-6 deficient and wild-type mice. On exposure to a high-fat diet, however, Gas-6-deficient mice had significantly less fat mass than their wild-type counterparts. CONCLUSIONS: Gas-6 enhances the accumulation of adipose tissue in diet-induced obese mice. [less ▲]

Detailed reference viewed: 16 (1 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 200 (11 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 32 (4 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 95 (8 ULg)