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J. Aragones,
M. Schneider,
K. Van Geyte,
P. Fraisl,
T. Dresselaers,
M. Mazzone,
R. Dirkx,
S. Zacchigna,
H. Lemieux,
N. H. Jeoung, [......],
R. A. Harris,
E. Gnaiger,
P. Hespel,
P. Van Hecke,
F. Schuit,
P. Van Veldhoven,
P. Ratcliffe,
M. Baes,
P. Maxwell, P. Carmeliet
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ABSTRACT: Het respiratoir distress syndroom (rds) is een frequente en ernstige aandoening bij prematuren die wordt veroorzaakt door een onvoldoende productie van surfactant.
In dit onderzoek tonen we aan dat in neonatale muizen zowel het verlies van hypoxie-induceerbare factor 2α als veranderde
expressie van vasculaire endotheliale groeifactor (vegf) resulteert in immaturiteit van de type-2-pneumocyten en fatale rds. Het intra-uterien of postnataal intratracheaal toedienen van vegf stimuleert de omzetting van glycogeen in surfactant en beschermt premature muizen tegen rds. Dit pneumotroop effect van vegf kan mogelijk een therapeutische toepassing vinden in het bevorderen van de longmaturatie bij prematuren.
Respiratory distress syndrome (rds), resulting from insufficient production of surfactant, is a common and severe complication of preterm delivery. In this
report, we show that loss of the hif-2α as well as altered vegf expression cause fatal rds in neonatal mice due to immaturity of type 2 pneumocytes. Intrauterine delivery or postnatal intratracheal instillation of
vegf stimulated conversion of glycogen to surfactant and protected preterm mice against rds. The pneumotrophic effect of vegf may have therapeutic potential for lung maturation in preterm infants.
Tijdschrift voor kindergeneeskunde 04/2012; 73(2):198-204.
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Bulletin de la Société belge d'ophtalmologie 01/2011;
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ABSTRACT: Strategies to alter angiogenesis have been successfully translated from the bench to bedside. With an estimated number of more than 500 million patients worldwide potentially benefiting from it, it is a prime example of targeted therapy that is increasingly changing the face of clinical medicine. Most efforts to stimulate or inhibit angiogenesis in the past were focused on the key angiogenic factor vascular endothelial growth factor (VEGF), resulting in the approval by the Food and Drug Administration of several drugs for the treatment of cancer and ocular disease. However, mounting clinical evidence reveals that inhibition of VEGF causes resistance and class-specific side effects, while therapeutic angiogenesis by delivering VEGF protein is more challenging than anticipated in human patients. Hence, alternatives are needed, and modulation of oxygen-sensitive enzymes (prolyl hydroxylase domain proteins) and of hypoxia induced transcription factors has recently emerged as a potential novel strategy to treat cancer and ischemic diseases. Furthermore, placental growth factor is a disease-specific angiogenic target, whose inhibition reduces cancer growth without causing major side effects, while its delivery induces revascularization of ischemic tissues. In this review, we summarize recent developments and discuss questions that arise in the exciting, rapidly developing field of angiogenic medicine, including a brief description of its possible implications in neurodegenerative diseases.
Journal of Thrombosis and Haemostasis 11/2008; 7(1):21-33. · 5.73 Impact Factor
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ABSTRACT: Recent evidence indicates that an imbalance between cardiomyocyte hypertrophy and blood vessel growth in the remote myocardium may contribute to heart failure in ischaemic heart disease. It remains, however, largely unknown which angiogenic factors are capable of stimulating vessel growth in the remote myocardium after myocardial infarction (MI) and whether systemic, rather than local, administration of such factors suffices to ameliorate post-MI cardiac recovery. We therefore analysed the effect of systemic placental growth factor (PlGF) delivery on myocardial recovery post-MI in mice. MI was induced by permanent ligation of the left anterior descending coronary (LAD) artery in C57Bl6/J mice, followed by systemic injection of a PlGF adenovirus, resulting in elevated circulating levels of PlGF for 4 weeks. Functional and morphological analysis revealed that PlGF treatment induced cardiomyocyte hypertrophy and improved cardiac recovery at day 28 post-MI. PlGF stimulated angiogenesis in the infarct border and vessel enlargement in the remote myocardium. In this mouse model, capillary-to-cardiomyocyte ratios in the remote myocardium were maintained post-MI, but PlGF increased the vascular perfusion area in balance with the cardiomyocyte hypertrophy. Overall, systemic delivery of PlGF improves cardiac performance and promotes adaptive remodelling of the post-MI heart.
The Journal of Pathology 10/2008; 216(2):236-44. · 6.32 Impact Factor
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ABSTRACT: Introduction: Murine placentation is associated with trophoblast cells invasion of the maternal endometrium and extensive maternal and foetal angiogenesis. Both processes involve proteases-dependent extracellular matrix remodelling. Among the protease inhibitors, plasminogen activator inhibitor-1 (PAI-1) is transiently produced by spongiotrophoblasts and trophoblast giant cells at days 10.5-11.5 day post-coitum (dpc). Although accumulating evidence demonstrates the key role of PA-1 in pathological angiogenesis, its function during placental vascularisation remains to be elucidated. PAI-1 knockout mice are fertile and the litter sizes are normal. We have therefore analysed the consequence of PAI-1 deficiency on murine placentation. Material and Methods: We have studied the possible role of PAI-1 by quantitating the placental vessel density, the relative thickness of the labyrinth, decidua and spongiotrophoblast at day 10.5, 12.5 and 14.5 dpc in mice deficient for PAI-1 or in control mice. An original method of computer-assisted image analysis allowed us to quantify alterations of several placental compartments identified with specific monoclonal antibodies (keratin, desmin, fibrinogen and MECA-32). To investigate the differentially expressed genes, we performed laser capture microdissection (LCM), followed by genome-wide expression profiling using high-density oligonucleotides microarray analysis (GeneChip Mouse Genome 430 2.0 Array, Affymetrix). Data were analysed using Ingenuity Pathways Analysis (Ingenuity Systems((R)), http://www.ingenuity.com). Results: At 10.5 and 12.5 dpc, an abnormal placental morphology was observed in both labyrinth and spongiotrophoblast layers in PAI-1-/- mice. Lack of PAI-1 resulted in a transient decreased maternal and fetal vascularisation of the placenta that caused (1) an enhancement in the decidua/labyrinth and labyrinth/spongiotrophoblast thickness ratios, (2) a significant increase of trophoblast density. Normalization of placental morphology occurred by day 14.5 dpc in PAI-1 deficient mice. Statistical analysis of microarrays revealed 706 genes differentially expressed between PAI-1 deficient and normal mice in the labyrinth zone at 10.5 dpc. At 14.5 dpc, only 205 genes are differentially expressed. Using Ingenuity Pathways Analysis, most of those genes were found to be associated to lipid metabolism, cellular growth and proliferation. Conclusion: Despite a transient PAI-1 requirement for optimal placental angiogenesis, this gene does not appear to be essential for trophoblast invasion and placentation.
American journal of reproductive immunology (New York, N.Y.: 1989) 08/2008; 60(1):85-6. · 3.05 Impact Factor
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ABSTRACT: The growth arrest-specific gene 6 (Gas6) plays a role in pro-atherogenic processes such as endothelial and leukocyte activation, smooth muscle cell migration and thrombosis, but its role in atherosclerosis remains uninvestigated. Here, we report that Gas6 is expressed in all stages of human and mouse atherosclerosis, in plaque endothelial cells, smooth muscle cells and macrophages. Gas6 expression is most abundant in lesions containing high amounts of macrophages, ie thin fibrous cap atheroma and ruptured plaque. Genetic loss of Gas6 does not affect the number and size of initial and advanced plaques in ApoE(-/-) mice, but alters its plaque composition. Compared to Gas6(+/+): ApoE(-/-) mice, initial and advanced plaques of Gas6(-/-): ApoE(-/-) mice contained more smooth muscle cells and more collagen and developed smaller lipid cores, while the expression of TGFbeta was increased. In addition, fewer macrophages were found in advanced plaques of Gas6(-/-): ApoE(-/-) mice. Hence, loss of Gas6 promotes the formation of more stable atherosclerotic lesions by increasing plaque fibrosis and by attenuating plaque inflammation. These findings identify a role for Gas6 in plaque composition and stability.
The Journal of Pathology 05/2008; 216(1):55-63. · 6.32 Impact Factor
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ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1, also known as serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1], member 1 [SERPINE1]) plays a pathogenetic role in renal fibrosis. It is upregulated in experimental and human diabetic nephropathy. These studies assessed the effect of PAI-1 deficiency and overproduction on renal disease in experimental diabetes.
Diabetes was induced by injection of streptozotocin in 6-week-old PAI-1-deficient mice, transgenic mice overexpressing Pai-1 and control mice. Animals were killed after 24 weeks of diabetes or after observation alone.
Pai-1 mRNA was upregulated in kidneys from genetically normal mice with diabetes and in non-diabetic Pai-1 transgenic mice. PAI-1 was not further increased in kidneys from Pai-1 transgenic mice with diabetes. Diabetes-associated albuminuria and glomerular injury, as well as renal alpha-smooth muscle actin production, were ameliorated in diabetic PAI-1-deficient mice, an amelioration associated with attenuated increases in renal matrix metallopeptidase-2 expression and activity. Diabetic Pai-1 transgenic mice did not develop increased albuminuria or glomerular injury, but the tubulointerstitial area was modestly enhanced. In addition to the findings in diabetic mice, abnormalities also developed in 30-week-old PAI-1-deficient and Pai-1 transgenic mice without diabetes. PAI-1 deficiency resulted in increased tubulointerstitial area, TGFB1 protein and alpha-smooth muscle actin. Non-diabetic 30-week-old Pai-1 transgenic mice developed similar renal abnormalities and increased matrix metallopeptidase-2 activity, together with a modest increase in serum glucose and HbA(1c).
These results demonstrate that endogenous PAI-1 deficiency protects mice from glomerular injury in longer term diabetes and that endogenous PAI-1 maintains normal renal interstitial structure in ageing not associated with diabetes.
Diabetologia 07/2007; 50(6):1315-26. · 6.81 Impact Factor
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ABSTRACT: Proteinases play a central role in the complex response of tissues to injury by influencing cellular behavior and matrix remodeling.
Considerable information on the biology of proteinases has been derived from gene targeting and gene transfer studies. One
of the best characterised proteinase systems is the plasminogen system, belonging to the large serine proteinase family. Using
mice with a targeted deficiency of plasminogen system components, it has become obvious that the plasminogen system can —
directly or indirectly by activation of matrix metalloproteinases — have divergent — even opposite — roles in disease favoring
healing in some cases and promoting tissue destruction in others. This Chapter discusses the mechanisms by which the plasminogen
system can influence the response to injury in the vessel wall, the heart, the nervous system, the lungs and the skin.
04/2006: pages 1-22;
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ABSTRACT: Apoptosis of vascular cells is considered to be a major determinant of atherosclerotic plaque vulnerability and potential rupture. Plasmin can be generated in atherosclerotic plaques and recent in vitro data suggest that plasminogen activation may trigger vascular smooth muscle cell (VSMC) apoptosis.
To determine whether plasminogen activation may induce aortic VSMC apoptosis ex vivo and in vivo.
Mice with single or combined deficiencies of apolipoprotein E (ApoE) and plasminogen activator inhibitor-1 (PAI-1) were used. Ex vivo incubation with plasminogen of isolated aortic tunica media from PAI-1-deficient mice induced plasminogen activation and VSMC apoptosis, which was inhibited by alpha2-antiplasmin. In vivo, levels of plasmin, active caspase 3 and VSMC apoptotic index were significantly higher in atherosclerotic aortas from mice with combined ApoE and PAI-1 deficiencies than in those from littermates with single ApoE deficiency. A parallel decrease in VSMC density was observed.
These data strongly suggest that plasminogen activation may contribute to VSMC apoptosis in atherosclerotic plaques.
Journal of Thrombosis and Haemostasis 04/2006; 4(3):664-70. · 5.73 Impact Factor
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ABSTRACT: The vasculature is the first organ to arise during development. Blood vessels run through virtually every organ in the body (except the avascular cornea and the cartilage), assuring metabolic homeostasis by supplying oxygen and nutrients and removing waste products. Not surprisingly therefore, vessels are critical for organ growth in the embryo and for repair of wounded tissue in the adult. Notably, however, an imbalance in angiogenesis (the growth of blood vessels) contributes to the pathogenesis of numerous malignant, inflammatory, ischaemic, infectious and immune disorders. During the last two decades, an explosive interest in angiogenesis research has generated the necessary insights to develop the first clinically approved anti-angiogenic agents for cancer and blindness. This novel treatment is likely to change the face of medicine in the next decade, as over 500 million people worldwide are estimated to benefit from pro- or anti-angiogenesis treatment. In this following chapter, we discuss general key angiogenic mechanisms in health and disease, and highlight recent developments and perspectives of anti-angiogenic therapeutic strategies.
Handbook of experimental pharmacology 02/2006;
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12/2005: pages 1-3;
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ABSTRACT: Mutations in the cardiac sodium channel, SCN5A, have been associated with one type of long-QT syndrome, with isolated cardiac conduction defects and Brugada syndrome. The sodium channelopathies exhibit marked variation in clinical phenotypes. The mechanisms underlying the phenotypical diversity, however, remain unknown. Exonic SCN5A mutations can be detected in 20% of Brugada syndrome patients.
An intronic mutation (c.4810+3_4810+6dupGGGT) in the SCN5A gene, located outside the consensus splice site, was detected in this study in a family with a highly variable clinical phenotype of Brugada syndrome and/or conduction disease and in a patient with Brugada syndrome. The mutation was not found in a control panel of 100 (200 alleles) ethnically matched normal control subjects. We provide in vivo and in vitro evidence that the mutation can disrupt the splice donor site, activate a cryptic splice site, and create a novel splice site. Notably, our data show that normal transcripts can be also derived from the mutant allele.
This is the first report of an unconventional intronic splice site mutation in the SCN5A gene leading to cardiac sodium channelopathy. We speculate that its phenotypical diversity might be determined by the ratio of normal/abnormal transcripts derived from the mutant allele.
Journal of Medical Genetics 06/2005; 42(5):e29. · 6.36 Impact Factor
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ABSTRACT: 1alpha,25(OH)2-vitamin D strongly regulates the expression of the epithelial calcium channel CaT1. CaT1 expression is reduced in ERKOalpha mice and induced by estrogen treatment, pregnancy, or lactation in VDR WT and KO mice. Estrogens and vitamin D are thus independent potent regulators of the expression of this calcium influx mechanism, which is involved in active intestinal calcium absorption.
Active duodenal calcium absorption consists of three major steps: calcium influx into, transfer through, and extrusion out of the enterocyte. These steps are carried out by the calcium transport protein 1 (CaT1), calbindin-D9K, and the plasma membrane calcium ATPase (PMCA1b), respectively. We investigated whether estrogens or hormonal changes during the female reproductive cycle influence the expression of these genes, and if so, whether these effects are vitamin D-vitamin D receptor (VDR) dependent.
We evaluated duodenal expression patterns in estrogen receptor (ER)alpha and -beta knockout (KO) mice, as well as in ovariectomized, estrogen-treated, pregnant, and lactating VDR wild-type (WT) and VDR KO mice.
Expression of calcium transporter genes was not altered in ERKObeta mice. CaT1 mRNA expression was reduced by 55% in ERKOalpha mice, while the two other calcium transporter genes were not affected. Ovariectomy caused no change in duodenal expression pattern of VDR WT and KO mice, whereas treatment with a pharmacologic dose of estrogens induced CaT1 mRNA expression in VDR WT (4-fold) and KO (8-fold) mice. Pregnancy enhanced CaTI expression equally in VDR WT and KO mice (12-fold). Calbindin-D9K and PMCA1b expression increased to a lesser extent and solely in pregnant VDR WT animals. In lactating VDR WT and KO mice, CaT1 mRNA expression increased 13 times, which was associated with a smaller increase in calbindin-D9K protein content and PMCA1b mRNA expression.
Estrogens or hormonal changes during pregnancy or lactation have distinct, vitamin D-independent effects at the genomic level on active duodenal calcium absorption mechanisms, mainly through a major upregulation of the calcium influx channel CaT1. The estrogen effects seem to be mediated solely by ERalpha.
Journal of Bone and Mineral Research 11/2003; 18(10):1725-36. · 6.37 Impact Factor
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ABSTRACT: In contrast to VEGF and its receptor VEGFR-2, PlGF and its receptor VEGFR-1 have been largely neglected and therefore their potential for therapy has not been previously explored. In this review, we describe the molecular properties of PlGF and VEGFR-1 and how this translates into an important role for PlGF in the angiogenic switch in pathological angiogenesis, by interacting with VEGFR-1 and synergizing with VEGF. PlGF was effective in the growth of new and stable vessels in cardiac and limb ischemia, through its action on different cell types (i.e. endothelial, smooth muscle and inflammatory cells and their precursors) that play a cardinal role in blood vessel formation. Accordingly, blocking its receptor VEGFR-1 with monoclonal antibodies (anti-VEGFR-1 mAb), expressed on al these cell types, successfully attenuated blood vessel formation during cancer, ischemic retinopathy and rheumatoid arthritis. In addition, while blocking this receptor was effective in reducing inflammatory disorders like atherosclerosis and rheumatoid arthritis, blocking the anti-angiogenic receptor VEGFR-2 was without effect. This indicates that in the latter diseases the beneficial effects of anti-VEGFR1 mAb were mainly due to its effect on inflammatory cells. Importantly, VEGFR-1 was also present on hematopoietic stem/progenitor cells, the precursors of inflammatory cells. Thus, these preclinical studies show proof-of-principle that PlGF and VEGFR-1 are promising therapeutic targets to treat angiogenesis and inflammation related disorders. Clinical trials will reveal whether this is also true for patients.
Journal of Thrombosis and Haemostasis 08/2003; 1(7):1356-70. · 5.73 Impact Factor
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Verhandelingen - Koninklijke Academie voor Geneeskunde van België 02/2003; 65(5):281-2.
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R Pawlinski,
A Fernandes,
B Kehrle,
B Pedersen,
G Parry,
J Erlich,
R Pyo,
D Gutstein,
J Zhang,
F Castellino,
E Melis, P Carmeliet,
G Baretton,
T Luther,
M Taubman,
E Rosen,
N Mackman
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ABSTRACT: Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that mice expressing low levels of human TF ( approximately 1% of wild-type levels) in an mTF(-/-) background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a selective heart defect that consisted of hemosiderin deposition and fibrosis. Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left ventricular function in 8-month-old low-TF mice compared with age-matched wild-type mice. Mice expressing low levels of murine FVII ( approximately 1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, FIX(-/-) mice, a model of hemophilia B, had normal hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.
Proceedings of the National Academy of Sciences 12/2002; 99(24):15333-8. · 9.68 Impact Factor
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genesis 03/2002; 32(2):177-8. · 2.53 Impact Factor
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ABSTRACT: Expression analysis and epidemiologic studies have provided indirect evidence that proteinases and growth factors play a role in the development of atherosclerosis and complications such as aneurysm formation and plaque rupture. Studies using genetically altered mice have proven to be an elegant tool to study the causal involvement of these factors in atherogenesis and to gain insight into the underlying mechanisms. Recently, proteinases of the plasminogen and matrix metalloproteinase (MMP) systems as well as their inhibitors have received much attention, and these studies together have emphasized the complexity of their role in vascular disease. This overview summarizes the current knowledge on plasminogen activator inhibitor-1 (PAI-1) in the progression of atherosclerosis and the influence of MMPs in aneurysm formation. In addition, a possible role for Gas6, the product of growth arrest-specific gene 6, in atherosclerotic lesion development is put into perspective.
Annals of the New York Academy of Sciences 01/2002; 947:124-32; discussion 132-3. · 3.15 Impact Factor
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ABSTRACT: Deprivation of oxygen (hypoxia) and/or glucose (hypoglycemia) represents a serious stress that affects cellular survival. The hypoxia-inducible transcription factor-1alpha (HIF-1alpha), which has been implicated in the cellular response to hypoxia (Semenza, G. L. (1999) Annu. Rev. Cell Dev. Biol. 15, 551-578), mediates apoptosis during hypoxia (Halterman, M. W., Miller, C. C., and Federoff, H. J. (1999) J. Neurosci. 19, 6818-6824 and Carmeliet, P., Dor, Y., Herbert, J. M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., Koch, C. J., Ratcliffe, P., Moons, L., Jain, R. K., Collen, D., and Keshet, E. (1998) Nature 394, 485-490), but the function of its homologue HIF-2alpha remains unknown. Therefore, the role of HIF-2alpha in cellular survival was studied by targeted inactivation of the HIF-2alpha gene (HIF-2alpha(-/-)) in murine embryonic stem (ES) cells. In contrast to HIF-1alpha deficiency, loss of HIF-2alpha did not protect ES cells against apoptosis during hypoxia. Both HIF-1alpha(-/-) and HIF-2alpha(-/-) ES cells were, however, resistant to apoptosis in response to hypoglycemia. When co-cultured with wild type ES cells, HIF-2alpha(-/-) ES cells became rapidly and progressively enriched in hypoglycemia but not in hypoxia. Thus, HIF-1alpha and HIF-2alpha may have distinct roles in responses to environmental stress, and despite its name, HIF-2alpha may be more important in the survival response to environmental variables other than the level of oxygen.
Journal of Biological Chemistry 11/2001; 276(42):39192-6. · 4.77 Impact Factor
