Personal tools
You are here: Home → Home → Partners List → Partners
Navigation
 
Document Actions

Partners

by evgnadmin — last modified 2008-02-22 16:50

1Inserm U36 - Pierre Corvol - Paris

The group headed by Pierre Corvol focuses on angiogenesis and vascular remodeling following ischemia-induced hypoxia, related to cardiac and critical leg ischemia. Particular emphasis is placed on the discovery of new hypoxia/ischemia induced-transcripts (HiTs). By using differential gene expression (DGE) analysis, 350 genes (including the novel angiogenic factor, Angiopoietin-like 4 protein) have been found to be differentially expressed in endothelial cells (HMEC) during hypoxia. The group also designed endothelio-centric gene arrays for the study of vascular gene expression in pathological specimens from various cardiovascular diseases.


Inserm U367 - François Alhenc-Gelas - Paris

The team headed by François Alhenc-Gelas studies the role of vasoactive peptide systems, especially the Renin-angiotensin and Kallikrein-kinin systems, in cardiovascular function and in the development of disease. The group possesses complementary expertise in molecular biology, animal (murine) physiology and pathology, and cardiovascular medicine. They have also developed a platform for cardiovascular and renal physiological analysis of mice and have created and/or studied several mutated strains over the past years.


>Inserm U441 - Cécile Duplaa - Bordeaux

The group headed by Jacques Bonnet is interested in the processes controlling new vessel formation and vascular cell recruitment, associated with a novel signalling, Wnt and its receptors, frizzled (Fz) or with TGFb. The Wnt/Fz and TGFb signalling pathways are involved in the reorganisation of the cytoskeleton, as well as in the regulation of cell-cell interactions. Monomeric GTPases are Wnt/Fz and TGFb targets, which act as molecular switches in signal transmission from the cell surface receptors to intracellular effectors. The group studies the regulation of cellular signalling by monomeric GTPases in vascular endothelial cells.


>Inserm U525 - Florent Soubrier - Paris

The group headed by Florent Soubrier is working on the regulation of gene expression in endothelial cells and vascular smooth muscle cells. The main objectives of the group include genomic approach of differential gene expression analysis in vascular cells in experimental models of endothelial dysfunction, and identification of target genes of transcription factors involved in the endothelial cell response to hypoxia and growth factor, using viral vectors and RNA interference.


>Inserm U689 - Alain Tedgui - Paris

The group headed by Alain Tedgui works on the role of apoptosis and inflammation in atherothrombosis. It provided the first evidence that apoptotic microparticles that accumulate within the atherosclerotic plaque are a major determinant of plaque thrombogenicity, and proposed endothelial apoptosis as a trigger of plaque surface erosion and thrombosis. Circulating microparticle levels are markedly enhanced patients with acute coronary syndromes or myocardial infarction, and retain the potential of inducing endothelial dysfunction. The group also studies the role of the inflammatory balance in plaque development and stability. Using mouse models of atherosclerosis, it showed that IL-10 and TGF-%uF062 exert potent anti-atherogenic activities, and first showed that the IL-18/IL-18 binding protein signalling pathway is critical in atherosclerotic plaque develoment and stability. The group of Bernard Levy investigates the role of inflammatory mediators and vasocative peptides in post-ischemic angiogenesis/vasculogenesis using a mouse model of hindlimb ischemia. This group reported the dual effect of angiotensin II on ischemia-induced angiogenesis via its type 1 (pro-angiogenic) and types 2 receptors (antiangiogenic). The group is currently investigating angiogenesis in diabetes to deciphering the mechanisms responsible for the paradoxical increased retinopathy-associated angiogenesis and decreased peripheral angiogenesis.


>Inserm U545 - Bart Staels - Lille

The group headed by Bart Staels has pioneered the deciphering of the anti-inflammatory properties of the nuclear receptors PPAR in vascular cells. The group has long-standing expertise in studying gene regulation, particularly in the field of nuclear receptors, including LXR, Rev-erb and RORs, that are expressed in the atherosclerotic plaque and in its principal cell types (macrophages, SMC, endothelial cells). The group applies whole genome approaches (microarray analysis) to identify target genes, and generate genetically modified animal models (knock-out, knock-in) to study their pathophysiological functions. This knowledge will be beneficial to the programme particularly in the determination of the function of transcription factors and pathways.


>Inserm U589 - Jean-François Arnal - Toulouse

The group headed by Jean-François Arnal is working on the role of estrogens and growth factors in atherosclerosis. The group evaluated the effects of estradiol (E2) on the endothelium and on the inflammatory/immune system in the context of atherosclerosis, aimed at understanding the atheroprotective mechanisms of E2 in women, and the paradoxical lack of protective effect of hormone replacement therapy in primary and secondary prevention of cardiovascular diseases as reported in WHI and HERS studies, respectively. Its findings that E2 prevents fatty steak formation (first stage of atherosclerosis) in mouse models of atherosclerosis, but fails to protect hypercholesterolemic mice deficient in mature B and T lymphocytes might bring some explanation to this issue of major clinical importance.

2 Bristol Heart Institute, Department of Cardiac, Anaesthetic and Radiological Sciences - Paolo Madeddu - Bristol

The group of Paolo Madeddu has discovered 3 different angiogenic pathways in the last years (human tissue kallikrein, PAR-2, and NGF). This group performs phenotypic analysis of circulating EPCs and resident ECs in patients with ischemic disease, by the use of cell biology tests and proteomics. Angiogenic growth factors are measured in the same patients for monitoring the course of the disease. EPCs and skeletal myoblasts are injected into ischemic tissue to rescue periferal and myocardial ischemia. Clinical outcome is evaluated by a combination of intraventricular hemodynamic measurements and evaluation of left ventricular remodelling, apoptosis, fibrosis, and myocardial density of capillaries and arterioles.


;Department of Clinical Medicine - Andrew C Newby - Bristol

The group headed by Andrew C Newby at the Bristol Heart Institute studies how extracellular matrix remodelling contributes to atherosclerotic plaque expansion and plaque rupture/myocardial infarction. It was first to show that matrix degrading metalloproteinases (MMPs) are necessary for vascular SMC migration and proliferation. It also identified cyclin-dependent kinase inhibitors as pivotal in the suppression of SMC proliferation by the native extracellular matrix. It developed a mechanical approach using an external polyester support to inhibit both neointima formation and atherosclerosis in experimental vein grafts, which is in clinical trial. The group also developed a unique genetic mouse model of plaque rupture and is now using genetic crosses to define the role of matrix degrading enzymes. This model has been validated morphologically, pathologically and pharmacologically. It will be used in EVGN laboratories to elucidate precise mechanisms of plaque destabilisation and to find culprit molecules that could be targeted for therapy.

3Cardiovascular Physiology - Ingrid Fleming/Rudi Busse - Frankfurt

This group concentrates on the physiology and pathophysiology of endothelial cells and has played a key role in determining the mechanisms controlling the expression and activity of the vascular NO synthases and have been instrumental in highlighting the physiological role of epoxyeicosatrienoic acids (EETs), which are cytochrome P450-derived metabolites of arachidonic acid, in vascular signalling. Additional areas of focus are free radical generating enzymes in the vascular wall, in particular the NADPH oxidase. More recently, the group identified a novel mechanism of action of angiotensin converting enzyme (ACE) inhibitors, which are widely used to treat cardiovascular disease, and is currently elucidating ACE signalling pathways. This group generates and utilises a palette of modern techniques to study molecular events in cells, isolated vessels and in intact animals.


;Department of Cardiology - Andreas Zeiher - Frankfurt

This Department has long-standing expertise in the investigation of vasomotor responses in patients with coronary artery disease. Forearm blood flow as well as coronary blood flow are measured in humans. Recent studies focussed on the role of inflammation for disease progression in patients with acute coronary syndromes. Within the last years, the clinical use of stem/progenitor cells for vascular and cardiac regeneration is the major current focus of the Department. Meanwhile more than 100 patients have been treated with either bone marrow stem/progenitor cells or ex vivo expanded endothelial progenitor cells using intracoronary infusion of the different cell types.


;Molecular Cardiology - Stefanie Dimmeler - Frankfurt

This group is an interdisciplinary research unit with a major focus on vascular biology, atherosclerosis and angiogenesis. The specific research areas include 1) the dissection of the molecular signalling pathways involved in endothelial cell function, apoptosis, and aging, 2) nitric oxide and redox signalling, and 3) the investigation of endothelial progenitor cell mobilisation, differentiation and homing and their contribution to vascular and cardiac regeneration. Specific expertise is available in the areas signalling (protein phosphorylation, degradation etc.), redox signalling, and molecular and cellular biology (gene expression arrays, non-viral transfection, RNAi).


4Division of Cardiovascular Medicine - Martin Bennett - Cambridge

Research activities
The group headed by Martin Bennett has long-standing expertise in the regulation of vascular smooth muscle cell apoptosis and cell proliferation in atherosclerosis, both in humans and animal models. Moreover, they have extensive experience in the use of genetic vectors to increase or reduce gene expression in human vascular smooth muscle cells (SMC) in vitro, and in the development of transgenic models to suppress cell lineages involved in atherosclerosis in vivo. Recent work has used genetic screening to identify genes overexpressed in human atherosclerotic plaque vs. normal SMC, including those involved in in-stent stenosis, identifying novel targets for therapy. The group also has access to human cardiovascular disease and normal tissue bank specimens, and an extensive array of animal mRNAs and tissue from diseased and normal vessels.

Publications

  • Bennett, M, Macdonald, K, Chan, S-W, Simari, R, Luzio, J and Weissberg, P. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 1998; 282:290-293.

  • Bennett, M R, Macdonald, K, Chan, S W, Boyle, J J and Weissberg, P L. Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. Circ Res 1998; 82:704-712.

  • Patel, V A, Zhang, Q J, Siddle, K, Soos, M A, Goddard, M, Weissberg, P L and Bennett, M R. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ Res 2001; 88:895-902.

  • Scott, S, O'Sullivan, M, Hafizi, S, Shapiro, L M and Bennett, M R. Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53: Implications for Brachytherapy and Drug Treatment for Restenosis. Circ Res 2002; 90:398-404.

  • Zhang, Q J, Goddard, M, Shanahan, C, Shapiro, L and Bennett, M. Differential gene expression in vascular smooth muscle cells in primary atherosclerosis and in stent stenosis in humans. Arterioscler Thromb Vasc Biol 2002; 22:2030-6.


5Department of Genetics - Marten Hofker - Maastricht

To be completed


Department of Pathology - Mat J Daemen - Maastricht

This group studies differential gene expression in murine and human atherosclerosis, using micro array analysis and subtraction libraries, to identify novel targets in plaque stability. It has shown that it is possible to obtain several novel targets, to validate them in mouse models of atherosclerosis. The group has a large expertise in phenotyping of atherosclerotic lesions and has access to a large library of well documented human atherosclerotic specimen.


;Departments of Pharmacology and Physiology - H Struijker-Boudier / Jo DeMey - Maastricht

The group of Jo De Mey focuses on arterial remodeling and arteriogenesis in relation to endothelial activation and dysfunction. Using transgenic animals, chronic drug treatment, organ culture and differential gene expression techniques the interplay between arterial vasomotor, transcriptional, cellular de-differentiation and structural responses to shear stress activation of the endothelium, is unraveled. The aim of this functional genomics initiative is to restore timely collateral vessel formation in aging individuals. The group headed by Harry Struijker-Boudier focuses on angiogenesis in relevant animal models of myocardial and hindlimb ischemia in hypertension, diabetes, and myocardial infarction. Basal mechanisms of blood vessel growth are studied in in-vivo models in the chicken and mouse embryo. Functional consequences of therapeutic angiogenesis are studied with cardiac and peripheral hemodynamic measurements and histological evaluation of tissue vascular densities and vessel wall composition.


Departments of Virology and Immunology - CA Bruggeman - Maastricht

To be completed

;Center for Molecular Medicine - Guran Hansson - Stockholm

The group headed by GK Hansson is devoted to investigating the immune pathogenesis of atherosclerosis. Previous research in this laboratory has identified inflammation as a key element in atherosclerosis, with activated T cells and macropohages as pivotal components of the lesions. It was amongst the first to decipher the role of adaptative immunity in atheroclerosis. Current research focuses on atheroprotective as well as proatherosclerotic immunity, the role of T cell subsets in regulation of vascular inflammation and atherosclerosis, and the interplay between innate and adaptive immunity in the disease process.


6Department of Cell and Molecular Biology - Lorrentz Poellinger - Stockholm

The group headed by L. Poellinger focuses its activities on understanding the biology and mechanism of action of stress-regulated transcription factors belonging to the bHLH/PAS family of transcription factors, notably the hypoxia-inducible factor (HIF)-1%uF061. The laboratory is interested in defining potentially physiological (non-stress-related) pathways for regulation of these factors, performing structural studies on bHLH/PAS proteins, and to understand the mechanism of action of hypoxia-inducible positively and negatively acting transcription factors in endothelial cells

7New strategies to inhibit tumor angiogenesis - Elisabetta Dejanna - Milano Research activities

The group headed by Elisabetta Dejanna is concentrated on problems related to angiogenesis in different pathological conditions. It discovered three new adhesive proteins, present in endothelial cell-to-cell junctions, which are responsible for endothelial homotypic adhesion and organisation of new vascular structures. It developed and optimised conditions of embryonic stem cell (ES) differentiation to endothelial cells. The group has isolated, cultured and immortalized endothelial cells from ES cells and compare their functional behaviour with that of endothelial cells obtained from early embryos ( E 8.5-9.5) or adult tissues. It showed that endothelial cell lines from different sources (bone marrow, embryo or ES) are able to incorporate and eventually transdifferentiate to cardiomyocytes in the ischemic heart. The group has developed a variety of antibodies directed to endothelial cell specific antigens, immortalized endothelial cell lines and retroviral vectors contaning cDNA for different adhesive proteins or transcription factors, that will be shared in the EVGN.

Publications

  • Vittet, D., Buchou, T., Schweitzer, A., Dejana, E., and Huber, P. Targeted null-mutation in the vascular endothelial-cadherin gene impairs the organisation of vascular-like structures in embryoid bodies. Proc.Natl.Acad.Sci.U.S.A. 1997;94:6273-6278.

  • Bazzoni, G., Dejana, E., and Lampugnani, M. G. Endothelial adhesion molecules in the development of vascular tree: the garden of forking paths. Curr.Opin.Cell Biol., 1999;11:573-581.

  • Carmeliet, P., Lampugnani, M. G., Moons, L., Breviario, F., Collen, D., and Dejana, E. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis Cell, 1999;98:147-57.

  • Balconi, G., Spagnuolo, R., and Dejana, E. Development of endothelial cell lines from embryonic stem cells. A tool for studying genetically manipulated endothelial cells in vitro. Arterioscler.Thromb.Vasc.Biol., 2000; 20:1443-1451.

  • Condorelli, G., Borello, U., De Angelis, L., Latronico, M., Sirabella, D., Coletta, M., Galli, R., Balconi, G., Adorini, L., Naldini, L., Vescovi, A., Dejana, E., and Cossu, G. Cardiomyocytes induce endothelial cells to transdifferentiate into cardiac muscle: implications for myocardium regeneration, Proc.Natl.Acad.Sci.U.S.A., 2001;98:10733-10738.


8Department of Internal Medicine and Cardiology - Thomas Luscher - Zurich

Research activities
The group of Thomas Luscher studies the role of endothelium-derived mediators (NO, reactive oxygen species, prostaglandin H2, endothelin-1 and tissue factor) in the regulation of vascular tone, platelet-vessel wall interaction, coagulation, and vascular structure, using cellular and molecular techniques, as well as genetically engineered animal models. The group employs a palette of state of the art techniques (available to the EVGN) to perform high level clinical research focussed on endothelial dysfunction in patients with hypertension, hyperlipidemia, coronary artery disease and congestive heart failure.

Publications

  • Barton M, C.C. Haudenschild, L. d'Uscio, S. Shaw, K. Munter, T.F. Luscher. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc. Natl. Acad. Sci. USA 1998;95:14367-14372.

  • Eto M, C. Barandier, L. Rathgeb, T. Kozai, H. Joch, Z. Yang, T.F. Luscher. Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways: Role of Rho/ROCK and mitogen-activated protein kinase. Circ. Res. 2001;89:583-590.

  • Luscher TF, F. Enseleit, R. Pacher, V. Mitrovic, M.R. Schulze, R. Willenbrock, R. Dietz, V. Rousson, D. Hurlimann, S. Philipp, T. Notter, G. Noll, F. Ruschitzka. Hemodynamic and neurohumoral effects of selective endothelin A (ETA) receptor blockade in chronic heart failure: The heart failure ETA receptor blockade trial (HEAT). Circulation 2002;106:2666-2672.

  • Luscher TF on behalf of the ENCORE investigators. Effects of nifedipine and cerivastatin on coronary endothelial function. The ENCORE-1 trial. Circulation 2003;107:422-428, 2003.

  • Chenevard R, D. Hurlimann, M. Bechir, F. Enseleit, L. Spieker, M. Hermann, W. Riesen, S. Gay, R. Gay, M. Neidhart, T.F. Luscher, G. Noll, F. Ruschitzka. Selective COX-2 inhibition improves endothelial function in coronary artery disease. Circulation 2003;107:405-409.


9Department of Vascular Biology and Thrombosis research - Bernd Binder - Vienna

Research activities
The group headed by Bernd Binder is focused on the analysis of reactions of blood vessels during physiological, pathophysiological and clinical relevant processes including atherosclerosis, using biochemical, molecular biological, cell biological and animal experimental research tools. It develops strategies for diagnosis and treatment of diseases including new drugs and gene therapeutic approaches. Furthermore, biochemical and molecular biological analysis system should be developed for the diagnostic of normal and diseased patients.

Publications

  • Bochkov VN, Kadl A, Huber J et al. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature. 2002;419:77-81.

  • Breuss JM, Cejna M, Bergmeister H et al. Activation of nuclear factor-k B significantly contributes to lumen loss in a rabbit iliac artery balloon angioplasty model. Circulation. 2002;105:633-638.

  • Gruber F, Hufnagl P, Hofer-Warbinek R et al. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNFa induced PAI-1 expression. Blood. 2002.

  • Huber J, Vales A, Mitulovic G et al. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol. 2002;22:101-107.

  • Wiesner C, Hoeth M, Binder BR et al. A functional screening assay for the isolation of transcription factors. Nucleic Acids Res. 2002;30:e80.


Johannes Gutenberg University Mainz - Thomas Munzel - Mainz

Research activities
The group of Thomas Munzel concentrates on the role of the NADPH oxidase, NO synthase and xanthine oxidase in endothelial dysfunction in clinically relevant models such as angiotensin II-associated hypertension, nitrate tolerance, diabetes mellitus and congestive heart failure (cardiomyopathic hamster). This group has developed highly sensitive techniques to assess vascular NO production and NADPH oxidase activity by means of electron paramagnet resonance (EPR) in all animal models (including mice), and refined methodologies to quantify vascular superoxide production using chemiluminescence techniques (coeleterazine, lucigenin, L-012 enhanced chemiluminescence) and fluorescence-based assays (dihydroethidine). These outstanding methodologies will be shared within the EVGN.

Publications

  • Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104:2673-8.

  • Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88:E14-22.

  • Warnholtz A, Mollnau H, Heitzer T, Kontush A, Moller-Bertram T, Lavall D, Giaid A, Beisiegel U, Marklund SL, Walter U, Meinertz T, Munzel T. Adverse effects of nitroglycerin treatment on endothelial function, vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits. J Am Coll Cardiol. 2002;40:1356-63.

  • Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Walter U, Forstermann U, Meinertz T, Griendling K, Munzel T. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res. 2002;90:E58-65.

  • Schulz E, Tsilimingas N, Rinze R, Reiter B, Wendt M, Oelze M, Woelken-Weckmuller S, Walter U, Reichenspurner H, Meinertz T, Munzel T. Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation. 2002;105:1170-5.

11University of Bonn - Georg Nickenig - Bonn

Research activities
The group headed by Georg Nickenig is characterizing genes involved in adhesion and homing of endothelial progenitor cells (EPCs), including SDF-1 and CXCR4. This group conducts clinical research aimed at investigating the correlation between circulating numbers of EPCs, cardiovascular outcome and endothelial function. A clinical study on 500 patients with coronary artery disease is planned and will be incorporated in the EVGN.

Publications

  • Nickenig G, Strehlow K, Baumer AT, Wassmann S, Albory K, Sauer H, Bohm M.Differential effects of estrogen and progesterone on AT1 receptor gene expression in vascular smooth muscle cells. Circulation 2000;102:1828-1833

  • Nickenig G, Michaelsen F, Muller C, Vogel T, Strehlow K, Bohm M. Posttranscriptional regulation of the AT1 receptor mRNA. Identification of the mRNA binding motif and functional characterization. FASEB J, 2001;15:1490-2

  • Nickenig G, Michaelsen F, Muller C, Berger A, Vogel T, Sachinidis A, Vetter H, Bohm M. Destabilization of AT1 receptor mRNA by calreticulin. Circ Res 2002; 90:53-58

  • Wassmann S, Laufs U, Stamenkovic D, Linz W, Stasch JP, Ahlbory K, Rosen R, Bohm M, Nickenig G. Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation, 2002;105: 2083-2091

  • Nickenig G, Baudler S, Muller C, Werner N, Welzel H, Strehlow K, Bohm M. Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo. FASEB J, 2002;16:1077-1086;


12Institute for Cardiovascular Research - Victor WM van Hinsbergh - Amsterdam

Research activities
The group of Victor WM van Hinsbergh is involved in basic and translational studies on vascular activation in inflammation and diabetes, and modulation of vessel wall remodelling. The group has a strong tradition in human endothelial cell research. Among its expertises are gene transfer of growth factors, protease (inhibitors) and newly developed hybrid proteins; transgenic mice models of vascular remodelling; cell signalling and gene expression in endothelial cell activation and angiogenesis; and clinical evaluation of endothelial activation in cohorts of patients.

Publications

  • van Nieuw Amerongen GP, van Delft S, Vermeer MA, Collard J, van Hinsbergh VWM, Role of RhoA and Rho kinase in thrombin-induced endothelial permeability. Circ. Res., 2000;87:335-340.

  • van Nieuw Amerongen GP, Vermeer MA, Lankelma J, Emeis JJ, van Hinsbergh VWM, Simvastatin improves disturbed endothelial barrier function. Circulation, 2000,102:2803-2809.

  • Quax PHA, Lamfers MLM, Lardenoye JWHP, Grimbergen JM, de Vries MR, Slomp J, de Ruiter MC, Kockx MM, Verheijen JH, van Hinsbergh VWM, Adenoviral expression of a urokinase-receptor-targeted plasmin inhibitor inhibits neointima formation in murine and human blood vessels. Circulation, 2001;103:562-569.

  • Lamfers MLM, Grimbergen JM, Aalders MC, Havenga MJ, de Vries MR, Huisman LGM, van Hinsbergh VWM, Quax PHA, Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor TIMP-1.ATF suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1. Circ. Res. 2002;91:945-952.

  • Collen A, Hanemaaijer R, Lupu F, Quax PHA, van Lent N, Grimbergen J, Peters E, Koolwijk P, van Hinsbergh VWM, Membrane-type matrix metalloproteinase mediated angiogenesis in a fibrin-collagen matrix. Blood, 2003;101:1810-1817

13Center for Drug Research - Theo van Berkel - Leiden

Research activities
The group of T. van Berkel utilizes genomic approaches to identify target genes in atherosclerosis. It develops therapeutic modulation of target genes in order to treat or prevent atherosclerotic lesion formation. It first developed a mouse model with histological features of plaque disruption that are analogous to the clinical. These features occur at a high frequency following vascular stress induction, which is a stressor that is also known to lead to plaque rupture in humans. This model, therefore, provides a unique opportunity not only for the investigation of processes leading to atherosclerotic plaque rupture, but also for the evaluation of therapies aimed at plaque stabilization.

Publications

  • von der Thuesen JH, Kuiper J, Fekkes ML, de Vos P, van Berkel TJ, Biessen EA. Attenuation of atherogenesis by systemic and local adenovirus- mediated gene transfer of interleukin-10 in LDLr-/- mice. FASEB J. 2001;15:2730-2732

  • von der Thuesen JH, van Berkel TJ, Biessen EA. Induction of rapid atherogenesis by perivascular carotic collar placement in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Circulation 2001;103:1164-1170.

  • Molenaar TJ, Appeldoorn CC, de Haas SA, Michon IN, Bonnefoy A, Hoylaerts MF, Pannekoek H, van Berkel TJ, Kuiper J, Biessen EA. Specific inhibition of P-selectin-mediated cell adhesion by phage display-derived peptide antagonists. Blood. 2002;100:3570-3577

  • von der Thuesen JH, van Vlijmen BJ, Hoeben RC, Kockx MM, Havekes LM, van Berkel TJ, Biessen EA. Induction of atherosclerotic plaque rupture in apolipopotein E-/-mice after adenovirus-mediated transfer of p53. Circulation 2002;105:2064-2070

  • van Eck M, Bos IS, Kaminski WE, Orso E, Rothe G, Twisk J, Bottcher A, van Amersfoort ES, Christiansen-Weber TA, Fung- Leung WP, van Berkel TJ, Schmitz G. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recuitment into tissues. Proc. Natl. Acad Sci USA 2002;99:6298-6303.


14Department of Molecular Cardiology - Anton J.G. Horrevoets - Amsterdam

Research activities
The group of Anton J.G. Horrevoets studies vascular gene expression during atherosclerosis using Laser Capture Micro-dissection (LCM) technique and DNA micro-array analysis. A comparative analysis of data assembled by genome-wide micro-arraying with gene-specific long oligonucleotides will allow identification of patterns of gene expression relevant to atherosclerosis in man, that can be tested by intervention strategies, acting directly on the same pathway in murine models. The expertise in genomics of the atherosclerotic plaque is particularly relevant to the EVGN programme.

Publications

  • Anton J.G. Horrevoets, Ruud D. Fontijn, Anton Jan van Zonneveld, Carlie J.M. de Vries, Jan Wouter ten Cate and Hans Pannekoek. Vascular endothelial genes that are responsive to tumor necrosis factor-alpha in vitro are expressed in atherosclerotic lesions, including inhibitor of apoptosis 1, stannin and two novel genes: a combined approach of differential display and in situ hybridization to identify novel atherosclerotic gene. Blood 1999;93:3418-3431.

  • Marten A. Engelse, Jolanda M. Neele, Tanja A.E. van Achterberg, Ron H.N. van Schaik, Hans Pannekoek and Carlie J.M. de Vries. Human activin A expression is increased in atherosclerotic tissue and induces smooth muscle cell differentiation. Circ. Res. 1999;85:931-939.

  • Marten A. Engelse, JanWillem H.P. Lardenoye, Jolanda M. Neele, Jos M. Grimbergen, Margreet R. de Vries, Martine L.M. Lamfers, Hans Pannekoek, Paul H.A. Quax and Carlie J.M. de Vries. Adenoviral activin A expression prevents intimal hyperplasia in human and murine blood vessels by maintaining the contractile smooth muscle cell phenotype. Circ. Res. 2002;90:1128-1134.

  • Rob J. Dekker, Simone van Soest, Ruud D. Fontijn, Sonia Salamanca, Philip G. de Groot, Ed Th. VanBavel, Hans Pannekoek and Anton J.G. Horrevoets. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically Lung Kruppel like factor (KLF2). Blood 2002;100:1689-1698.

  • E. Karin Arkenbout, Vivian de Waard, Maaike van Bragt, Tanja A.E. van Achterberg, Jos M. Grimbergen, Bruno Pichon, Hans Pannekoek and Carlie J.M. de Vries: Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in the carotid artery ligation model in TR3-transgenic mice. Circulation 2002;106:1530-1535.


15Vita-Salute San Raffaele University - Attilio Maseri - Milano

Research activities

Initially, the group of Attilio Maseri is involved in in vivo detection of "unstable" atherosclerotic plaques in the coronary and carotid arteries by non invasive techniques (PET, MRI, ECO) and by intravascular catheter techniques. The aim is to image coronary and carotid arterial plaque inflammation, its temporal evolution and response to therapy in unstable patients. The group also seeks to establish correlation between non invasive imaging, unstable plaques and biopsy or endoarterectomy findings, with systemic inflammatory markers. Today, the Clinical Cardiovascular Biology (CCBV) Centre at the University Vita-Salute San Raffaele, coordinated by Prof Attilio Maseri, focuses on the role of inflammation and platelets in the pathogenesis of major acute coronary events. (1-3) There is a tight collaboration between the clinical area, in particular with the Coronary Care Unit of the San Raffaele University Hospital directed by Domenico Cianflone, and the research groups, because our goal is "to select paradigmatic subgroups of patients at the extreme ends of the spectrum of clinical presentation, follow them up in the time and to characterize their inflammatory and genotypic profile"(4) We recently collected multiple 300ml aliquots of plasma and serum together with genomic DNA in a total of about 500 patients with an acute myocardial infarction (AMI) as the very first manifestation of ischemic heart disease, with 500 matched controls. The FAMI study was multicentre, conducted in three countries with different prevalence of AMI: Italy, Scotland and China, organized by Prof Attilio Maseri, Drs Domenico Cianflone and Nicole Cristell in Italy, Dr Neil Uren in Edinburgh and Prof Daji Hu in Beijing. Aliquots of these samples will be used for our next biological studies and are available for collaborative studies with EVGN members. Research efforts comprise three main lines of interest:

1."Clinical Immunology"(Angelo Manfredi) focuses on leukocyte activation and interactions with platelets and microparticles in Acute Coronary Syndrome (ACS). Enrico Ammirati, responsible for the interaction with the EVGN, is investigating T-cell sub-populations, assessing the expression of chemo-attraction receptors (CCR5 and CXCR3), memory phenotype and T-cell receptor [TCR] ?-chain by 9-color cytofluorimetry. Dr Norma Maugeri focuses on the activation of granulocytes and monocytes and their interaction with platelets by citofluorimetry and confocal microscopy.

2."Genetics" (Giorgio Casari) focuses on gene-expression profiling and genomics aspects in genes expressed by activated platelets during ACS and on the inflammatory gene function interactions.

3."EcoContrast Imaging" coordinated by Stefano Coli and Marco Magnoni, focuses on the study of vasa vasorum in carotid atherosclerotic plaques and in inflammatory plaques as in Takayasu syndromes. Other interests are the characterization of epicardial visceral adipose tissue (Giacomo Ruotolo) in stable or unstable angina patients undergoing coronary artery bypass grafting.

Publications

  1. Libby, P., Ridker, P.M., and Maseri, A. 2002. Inflammation and atherosclerosis. Circulation 105:1135-1143.

  2. Buffon, A., Biasucci, L.M., Liuzzo, G., D'Onofrio, G., Crea, F., and Maseri, A. 2002. Widespread coronary inflammation in unstable angina. N Engl J Med 347:5-12.

  3. Lombardo, A., Biasucci, L.M., Lanza, G.A., Coli, S., Silvestri, P., Cianflone, D., Liuzzo, G., Burzotta, F., Crea, F., and Maseri, A. 2004. Inflammation as a possible link between coronary and carotid plaque instability. Circulation 109:3158-3163.

  4. Maseri, A. 2006. Viewpoint. Circulation 113:f29-30.


16Institute of Pathophysiology - Georg Wick - Innsbruck

Research activities
The group of Georg Wick studies the intrinsic age-related changes in gene expression by arterial vascular cells using cDNA microarrays to identify genes with functional relevance in processes intrinsic to vascular aging. Bioinformatical analyses of the primary data points using web-based homologies and protein domain search engines afford criteria to select subsets of genes of interest for further analysis. Using bio-optical techniques fluorescent proteins green fluorescent protein (GFP) fusion proteins allow subcellular visualization as well as the determination of their possible pro- and anti-aging functional effects in endothelial and smooth muscle cells.

Publications

  • M.Mayr, S.Kiechl, J.Willeit, G.Wick, Q.Xu; Infections, immunity, and atherosclerosis. Circulation 2000;102:833-839.

  • Q.Xu, G.Schett, C.Li, Y.Hu, G.Wick; Mechanical stress-induced heat shock protein 70 expression in vascular smooth muscle cells is regulated by Rac and Ras small G proteins but not mitogen-activated protein kinase. Circ. Res. 2000;86:1122-1128.

  • Q.Xu, G.Schett, H.Perschinka, M.Mayr, G.Egger, F.Oberhollenzer, J.Willeit, S.Kiechl, G.Wick; Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation 2000;102:14-20.

  • G.Wick, H.Perschinka, G.Millonig; Atherosclerosis as an autoimmune disease: an update. Trends in Immunol. 2001;12:665-669.

  • G.Millonig, H.Niederegger, W.Rabl, B.W.Hochleitner, D.Hoefer, N.Romani, G.Wick; Network of vascular-associated dendritic cells in intima of healthy young individuals. Arterioscler. Thromb. Vasc. Biol. 2001;21:503-508.


Department of Biotechnology and Molecular Medicine - Seppo Yla-Herttuala - Kuopio

Research activities

Yla-Herttuala's group has a long experience in the analysis of gene expression in atherosclerotic lesions and have demonstrated the expression of several important factors, such as scavenger receptors, low density lipoprotein-related protein, MCP-1, MCSF, several oxidative and antioxidative enzymes and growth factors, such as PDGF-C and D and VEGF-D and their receptors in atherosclerotic lesions. This group has invested heavily in laser capture microscopy and DNA array techniques to analyse gene expression profiles in selected areas in human atherosclerotic lesions and in lesions isolated from various types of transgenic and knockout mouse and rabbit lesions. The group has also been very active in analysing the effects of the members of the VEGF family on neovascularization in atherosclerotic lesions and in causing angiogenesis in ischemic muscle.

Publications

  • Laukkanen, J., Lehtolainen, P., Gough, P.J., Greaves, D.R., Gordon, S., Yla- Herttuala, S.: Adenovirus-mediated gene transfer of a secreted form of human macrophage scavenger receptor inhibits modified low density lipoprotein degradation and foam-cell formation in macrophages. Circulation 2000;101:1091-1096.

  • Hiltunen, M.O., Laitinen, M., Turunen, M.P., Jeltsch, M., Hartikainen, J., Rissanen, T.T., Laukkanen, J., Niemi, M., Kossila, M., Hakkinen, T.P., Kivela, A., Enholm, B., Mansukoski, H., Turunen, A-M., Alitalo, K., Yla-Herttuala, S.: Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta. Circulation 2000;102:2262-2268.

  • Makinen, T., Jussila, L., Veikkola, T., Karpanen, T., Kettunen, M.I., Pulkkanen, K.J., Kauppinen, R., Jackson, D.G., Kubo, H., Nishikawa, S-I., Yla-Herttuala, S., Alitalo, K. Inhibition of lymphangiogenesis with resulting lympedema in transgenic mice expressing soluble VEGF receptor-3. Nat. Med. 2001;7:199-205.

  • Laukkanen, M.O., Kivela, A., Rissanen, T.T., Rutanen, J., Karkkainen, M.K., Leppanen, O., Barsen, J.H., Yla-Herttuala, S. Adenovirus-mediated extracellular superoxide dismutase gene therapy reduces neointima formation in balloon- denuded rabbit aorta. Circulation 2002;106:1999-2003.

  • Hiltunen, M.O., Tuomisto, T.T., Niemi, M., Brasen, J.H., Rissanen, T.T., Toronen, P., Vajanto, I., Yla-Herttuala, S. Changes in gene expression in atherosclerotic plaques analyzed using DNA array. Atherosclerosis 2002;165:23-32.

19




Department of Oncological Science - Federico Bussolino - Torino

Research activities
The group headed by Federico Bussolino is studying the molecular mechanisms supporting the development of vascular system in embryo and in adult life. Evidences that nerves and blood vessels follow similar routes of migration during embryogenesis and parallel in some anatomical districts in adult life suggest that molecular pathways may be shared, and led the group to assess the role of molecules identified in axon guidance and in synapses formation (semaphorins, neuropilins and neurexins) as players in vascular tracking. It has demonstrated that Semaphorin 3A endows the vascular system with the plasticity required for its remodelling by controlling integrin-mediated endothelial cells adhesion and migration.

Publications

  • Soldi R, S. Mitola, M Strasly, P Defilippi, G. Tarone, F. Bussolino. Role of avb3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J 1999;18:882-892.

  • Sgadari, G Bacillari, E Toschi, D Carlei, I Bacigalupo, S Baccarini, C Palladino, P Leone, R Bagarini, L Malavasi, A Cafaro, M Falchi, D Valdembri, F Bussolino, P Monini, B Ensoli. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi's sarcoma. Nature Med 2002;8:225-232.

  • Valdembri, D. Serini,G. Vacca,, A., Ribatti,D., Bussolino, F. In vivo activation of Jak/Stat-3 pathway during agiogenesis induced by GM-CSF. FASEB J, 2002;16:225-227.

  • Serini G, D Ambrosi, E Giraudo , A Gamba, L Preziosi, F Bussolino. Modeling the early stages of vascular network assembly. EMBO J, 2003, 22(8):1771-9.

  • Roca, L. Primo, D. Valdembri, P. Declerck, P. Carmeliet, P. Gabriele. F. Bussolino. Hyperthermia inhibits angiogenesis by a plasminogen activator inhbibitor-1 dependent mechanism. Cancer Res, 2003, 63(7):1500-7.


20Cardiovascular Division - Qingbo Xu - London

Research activities
Qingbo Xu's group is carrying out research on inflammatory responses in atherosclerosis focussing on the pathogenic role of heat shock proteins (HSPs), on signal transductions in the vessel wall using classic and proteomic approaches and on mouse models of atherosclerosis. This group is in a leading position in the study of HSPs in atherogenesis, and has established the first mouse model of vein graft atherosclerosis, which is proven to be powerful in studying the mechanisms of progenitor cells participating in atherosclerosis. In addition, it generated the first PKC knockout mice and analysed protein profiles of cardiovascular cells in these mice.

Publications

  • Schett G, Redlich K, Xu Q, Bizan P, Groger M, Tohidast-Akrad M, Kiener H, Smolen J, and Steiner G. Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissues: Differential regulation of hsp70 expression and HSF1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. J. Clin. Invest. 1998;102:302-311.

  • Li C, Hu Y, Mayr M, and Xu Q. Cyclic strain stress-induced mitogen-activated protein kinase (MAPK) phosphatase-1 expression in vascular smooth muscle cells is regulated by ras/rac-MAPK pathways. J. Biol. Chem. 1999;274:25273-25280.

  • Leitges M, Mayr M, Braun U, Mayr U, Li C, Pfister G, Ghaffari-Tabrizi N, Baier G, Hu Y, Xu Q. Exacerbated vein graft arteriosclerosis in protein kinase Cdelta-null mice. J Clin Invest. 2001;108:1505-12.

  • Hu Y, Davison F, Ludewig B, Erdel M, Mayr M, Url M, Dietrich H, Xu Q. Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells. Circulation. 2002;106:1834-9.

  • Mayr U, Mayr M, Li C, Wernig F, Dietrich H, Hu Y, and Xu Q. Loss of p53 accelerates neointimal lesions of vein bypass grafts in mice. Circ. Res. 2002;90:197-204.


21Institute of Microbiology, Faculty of Medicine - Eli Keshet - Jerusalem

Research activities
The group of Eli Keshet focuses its activities on the pleiotropic roles of VEGF in neovascularization and vascular maintenance, especially on roles of VEGF in mediating vascular adjustments to perturbations in oxygen homeostasis, its role as a vascular survival factor and its new emerging role in orchesrating recruiting of endothelial progenitor cells for adult neovascularization. Research also makes extensive use of genetically engineered mice for critical evaluation of the feasibility of pro-angiogenic therapy.

Publications

  • Carmeliet, P, Dor, Y, Herbert, j-M, Fukumura, D, Brusselmans, K, Dewerchin, M, Neeman, M, Bono, F, Abramovitch, R, Maxwell, P, Koch, K, Ratcliffe, P, Moons, L, Jain, R, Collen , D and Keshet E. Role of HIF-1a in hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis. Nature 394: 485-490, 1998

  • Benjamin, L, Golijanin D, Itin A, Pode D, and Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J.Clin. Invest, 1999;103: 159-165.

  • Dor Y, Porat R and Keshet E. Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol, 2001;280:C1367-C1374.

  • Dor Y, Gamenisch TD, Itin A, Fishman GL, Mcdonald JA, Carmeliet P and Keshet E. A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 2001;128:1531-8.

  • Dor Y, Djonov V, abramovitch R, Itin A, fishman GI, Carmeliet P, Goelman G and Keshet E. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 2002;21:1939-1947,


Department of Cardiovascular Medicine - Asif Ahmed - Birmingham

Research activities
The group of Asif Ahmed examines the mechanism of VEGFR-1 action by investigating the role of phosphatidylinositol 3-kinase (PI3-Kinase) / Akt in regulating cellular functions. This is achieved by selective inhibition using VEGFR-1 receptor mutants, pharmacological inhibitors and/or over-expression of dominant-negative mutants of PTEN and Akt using recombinant, replication-deficient adenoviruses. This group also investigates the effect of Angiopoietin (Ang)-2 (an antagonist of Ang1 that regulates vascular maturation via its receptor Tie-2) on NO release, and determines the intracellular mechanism of this action using confocal microscopy, pharmacological inhibitors as well as adenoviruses encoding dominant negative and constitutively active genes.

Publications

  • Li XF, Shams M, Zhu JS, Khaliq A, Wilkes M, Whittle MJ, Barnes NM, and Ahmed A. Cellular localisation of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction: Angiotensin II stimulates the release of vasorelaxants. J Clin Invest 1998;101:442-454.

  • Acevedo CH and Ahmed A. Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy. J Clin Invest 1998;101:949-955.

  • Ahmed A, Dearn S, Sangha R, Li XF, Shams M, Rola-Pleszczynski M. and Jiang J. Localization, quantification and activation of platelet-activating factor receptor in human endometrium during the menstrual cycle: PAF stimulates NO, VEGF and FAKpp125. FASEB J 1998;12:831-843.

  • Bussolati B, Dunk CE, Grohmann M, Kontos CD, Mason J. and Ahmed A. Vascular endothelial growth factor receptor-1 (VEGFR-1) receptor suppresses VEGFR-2-mediated mitogenesis and promotes endothelial cell organisation via nitric oxide. Am J Pathol 2001;159:993-1008.

  • Hewett P, Nijjar S, Shams M, Gupta J. and Ahmed A. Down-regulation of angiopoietin-1 expression in menorrhagia. Am J Pathol 2002;160:773-80.


23Division of Medicine - James Leiper - London

Research activities
James Leiper's group has long-standing expertise in endothelial cell biology and NO signalling. It has identified routes of production and metabolism of asymmetric dimethylarginine (ADMA), a naturally occurring inhibitor of NO synthase, and in particular has focussed on the role of dimethylarginine dimethylaminohydrolase (DDAHs) in the regulation of ADMA levels and NO synthase pathways. Interests span from structural biology through to in vivo studies and exploration of disease associations and genotype/phenotype relationships.

Publications

  • Murray Rust J, Leiper J, McAllister M, Tilley S, Santa Maria J, Vallance P, McDonald N. Crystal structure of dimethylamine dimethylaminohydrolase (DDAH): insights into the hydrolysis of cellular inhibitos of nitric oxide synthase. Nature Structural Biology 2001;8:679-683.

  • Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity. PNAS 2002;99:13527-13532

  • Kharbanda R, Walton B, Allen M, Klein N, Hingorani A, MacAllister R, Vallance P. Prevention of inflammation-induced endothelial dysfunction: a novel vasculoprotective action of aspirin. Circulation 2002;105:2600-2604

  • Achan V, Tran L, Leiper J, Vallance P. All-trans retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimthylarginine dimethylaminohydrolase. Circ Res 2002;90:764-769.

  • Robin J, MacAllister R, Hingorani A, Vallance P. Protease activated receptor 2 mediated vasodilatation in humans in vivo: role of nitric oxide and prostanoids. Circulation 2003;107:954-9.


24Cardiovascular Laboratory - François Mach - Geneva

Research activities
The group of François Mach is focused on the immuno-inflammatory mechanism implicated during the process of atherogenesis. Investigations are performed in vitro and in vivo on the screening for several anti-inflammatory compounds and immunosuppressors, to investigate in details their potential beneficial effects on the expression and regulation of pro-inflammatory molecules such as cytokines, chemokines, adhesion molecules, MMPs and gap junction proteins.

Publications

  • Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature;1998 394:200-203.

  • Kwak B, Mulhaupt F, Myit S, Mach F. Statins (HMG-CoA reductase inhibitors) as a novel type of immunosuppressor. Nature Med.;2000 6:1399-1402. B, Myit S, Mulhaupt F, Veillard N, Pelli G, Mach F.

  • PPARg but not PPARa activators reduce IFN-g induced MHC class II expression on human endothelial cells and monocyte/macrophages: Role for PPARs as immunosuppressor? Circ Res;2002 90:356-62.

  • Kwak B, Mulhaupt F, Veillard N, Pelli G, Gros G, Mach F. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol.;2002 22:225-30.

  • Kwak B, Veillard N, Pelli G, Mulhaupt F, James R, Chanson M, Mach F. Reduced connexin43 expression inhibits atherosclerotic lesion formation in LDL-receptor deficient mice. Circulation 2003;107:1033-9.


25Animal core facilities and phenotyping platform - Johan Auwerx - Strasbourg

Research activities
The Institut Clinique de la Souris (ICS) http://www-mci.u-strasbg.fr, headed by Johan Auwerx and Pierre Chambon will provide outstanding expertise in the production of transgenic animals, as well as in mouse phenotyping. The activities of ICS relevant to the EVGN programme can be divided into two aspects: Targeted mutagenesis: The ICS uses a targeted mutagenesis strategy with a special emphasis on spatially- and temporally-controlled somatic mutagenesis in the mouse so as to study mammalian functional genomics throughout development and post-natal life. The ICS was amongst the 1st centers to implement such a temporally-controlled somatic mutagenesis strategy. At present the ICS has generated over 800 mice lines (> 300 through targeted mutagenesis). Mouse phenotyping: The ICS recently established an in-depth high throughput mice phenotypic screening platform covering all important organ systems by regrouping molecular biologists and clinical scientists in an interactive environment. The further development of high throughput phenotyping at the ICS is fostered by its prime role in the EU funded Eumorphia programme (5th FP), focussed on the standardization of mouse phenotyping. This integrative approach facilitates the development of mice models for human disease. The cardiovascular phenotyping platform of the ICS is based on typical clinical investigations adapted to mice such as, clinical chemistry (including biochemical, haematological, immunological and metabolic evaluation), invasive and non-invasive blood pressure measurements, telemetry, electrocardiography and echocardiography. The ICS contains an animal house with a total capacity of ± 70.000 mice. The ICS will provide a core service to the EVGN by: - Sharing already existing mutant mouse lines under the conditions specified in the Consortium Agreement. - Producting additional mutant mice lines through homologous recombination in ES cells and of transgenic mouse lines cell-type-selectively expressing the inducible Cre-ERT2 recombinase to generate cell-type-specific temporally-controlled somatic mutations in mice harbouring "floxed" alleles. - Animal breeding and generation of mice colonies - Comprehensive phenotypic testing (including the CV system) of the mice. - Training of biologists, physicians, and bio-informaticians, who are indispensable for the cardiovascular phenotyping and who can exchange between the different institutions.

Publications

  • Claudel T, M. Leibowitz, C. Fievet, A. Tailleux, J. Repa, G. Torpier, J. Lobaccaro, J. Paterniti, D. Mangelsdorf, R. Heyman, J. Auwerx. Reduction of atherosclerosis in apolipoprotein E knock-out mice by activation of the retinoid X receptor. Proc. Natl. Acad. Sci. USA 2001;98:2610-2615.

  • Imai T, M. Jiang, P. Chambon, and D. Metzger. Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor a mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ERT2) in adipocytes. Proc. Natl. Acad. Sci. USA, 2001;98:224-228.

  • Imai T, M. Jiang, P. Kastner, P. Chambon, and D. Metzger. Selective ablation of retinoid X receptor a in hepatocytes impairs their lifespan and regenerative capacity. Proc. Natl. Acad. Sci. USA, 2001;98:4581-4586.

  • Picard F, M. Gehin, J.-S. Annicotte, S. Rocchi, M.-F. Champy, B.W. O'Malley, P. Chambon, and J. Auwerx. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 2002;111:931-941.

  • Tabernero A, J.M. Reimund, S. Chasserot, C.D. Muller, and R. Andriantsitohaina. Cyclooxygenase-2 expression and role of vasoconstrictor prostanoids in small mesenteric arteries from patients with Crohn's disease. Circulation 2003;107:1407-1410.

26Ark Therapeutics Ltd - David Ellam - London

Research activities
Ark Therapeutics is an emerging healthcare group with one product introduced into hospitals and three further lead products in late stage clinical development. Capitalising on over ten years of research in vascular biology and gene-based medicine, Ark has created a balanced portfolio of proprietary healthcare products targeted at specific unmet clinical needs within vascular disease and cancer. Ark Therapeutics will give its advices as a consultant to the EVGN on potentially exploitable findings. Ark Therapeutics is particularly interested by the commercial exploitation in the area of gene therapy. Efforts will be devoted to exploit any appropriate intellectual property generated in this area.


27Technoclone GmbH - Veronika Binder - Vienna

Research activities
Technoclone's mission is to provide customer with quality test systems for in vitro diagnostics with special emphasis in the area of thrombosis and cardiovascular diseases. Technoclone currently develops new assay systems for thrombin generation and for the functional analysis of the von Willebrand factor cleaving protease ADAM-TS13. Assay technology includes generation of monoclonal antibodies, recombinant proteins, phospholipid and microcarrier vesicles that are applied for antigen and functional assays in discontinuous and continuous systems.

28






Management activities - Catherine Clusel - Paris

Management office for EVGN
Inserm Transfert is a private company (subsidiary of Inserm) which was created in 2001 to facilitate and improve technology transfer between Inserm research units and the private sector. Inserm Transfert is structured into five different departments dealing respectively with: start-up creation, preclinical and clinical trials (proof of concept), technology transfert management, industrial sponsorship and European project management. Dr Catherine Clusel, the EVGN dedicated Project Manager, is fully involved in the set-up and the follow-up of a coherent management framework, dealing with: - Project management (surveillance of milestones and goals, timetabling of reports and documents, awareness of new impacting information, assessments of efforts and budget) - Legal and financial management of the EVGN (a collaborative work between each partner's administration regarding budget management, consortium agreement updating, periodic reporting control, contractual regulation accordance) - Resource management (equipment, consumables, personnel, best practice, standardised protocols) - Knowledge management (generation of an organizational memory, development of a higher standard of skill and impact) - Intellectual property management (in close liaison with the exploitation sub-committee of the network) - Communication (in direct link with the communication sub-committee of the network) - Perpetuation of the EVGN beyond FP6 funding Nicolas Vautrin, the dedicated Junior Project Manager, participates in the follow-up of the EVGN project. His knowledge in European financial rules is a strong value for the EVGN Network management team.

 30

Research activities - Ryszard Korbut- Krakow
The group headed by prof. R. Korbut is devoted to investigating the endothelial dysfunctions related to atherogenesis, hypertension, obesity and diabetes. Previous research in this laboratory has identified prostacyclin (prof. R. Gryglewski -retired) and reactive oxygen species as important vascular mediators. Over past few years we have investigated role of nitric oxide in endotoxic shock, role of cyclooxygenase products in inflammation and endothelial actions of cardiovascular drugs. Scientific Team: Ryszard Korbut, Tomasz Guzik, Stefan Chlopicki, Rafal Olszanecki, Jacek Jawien, Pawel Wolkow, Wojciech Uracz, Ewa Marcinkiewicz (1 Professor, 3 Associated Prof.,11 Post Doc`s, 3 PhD students, 9 technicians Labs: Experimental Pharmacology (Isolated Heart, Lung & Vessels Pharmacologycal Analysis (HPLC, LC MS) Biochemistry & Mollecular Pharmacology (Tissue Culture. Immunochemistry, PCR, RIA)

29Jagiellonian University - Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology - Jozef Dulak - Krakow

Research activities
For several years we have been investigating the mechanisms of modulating angiogenesis by overexpression of the genes involved in redox reactions. We have demonstrated that enhancement of VEGF synthesis can be attained by gene transfer of nitric oxide synthases or heme oxygenase-1 (HO-1) (1-3). Recent data, obtained partially by our group, indicate that HO-1 is also crucial for the pro-angiogenic activity of SDF-1 (4). We are elaborating on the vasculoprotective effects of HO-1 (eg. 5)., which has been demonstrated to prevent endothelial injury, inhibit the development of restenosis or exert protective effect against myocardial infarction. Our group has developed models for investigation of neovascularisation and elaborated on viral vectors for overexpression of pro-angiogenic genes and heme oxygenase-1. We have the established colony of HO-1 knockout mice. The methods and mice will contribute to the EVGN research and can be shared with other partners.

Publications

  • Dulak J, Jozkowicz A, Foresti R., Kasza A, Frick M, Huk I, Pachinger O, Weidinger F. Motterlini R. Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells. Antioxid Redox Signal, 2002; 4:229-240

  • Jozkowicz A, Cooke JP, Guevara I, Huk I, Funovics P, Pachinger O, Weidinger F, Dulak J. Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF. Cardiovasc Res, 2001; 51: 773-783

  • Cisowski J, Loboda A, Jozkowicz A, Chen S, Agarwal A, Dulak J. Role of heme oxygenase-1 in hydrogen peroxide-induced VEGF synthesis: effect of HO-1 knockout. Biochem Biophys Res Commun 2005: 326: 670-676

  • Deshane J, Chen S, Caballero S, Grochot-Przeczek A, Was H, Li Calzi S, Lach R, Hock TD, Chen B, Hill-Kapturczak N, Siegal GP, Dulak J, Jozkowicz A, Grant MB, Agarwal A. Stromal cell-derived factor-1 promotes angiogenesis via a heme oxygenase-1 dependent pathway. J Exp Med, 2007, J Exp Med, 2007 Mar 19;204(3):605-18. Epub 2007 Mar 5.

  • Jofre-Monseny L, Loboda A, Wagner AE, Huebbe P, Boesch-Saadatmandi C, Jozkowicz A, Minihane A-M, Dulak J, Rimbach G. Effects of apoE genotype on macrophage inflammation and heme-oxygenase-1 expression. Biochem Biophys Res Commun, 2007 May 25;357(1):319-24. Epub 2007 Apr 2.


30Research activities - Michal Tendera - Krakow

The major field of our scientific interest is the mobilization of adult bone-marrow derived stem cells in acute myocardial infarction. Our studies revealed a significant mobilization of stem cells expressing CD34, CD117, c-met and CXCR4 antigens along with increase of inflammatory/haematopoietic cytokines early in acute myocardial infarction (STEMI).
Moreover, we documented that synchronously with the rise of CD34+/CXCR4+ cells number there is also a marked increase of mRNA expression for cardiac (Nkx2.5/Csx GATA-4 MEF2C), endothelial (VE-cadherin, von Willebrand) and muscle (Myf5, MyoD, myogenin) markers in peripheral blood mononuclear cells. In our opinion these findings support the hypothesis of tissue-committed stem cells. Our collaborators lead by Prof. Mariusz Ratajczak were among the first to formulate and publish the concept of tissue-committed stem cells that are present in bone-marrow and other niches such as skeletal muscles. These cells can be recruited and chemoattracted by SDF-1 produced by various tissues including ischemic myocardium and can contribute to myocardial regeneration. We plan to develop this hypothesis further by assessing of following mechanisms in animal experiments and in human studies:

1) specificity of the ischemia-induced stem cell mobilization.
We designed the experiments to evaluate if the cell mobilization and expression profiles of tissue-specific genes differ in acute myocardial infarction and non-ischemic forms of tissue injury. Our aims include the microarray assessment of the gene expression profile in different populations of cells mobilized in AMI.

2) Comparison of the efficiency of sorted subpopulation of CD34+/CXCR4+ cells and unselected bone-marrow-derived progenitor cells in treatment of patients with acute myocardial infarction and low left ventricular ejection fraction.
The subpopulation of CD34+/CXCR4+ cells most likely contains the tissue-specific stem cells. This approach is novel and original, because so far no study identified the type of cells that actually contribute to stem cell-induced improvement in myocardial function in patients with AMI which were treated with unselected population of cells. The REGENT trial (prospective, randomized, multicentre traial comparing unselected BM mononuclear cells and sorted CD34/CXCR4+ cells in patients with myocardial infarction and low left ventricular ejection fraction). coordinated by our clinic and designed to answer this question is currently enrolling patients (so far 78 treated, 200 planned).

3) Evaluation of the influence of statins administered early in AMI on the mobilization of stem cells.
We completed the pilot LAVA trial and the results were presented at 2005 American College of Cardiology Meeting and in the featured abstract session of the European Society of Cardiology Congress in Stockholm.

  • Wojakowski W, Tendera M, Michalowska A, Majka M, Kucia M, Maslankiewicz K, Wyderka R, Ochala A, Ratajczak MZ: Mobilization of tissue-commited (CD34+, CD 117+, CXCR4+, c-met+) stem cells into peripheral blood in patients with acute myocardial infarction. Circulation 2004, 110, 3213-3220.

  • Wojakowski W, Tendera M, Zebzda A, Michalowska A, Majka M, Kucia M, Maslankiewicz K, Wyderka R, Krol M, Ochala A, Kozakiewicz K, Ratajczak MZ. Mobilization of CD34+, CD117+, CXCR4+, c-met+ stem cells is correlated with left ventricular ejection fraction and plasma NT-proBNP levels in patients with acute myocardial infarction. Eur Heart J. 2005 Nov 2; [Epub ahead of print]

  • Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek, A, Ratajczak J, Ratajczak MZ. Trafficking of Normal Stem Cells and Metastasis of Cancer Stem Cells Involve Similar Mechanisms: Pivotal Role of the SDF-1-CXCR 4 Axis. Stem Cells. 2005 May 11; [Epub ahead of print]

  • Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005 Dec;26(23):2529-36. Epub 2005 Oct 7.
Powered by Plone CMS, the Open Source Content Management System

This site conforms to the following standards: