Peter Carmeliet

Vesalius Research Center, Louvain, Flemish, Belgium

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Publications (503)5836.29 Total impact

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    ABSTRACT: In endothelial cells, binding of vascular endothelial growth factor (VEGF) to the receptor VEGFR2 activates multiple signaling pathways that trigger processes such as proliferation, survival, and migration that are necessary for angiogenesis. VEGF-bound VEGFR2 becomes internalized, which is a key step in the proangiogenic signal. We showed that the urokinase plasminogen activator receptor (uPAR) interacted with VEGFR2 and described the mechanism by which this interaction mediated VEGF signaling and promoted angiogenesis. Knockdown of uPAR in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling, and uPAR deficiency in mice prevented VEGF-induced angiogenesis. Upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) to VEGFR2, which induced VEGFR2 internalization. Thus, the uPAR-VEGFR2 interaction is crucial for VEGF signaling in endothelial cells.
    Science Signaling 11/2015; 8(403):ra117. DOI:10.1126/scisignal.aaa2403 · 6.28 Impact Factor
  • Ulrike Harjes · Joanna Kalucka · Peter Carmeliet ·
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    ABSTRACT: Tumour angiogenesis has long been recognised as a target for anti-cancer therapy. The current approach of inhibiting the VEGF pathway has shown benefit in the clinic, though less than anticipated. We recently documented that glycolytic metabolism in endothelial cells (ECs) fuels angiogenesis, rendering it a possible target for inhibiting vascular growth in pathological conditions. More recently, we reported that the oxidation of fatty acids (FA) is irreplaceable for EC proliferation by providing carbons for de novo nucleotide synthesis. Furthermore, ECs are rather unique in this respect, creating novel therapeutic opportunities. Here, we review and compare the current understanding of FA utilisation in ECs and tumour cells (TCs).
    Critical reviews in oncology/hematology 11/2015; DOI:10.1016/j.critrevonc.2015.10.011 · 4.03 Impact Factor
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    ABSTRACT: Hematopoietic stem cells (HSCs) in the fetal liver (FL) unlike adult bone marrow (BM) proliferate extensively, posing different metabolic demands. However, metabolic pathways responsible for the production of energy and cellular building blocks in FL HSCs have not been described. Here, we report that FL HSCs use oxygen dependent energy generating pathways significantly more than their BM counterparts. RNA-Seq analysis of E14.5 FL versus BM derived HSCs identified increased expression levels of genes involved in oxidative phosphorylation (OxPhos) and the citric acid cycle (TCA). We demonstrated that FL HSCs contain more mitochondria than BM HSCs, which resulted in increased levels of oxygen consumption and reactive oxygen species (ROS) production. Higher levels of DNA repair and antioxidant pathway gene expression may prevent ROS-mediated (geno)toxicity in FL HSCs. Thus, we here for the first time highlight the underestimated importance of oxygen dependent pathways for generating energy and building blocks in FL HSCs.
    Stem Cell Research 11/2015; 15(3). DOI:10.1016/j.scr.2015.11.001 · 3.69 Impact Factor
  • Anna Kuchnio · Mieke Dewerchin · Peter Carmeliet ·

    Oncotarget 10/2015; 6(34). DOI:10.18632/oncotarget.6216 · 6.36 Impact Factor
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    ABSTRACT: Cell division is a metabolically demanding process, requiring the production of large amounts of energy and biomass. Not surprisingly therefore, a cell's decision to initiate division is co-determined by its metabolic status and the availability of nutrients. Emerging evidence reveals that metabolism is not only undergoing substantial changes during the cell cycle, but it is becoming equally clear that metabolism regulates cell cycle progression. Here, we overview the emerging role of those metabolic pathways that have been best characterized to change during or influence cell cycle progression. We then studied how Notch signaling, a key angiogenic pathway that inhibits endothelial cell (EC) proliferation, controls EC metabolism (glycolysis) during the cell cycle.
    Cell cycle (Georgetown, Tex.) 10/2015; DOI:10.1080/15384101.2015.1090068 · 4.57 Impact Factor
  • Saar Vandekeere · Mieke Dewerchin · Peter Carmeliet ·
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    ABSTRACT: During vessel sprouting, endothelial "tip" cells migrate at the forefront, while the endothelial "stalk" cells elongate the sprout; endothelial "phalanx" cells line quiescent vessels. Tip and stalk cells can dynamically switch phenotypes under the control of VEGF and Notch signaling. Novel findings now show that in addition to signaling cascades, metabolism co-regulates the formation of the new vasculature. Recent studies demonstrated that endothelial cells (ECs) rely primarily on glycolysis for ATP production, that glycolysis is further enhanced in angiogenic ECs, and that the key glycolytic regulator PFKFB3 co-determines angiogenesis by controlling the balance of tip versus stalk cells and promoting a migratory tip cell phenotype. On the other hand, fatty acid oxidation regulates endothelial stalk cell proliferation by providing carbon sources for biosynthetic processes, more particularly for de novo nucleotide synthesis for DNA replication. Here, we overview the current understanding of the various metabolic pathways in ECs and their impact on vessel formation in health and disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Microcirculation (New York, N.Y.: 1994) 08/2015; 22(7). DOI:10.1111/micc.12229 · 2.57 Impact Factor
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    ABSTRACT: The active form of vitamin D, 1,25(OH)2D, is a crucial regulator of calcium homeostasis, especially through stimulation of intestinal calcium transport. Lack of intestinal vitamin D receptor (VDR) signaling does however not result in hypocalcemia, because the increased 1,25(OH)2D levels stimulate calcium handling in extra-intestinal tissues. Systemic VDR deficiency, on the other hand, results in hypocalcemia because calcium handling is impaired not only in the intestine, but also in kidney and bone. It remains however unclear whether low intestinal VDR activity, as observed during aging, is sufficient for intestinal calcium transport and for mineral and bone homeostasis. To this end, we generated mice that expressed the Vdr exclusively in the gut, but at reduced levels. We found that ~15% of intestinal VDR expression greatly prevented the Vdr null phenotype in young-adult mice, including the severe hypocalcemia. Serum calcium levels were, however, in the low-normal range, which may be due to the suboptimal intestinal calcium absorption, renal calcium loss, insufficient increase in bone resorption and normal calcium incorporation in the bone matrix. In conclusion, our results indicate that low intestinal VDR levels improve intestinal calcium absorption compared to Vdr null mice, but also show that 1,25(OH)2D-mediated fine-tuning of renal calcium reabsorption and bone mineralization and resorption is required to maintain fully normal serum calcium levels. Copyright © 2015. Published by Elsevier Inc.
    Bone 08/2015; 81. DOI:10.1016/j.bone.2015.08.023 · 3.97 Impact Factor
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    ABSTRACT: Growth factor therapies to induce angiogenesis and thereby enhance the blood perfusion, hold tremendous potential to address the shortcomings of current impaired/diabetic wound care modalities. Vascular endothelial growth factor stimulates (VEGF) wound healing via multiple mechanisms. Poly(lactic-co-glycolic acid) (PLGA) supplies lactate that accelerates neovascularization and promotes wound healing. Hence, we hypothesized that the administration of VEGF encapsulated in PLGA nanoparticles (PLGA-VEGF NP) would promote fast healing due to the sustained and combined effects of VEGF and lactate. In a splinted mouse full thickness excision model, compared with untreated, VEGF and PLGA NP, PLGA-VEGF NP treated wounds showed significant granulation tissue formation with higher collagen content, re-epithelialization and angiogenesis. The cellular and molecular studies revealed that PLGA-VEGF NP enhanced the proliferation and migration of keratinocytes and upregulated the expression of VEGFR2 at mRNA level. We demonstrated the combined effects of lactate and VEGF for active healing of non-diabetic and diabetic wounds. Copyright © 2015. Published by Elsevier Inc.
    Nanomedicine: nanotechnology, biology, and medicine 07/2015; DOI:10.1016/j.nano.2015.07.006 · 6.16 Impact Factor
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    ABSTRACT: Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2's therapeutic potential. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 12(6). DOI:10.1016/j.celrep.2015.07.010 · 8.36 Impact Factor
  • Anna Rita Cantelmo · Aleksandra Brajic · Peter Carmeliet ·
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    ABSTRACT: Angiogenesis has been traditionally studied by focusing on growth factors and other proangiogenic signals, but endothelial cell (EC) metabolism has not received much attention. Nonetheless, glycolysis, one of the major metabolic pathways that converts glucose to pyruvate, is required for the phenotypic switch from quiescent to angiogenic ECs. During vessel sprouting, the glycolytic activator PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3) promotes vessel branching by rendering ECs more competitive to reach the tip of the vessel sprout, whereas fatty acid oxidation selectively regulates proliferation of endothelial stalk cells. These studies show that metabolic pathways in ECs regulate vessel sprouting, more importantly than anticipated. This review discusses the recently discovered role of glycolysis and fatty acid oxidation in vessel sprouting. We also highlight how metabolites can influence EC behavior as signaling molecules by modulating posttranslational modification.
    The Cancer Journal 07/2015; 21(4):244-9. DOI:10.1097/PPO.0000000000000133 · 4.24 Impact Factor
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    M.T. Rätsep · P. Carmeliet · M.A. Adams · B.A. Croy ·

    Placenta 05/2015; 36(5). DOI:10.1016/j.placenta.2015.02.015 · 2.71 Impact Factor
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    Circulation Research 04/2015; 116(11). DOI:10.1161/RES.0000000000000054 · 11.02 Impact Factor
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    ABSTRACT: The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.
    Nature 04/2015; 520(7546). DOI:10.1038/nature14362 · 41.46 Impact Factor
  • Annalisa Zecchin · Aleksandra Brajic · Peter Carmeliet ·
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    ABSTRACT: Endothelial cells (ECs) line blood vessels and function as a vital conduit for oxygen and nutrients, but can also form vascular niches for various types of stem cells. While mostly quiescent throughout adult life, ECs can rapidly switch to a highly active state, and start to sprout in order to form new blood vessels. ECs can also become dysfunctional, as occurs in diabetes and atherosclerosis. Recent studies have demonstrated a key role for EC metabolism in the regulation of angiogenesis, and showed that EC metabolism is even capable of overriding genetic signals. In this review, we will review the basic principles of EC metabolism and focus on the metabolic alterations that accompany EC dysfunction in diabetes and vessel overgrowth in cancer. We will also highlight how EC metabolism influences EC behavior by modulating post-translational modification and epigenetic changes, and illustrate how dietary supplementation of metabolites can change EC responses. Finally, we will discuss the potential of targeting EC metabolism as a novel therapeutic strategy.
    04/2015; 10(2):125-140. DOI:10.1007/s11515-015-1350-6
  • Guy Eelen · Pauline de Zeeuw · Michael Simons · Peter Carmeliet ·
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    ABSTRACT: Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg, vascular endothelial growth factor) and other signals (eg, Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or affects the metabolism of other cell types contributing to the pathology. We focus on the biology of ECs in tumor blood vessel and diabetic ECs in atherosclerosis as examples of the role of endothelial metabolism in key pathological processes. Finally, current as well as unexplored EC metabolism-centric therapeutic avenues are discussed. © 2015 American Heart Association, Inc.
    Circulation Research 03/2015; 116(7):1231-1244. DOI:10.1161/CIRCRESAHA.116.302855 · 11.02 Impact Factor
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    Pauline de Zeeuw · Brian W Wong · Peter Carmeliet ·
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    ABSTRACT: In healthy individuals, the endothelium plays a fundamental role in normal health in the maintenance of vascular homeostasis. Endothelial cell (EC) dysfunction results in the development of several pathologies. In diabetes, in particular, sustained hyperglycemia, a characteristic of diabetes, contributes to EC dysfunction and consequently mediates the pathogenesis of diabetes-associated micro- and macrovasculopathies. Hyperglycemia-induced EC dysfunction is triggered by elevated levels of oxidative stress derived from several mechanisms, with the mitochondria as a key source, and is exacerbated by a subsequent hyperglycemia-induced self-perpetuating cycle of oxidative stress and aberrant metabolic memory. Recent reports have highlighted the importance of metabolic pathways in EC and suggested the therapeutic potential of targeting EC metabolism. This review focuses on the current knowledge regarding differences in the metabolism of healthy ECs vs. diabetes-associated dysfunctional ECs, and outlines how EC metabolism may be targeted for therapeutic benefit.
    Circulation Journal 03/2015; 79(5). DOI:10.1253/circj.CJ-15-0230 · 3.94 Impact Factor
  • Annalisa Zecchin · Gitte Borgers · Peter Carmeliet ·
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    ABSTRACT: Endothelial cells line the blood vessel lumen and are critical for blood flow homeostasis. Excessive and deregulated vessel overgrowth is a hallmark of pathological (tumor) angiogenesis. The purpose of this review is to describe the metabolic features of endothelial cells, in comparison with those of the cancer cells, and to discuss novel antiangiogenesis approaches based on targeting endothelial cell metabolism. To form new blood vessels, endothelial cells switch from quiescence to a highly active state, characterized by migration and proliferation of endothelial cells. To date, growth factors, cytokines, and other molecules have been demonstrated to regulate vessel sprouting. However, recent evidence indicates that endothelial cell metabolism also importantly regulates angiogenesis. Whereas cancer cell metabolism has been studied extensively, endothelial cell metabolism is still in its infancy. We will discuss metabolic pathways that regulate vessel sprouting, and highlight the commonalities with cancer cells for as much as studied. We will also consider new opportunities for the development of alternative antiangiogenic therapies by targeting endothelial cell metabolism.
    Current Opinion in Hematology 03/2015; 22(3). DOI:10.1097/MOH.0000000000000138 · 3.97 Impact Factor
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    ABSTRACT: Metabolic switches in various immune cell subsets enforce phenotype and function. In the present study, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces human monocyte-derived tolerogenic dendritic cells (DC) by metabolic reprogramming. Microarray analysis demonstrated that 1,25(OH)2D3 upregulated several genes directly related to glucose metabolism, tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). Although OXPHOS was promoted by 1,25(OH)2D3, hypoxia did not change the tolerogenic function of 1,25(OH)2D3-treated DCs. Instead, glucose availability and glycolysis, controlled by the PI3K/Akt/mTOR pathway, dictate the induction and maintenance of the 1,25(OH)2D3-conditioned tolerogenic DC phenotype and function. This metabolic reprogramming is unique for 1,25(OH)2D3, because the tolerogenic DC phenotype induced by other immune modulators did not depend on similar metabolic changes. We put forward that these metabolic insights in tolerogenic DC biology can be used to advance DC-based immunotherapies, influencing DC longevity and their resistance to environmental metabolic stress. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 02/2015; 10(5). DOI:10.1016/j.celrep.2015.01.013 · 8.36 Impact Factor
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    ABSTRACT: -Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking. -Using microarray profiling on freshly isolated ECs from heart, brain and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport-related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs in part by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term this combined haplodeficiency resulted in impaired cardiac contractility. -Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil two of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.
    Circulation 01/2015; 131(9). DOI:10.1161/CIRCULATIONAHA.114.013721 · 14.43 Impact Factor
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    ABSTRACT: In healthy human pregnancies, placental growth factor (PGF) concentrations rise in maternal plasma during early gestation, peak over weeks 26-30, then decline. Since PGF in non-gravid subjects participates in protection against and recovery from cardiac pathologies, we asked if PGF contributes to pregnancy-induced maternal cardiovascular adaptations. Cardiovascular function and structure were evaluated in virgin, pregnant and postpartum C56BL/6-Pgf(-/-) (Pgf(-/-)) and C57BL/6-Pgf(+/+) (B6) mice using plethysmography, ultrasound, qPCR and cardiac and renal histology. Pgf(-/-) females had higher systolic blood pressure in early and late pregnancy but an extended, abnormal midpregnancy interval of depressed systolic pressure. Pgf(-/-) cardiac output was lower than gestation day (gd)-matched B6 after mid-pregnancy. While Pgf(-/-) left ventricular mass was greater than B6, only B6 showed the expected gestational gain in left ventricular mass. Expression of vasoactive genes in the left ventricle differed at gd8 with elevated Nos expression in Pgf(-/-) but not at gd14. By gd16, Pgf(-/-) kidneys were hypertrophic and had glomerular pathology. This study documents for the first time that PGF is associated with the systemic maternal cardiovascular adaptations to pregnancy. Copyright 2014 by The Society for the Study of Reproduction.
    Biology of Reproduction 12/2014; 92(2). DOI:10.1095/biolreprod.114.124677 · 3.32 Impact Factor

Publication Stats

52k Citations
5,836.29 Total Impact Points


  • 2008-2015
    • Vesalius Research Center
      Louvain, Flemish, Belgium
    • Imperial College London
      Londinium, England, United Kingdom
  • 1996-2014
    • Vlaams Instituut voor Biotechnologie
      • Molecular Cell Biology
      Gand, Flemish, Belgium
  • 1990-2014
    • University of Leuven
      • • Vesalius Research Center
      • • Division of Gene Technology
      • • Center for Molecular and Vascular Biology
      Louvain, Flemish, Belgium
  • 1989-2013
    • Catholic University of Louvain
      Лувен-ла-Нев, Walloon, Belgium
  • 2011
    • Universiteit Hasselt
      • Biomedical Research Institute (BIOMED)
      Hasselt, Flemish, Belgium
    • Universität Heidelberg
      • Department of General, Visceral and Transplantation Surgery
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2009
    • Universitair Psychiatrisch Centrum KU Leuven
      Cortenberg, Flanders, Belgium
  • 2006
    • CSU Mentor
      Long Beach, California, United States
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2000-2005
    • Maastricht University
      Maestricht, Limburg, Netherlands
    • Massachusetts General Hospital
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2003
    • Monash University (Malaysia)
      Labuan, Labuan, Malaysia
    • Wistar Institute
      • Melanoma Research Center
      Filadelfia, Pennsylvania, United States
    • Centre Hospitalier Universitaire de Liège
      Luik, Walloon Region, Belgium
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2002-2003
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2001
    • University of Vienna
      Wien, Vienna, Austria
    • University of Helsinki
      Helsinki, Uusimaa, Finland
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 1998
    • Thrombosis Research Institute
      Londinium, England, United Kingdom