Peter Carmeliet

Vesalius Research Center, Louvain, Flemish, Belgium

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Publications (469)5304.95 Total impact

  • 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; DOI:10.1111/micc.12229 · 2.26 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; DOI:10.1016/j.bone.2015.08.023 · 4.46 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 · 5.98 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; 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 · 3.61 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 · 3.29 Impact Factor
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    Circulation Research 04/2015; 116(11). DOI:10.1161/RES.0000000000000054 · 11.09 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 · 42.35 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 · 11.09 Impact Factor
  • 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 · 3.69 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 · 4.05 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 · 14.95 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 · 3.45 Impact Factor
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    ABSTRACT: For eukaryotic cells to function properly, they divide their intracellular space in subcellular compartments, each harboring specific metabolic activities. In recent years, it has become increasingly clear that compartmentalization of metabolic pathways is a prerequisite for certain cellular functions. This has for instance been documented for cellular migration, which relies on subcellular localization of glycolysis or mitochondrial respiration in a cell type-dependent manner. Although exciting, this field is still in its infancy, partly due to the limited availability of methods to study the directionality of metabolic pathways and to visualize metabolic processes in distinct cellular compartments. Nonetheless, advances in this field may offer opportunities for innovative strategies to target deregulated compartmentalized metabolism in disease. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Current Opinion in Biotechnology 12/2014; 34C:73-81. DOI:10.1016/j.copbio.2014.11.022 · 8.04 Impact Factor
  • ASH Annual Meeting 2014; 12/2014
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    ABSTRACT: Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability.
    Nature Communications 11/2014; 5:5582. DOI:10.1038/ncomms6582 · 10.74 Impact Factor
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    ABSTRACT: The tight interrelationship between peroxisomes and mitochondria is illustrated by their cooperation in lipid metabolism, antiviral innate immunity and shared use of proteins executing organellar fission. In addition, we previously reported that disruption of peroxisome biogenesis in hepatocytes severely impacts on mitochondrial integrity, primarily damaging the inner membrane. Here we investigated the molecular impairments of the dysfunctional mitochondria in hepatocyte selective Pex5 knockout mice. First, by using blue native electrophoresis and in-gel activity stainings we showed that the respiratory complexes were differentially affected with reduction of complexes I and III and incomplete assembly of complex V, whereas complexes II and IV were normally active. This resulted in impaired oxygen consumption in cultured Pex5(-/-) hepatocytes. Second, mitochondrial DNA was depleted causing an imbalance in the expression of mitochondrial- and nuclear-encoded subunits of the respiratory chain complexes. Third, mitochondrial membranes showed increased permeability and fluidity despite reduced content of the polyunsaturated fatty acid docosahexaenoic acid. Fourth, the affected mitochondria in peroxisome deficient hepatocytes displayed increased oxidative stress. Acute deletion of PEX5 in vivo using adeno-Cre virus phenocopied these effects, indicating that mitochondrial perturbations closely follow the loss of functional peroxisomes in time. Likely to compensate for the functional impairments, the volume of the mitochondrial compartment was increased several folds. This was not driven by PGC-1α but mediated by activation of PPARα, possibly through c-myc overexpression. In conclusion, loss of peroxisomal metabolism in hepatocytes perturbs the mitochondrial inner membrane, depletes mitochondrial DNA and causes mitochondrial biogenesis independent of PGC-1α. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 11/2014; 1853(2):285-298. DOI:10.1016/j.bbamcr.2014.11.017 · 5.30 Impact Factor

Publication Stats

40k Citations
5,304.95 Total Impact Points

Institutions

  • 2008–2015
    • Vesalius Research Center
      Louvain, Flemish, Belgium
    • Imperial College London
      Londinium, England, United Kingdom
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1996–2014
    • Vlaams Instituut voor Biotechnologie
      Gand, Flemish, Belgium
  • 1995–2014
    • University of Leuven
      • • Division of Gene Technology
      • • Vesalius Research Center
      • • Center for Molecular and Vascular Biology
      Louvain, Flemish, Belgium
  • 2013
    • Boston Biomedical Research Institute
      Boston, Massachusetts, United States
  • 2004–2013
    • 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
  • 2005
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
  • 2000–2005
    • Maastricht University
      Maestricht, Limburg, Netherlands
  • 2003
    • Wistar Institute
      • Melanoma Research Center
      Filadelfia, Pennsylvania, United States
    • Monash University (Malaysia)
      Labuan, Labuan, Malaysia
    • 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
  • 1998
    • Thrombosis Research Institute
      Londinium, England, United Kingdom