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Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity

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  • Koen Veys, KU Leuven, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Zheng Fan, Swiss Federal Institute of Technology Zurich
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  • Moheb Ghobrial, Swiss Federal Institute of Technology Zurich, University of Zurich
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  • Ann Bouché, KU Leuven, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Melissa García-Caballero, KU Leuven, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Kim Vriens, KU Leuven, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Nadine Vasconcelos Conchinha, KU Leuven, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Aline Seuwen, University of Zurich/ETH
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  • Felix Schlegel, University of Zurich/ETH
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  • Tatiane Gorski, University of Zurich/ETH
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  • Melissa Crabbé, KU Leuven
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  • Paola Gilardoni, University of Zurich/ETH
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  • Raphaela Ardicoglu, University of Zurich/ETH
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  • Johanna Schaffenrath, University of Zurich/ETH
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  • Cindy Casteels, KU Leuven
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  • Gino De Smet, Vrije Universiteit Brussel
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  • Ilse Smolders, Vrije Universiteit Brussel
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  • Koen Van Laere, KU Leuven
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  • E. Dale Abel, University of Iowa, University of Zurich/ETH
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  • Sarah Maria Fendt, KU Leuven, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Aileen Schroeter, University of Zurich/ETH
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  • Joanna Kalucka
  • Anna Rita Cantelmo, KU Leuven, Université de Lille, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Thomas Wälchli, University of Zurich, University of Geneva, University of Toronto
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  • Annika Keller, University of Zurich/ETH
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  • Peter Carmeliet, KU Leuven, Center for Cancer Biology, University of Leuven, Leuven, Belgium.
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  • Katrien De Bock, Swiss Federal Institute of Technology Zurich, University of Zurich/ETH

RATIONALE: Endothelial cells (ECs) are highly glycolytic and generate the majority of their energy via the breakdown of glucose to lactate. At the same time, a main role of ECs is to allow the transport of glucose to the surrounding tissues. GLUT1 (glucose transporter isoform 1/Slc2a1) is highly expressed in ECs of the central nervous system (CNS) and is often implicated in blood-brain barrier (BBB) dysfunction, but whether and how GLUT1 controls EC metabolism and function is poorly understood. OBJECTIVE: We evaluated the role of GLUT1 in endothelial metabolism and function during postnatal CNS development as well as at the adult BBB. METHODS AND RESULTS: Inhibition of GLUT1 decreases EC glucose uptake and glycolysis, leading to energy depletion and the activation of the cellular energy sensor AMPK (AMP-activated protein kinase), and decreases EC proliferation without affecting migration. Deletion of GLUT1 from the developing postnatal retinal endothelium reduces retinal EC proliferation and lowers vascular outgrowth, without affecting the number of tip cells. In contrast, in the brain, we observed a lower number of tip cells in addition to reduced brain EC proliferation, indicating that within the CNS, organotypic differences in EC metabolism exist. Interestingly, when ECs become quiescent, endothelial glycolysis is repressed, and GLUT1 expression increases in a Notch-dependent fashion. GLUT1 deletion from quiescent adult ECs leads to severe seizures, accompanied by neuronal loss and CNS inflammation. Strikingly, this does not coincide with BBB leakiness, altered expression of genes crucial for BBB barrier functioning nor reduced vascular function. Instead, we found a selective activation of inflammatory and extracellular matrix related gene sets. CONCLUSIONS: GLUT1 is the main glucose transporter in ECs and becomes uncoupled from glycolysis during quiescence in a Notch-dependent manner. It is crucial for developmental CNS angiogenesis and adult CNS homeostasis but does not affect BBB barrier function.

Original languageEnglish
JournalCirculation Research
Volume127
Issue4
Pages (from-to)466-482
Number of pages17
ISSN0009-7330
DOIs
Publication statusPublished - Jul 2020

    Research areas

  • blood-brain barrier, endothelium, extracellular matrix, glucose transport, glycolysis, homeostasis

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