title: Glut1/SLC2A1 is crucial for the development of the blood-brain barrier in vivo.
abstract: OBJECTIVE
  The overall permeability of the blood-brain barrier (BBB) is regulated by specialized cerebral endothelial cells and their junctional complexes, consisting of adherens junctions (AJs) and tight junctions (TJs). Among the members of the glucose transporters (Glut), Glut1 is a unique molecule expressed in the cerebral endothelial cells. Glut1 and the junctional proteins are concomitantly downregulated in situations in which breakdown of the BBB has taken place. We hypothesized that the expression of Glut1 may play a significant role in the development of the cerebral microvasculature with BBB properties. To date, there is no information on the role of Glut1 during the development of BBB. In the present study, the in vivo effects of Glut1 knockdown on the cerebral vascular development were investigated.
  
  
  METHODS
  Zebrafish was used as a model organism. We confirmed that the structure of the zebrafish homologue of Glut1 is highly similar to the human Glut1 and that the function of the Glut1-mediated cerebral uptake of glucose is evolutionally conserved.
  
  
  RESULTS
  In the Glut1 knockdown model, we observed loss of the cerebral endothelial cells, with concomitant downregulation of the junctional proteins important for intactness of the AJs/TJs and impaired cerebral circulation. The resulting leaky BBB caused vasogenic brain edema.
  
  
  CONCLUSIONS
  The data suggest a crucial role of Glut1 in the development of the cerebral endothelial cells with BBB properties in vivo. The findings suggest that modulation of Glut1 expression and function may open new directions of research for therapeutic strategies to prevent vasogenic brain edema.
authors.affiliation: Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Ping-Pin
authors.initials: PP
authors.lastname: Zheng
authors.forename: Edwin
authors.initials: E
authors.lastname: Romme
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.forename: Clemens M F
authors.initials: CM
authors.lastname: Dirven
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051401:Aquaporin 4 / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D062507:Claudin-5; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005353:Fibronectins / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D023421:Models, Animal; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014741:Video Recording; D015027:Zebrafish
chemical_list: D051401:Aquaporin 4; C107466:CLDN5 protein, human; D062507:Claudin-5; D005353:Fibronectins; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D005947:Glucose