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. INTERPRETATION: 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.
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 humanGlut1 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. INTERPRETATION: 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: Hans C Helms; N Joan Abbott; Malgorzata Burek; Romeo Cecchelli; Pierre-Olivier Couraud; Maria A Deli; Carola Förster; Hans J Galla; Ignacio A Romero; Eric V Shusta; Matthew J Stebbins; Elodie Vandenhaute; Babette Weksler; Birger Brodin Journal: J Cereb Blood Flow Metab Date: 2016-02-11 Impact factor: 6.200
Authors: Ethan A Winkler; Yoichiro Nishida; Abhay P Sagare; Sanket V Rege; Robert D Bell; David Perlmutter; Jesse D Sengillo; Sara Hillman; Pan Kong; Amy R Nelson; John S Sullivan; Zhen Zhao; Herbert J Meiselman; Rosalinda B Wendy; Jamie Soto; E Dale Abel; Jacob Makshanoff; Edward Zuniga; Darryl C De Vivo; Berislav V Zlokovic Journal: Nat Neurosci Date: 2015-03-02 Impact factor: 24.884