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RSS FeedsIJMS, Vol. 21, Pages 1341: The Rho/Rac Guanine Nucleotide Exchange Factor Vav1 Regulates Hif-1? and Glut-1 Expression and Glucose Uptake in the Brain (International Journal of Molecular Sciences)

 
 

18 february 2020 03:02:53

 
IJMS, Vol. 21, Pages 1341: The Rho/Rac Guanine Nucleotide Exchange Factor Vav1 Regulates Hif-1? and Glut-1 Expression and Glucose Uptake in the Brain (International Journal of Molecular Sciences)
 




Vav1 is a Rho/Rac (Ras-related C3 botulinum toxin substrate) guanine nucleotide exchange factor expressed in hematopoietic and endothelial cells that are involved in a wide range of cellular functions. It is also stabilized under hypoxic conditions when it regulates the accumulation of the transcription factor HIF (Hypoxia Inducible Factor)-1α, which activates the transcription of target genes to orchestrate a cellular response to low oxygen. One of the genes induced by HIF-1α is GLUT (Glucose Transporter)-1, which is the major glucose transporter expressed in vessels that supply energy to the brain. Here, we identify a role for Vav1 in providing glucose to the brain. We found that Vav1 deficiency downregulates HIF-1α and GLUT-1 levels in endothelial cells, including blood-brain barrier cells. This downregulation of GLUT-1, in turn, reduced glucose uptake to endothelial cells both in vitro and in vivo, and reduced glucose levels in the brain. Furthermore, endothelial cell-specific Vav1 knock-out in mice, which caused glucose uptake deficiency, also led to a learning delay in fear conditioning experiments. Our results suggest that Vav1 promotes learning by activating HIF-1α and GLUT-1 and thereby distributing glucose to the brain. We further demonstrate the importance of glucose transport by endothelial cells in brain functioning and reveal a potential new axis for targeting GLUT-1 deficiency syndromes and other related brain diseases.


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43 viewsCategory: Biochemistry, Biophysics, Molecular Biology
 
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