| First Author | Hong J | Year | 2020 |
| Journal | Int J Mol Sci | Volume | 21 |
| Issue | 4 | PubMed ID | 32079227 |
| Mgi Jnum | J:304892 | Mgi Id | MGI:6510126 |
| Doi | 10.3390/ijms21041341 | Citation | Hong J, et al. (2020) The Rho/Rac Guanine Nucleotide Exchange Factor Vav1 Regulates Hif-1alpha and Glut-1 Expression and Glucose Uptake in the Brain. Int J Mol Sci 21(4):1341 |
| abstractText | 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)-1alpha, which activates the transcription of target genes to orchestrate a cellular response to low oxygen. One of the genes induced by HIF-1alpha 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-1alpha 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-1alpha 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. |
