Vav1-HIF1-Glut1, a novel axis to initiate neurodegenerative disorders

Vav1 is a Rho/Rac (Ras-related C3 botulinum toxin substrate) guanine nucleotide exchange factor (GEF) expressed in immune cells and endothelial cells involved in a wide range of cellular functions, including protumorigenesis and inflammation. Vav1 is unstabilized in normoxic conditions and stable in hypoxic conditions. When Vav1 is stable, Vav1 increases the accumulation of the transcription factor HIF (Hypoxia Inducible Factor)-1α, which activates the transcription of target genes on HIF-related element (HRE) to initiate a cellular response to low oxygen. One of the genes induced by HIF-1α is GLUT (Glucose Transporter)-1, the major glucose transporter expressed in vessels that supply glucose, the brain's energy source. Here, we identify a role for Vav1 in providing glucose to the brain to suppress neurodegeneration. We observed that Vav1 deficiency suppresses HIF-1α and GLUT-1 levels in endothelial cells, including blood-brain barrier cells. The decrease of GLUT-1, in turn, reduces glucose uptake to endothelial cells both in vitro and in vivo and reduces glucose transportation to neurons and astrocytes.Furthermore, endothelial cell-specific Vav1 conditional knock-out mice show glucose uptake deficiency as well as impaired brain coordination. Our findings suggest that Vav1 promotes learning and memory by activating HIF-1α and GLUT-1, thereby transporting 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 neurodegenerative disorders. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (No. 2021R1I1A3043909). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.