Neuronal Activity-Driven Shift from Angiogenesis to Vascular Maturation through Metabolic Changes

초록

Brain endothelial cells (BECs) play a crucial role in maintaining the brain's metabolic state by forming the blood-brain barrier (BBB), which regulates the selective exchange of metabolites, nutrients, waste products, and other molecules between the bloodstream and the brain parenchyma. Notably, neuronal activation also influences the brain's metabolic environment by regulating the expression and localization of metabolite transporters in BECs. For a long time, glucose has been considered the brain’s primary source, while lactate was viewed merely as a byproduct. However, recent studies have shown that lactate can also serve as fuel and, according to the lactate shuttle hypothesis, acts as a key signaling molecule. In this study, we investigated metabolic changes and their functional implications during visual cortex development, driven by neuronal activation. We performed translatome analysis using the RiboTag method to compare BECs at postnatal day 10 (P10) and P30, before and after eye-opening, identifying 32 genes regulated by neuronal activation. We confirmed that light exposure induces developmental changes in gene expression, which were abolished in dark-reared mice. Among these genes, we focused on two metabolite transporters: glucose transporter GLUT1, which is involved in vascular maturation, and lactate transporter MCT1, which plays a role in angiogenesis. Interestingly, our translatome analysis revealed a significant increase in GLUT1 expression and a marked decrease in MCT1 expression, with these changes reversed in the absence of light. Furthermore, vascular leakage and immature astrocytes were observed in the visual cortex in dark-reared mice. We also found that TGF-β signaling plays a key role in the reciprocal switch of MCT1 and GLUT1 in BECs. In conclusion, neuronal activity shifts the balance from lactate-driven angiogenesis to glucose-mediated vascular maturation by modulating MCT1 and GLUT1 expression in BECs through the suppression of TGF-β signaling via astrocytes, thereby promoting vascular maturation and BBB formation.