Document Type
Article
Publication Date
10-4-2025
Abstract
Neural activity drives blood vessel (BV) formation and energy substrate delivery in the developing brain to meet rising metabolic demands; however, the underlying mechanisms remain poorly understood. In this study, we exposed neonatal mice to chronic whisker stimulation (WS), a paradigm known to enhance BV formation in the somatosensory (S1) cortex. Transcriptomic (RNA-seq) and spatial (RNA-scope) analyses revealed that WS upregulated monocarboxylate transporter 2 (MCT2) in cortical neurons and MCT1 in endothelial cells (ECs). These changes coincided with increased cortical lactate levels, elevated astrocytic vascular endothelial growth factor A (VEGFa), and enhanced angiogenesis. Functional experiments demonstrated that neuronal MCT2 is essential for mediating WS-induced angiogenic and metabolic responses. Mechanistically, MCT2 facilitatesₗ -lactate influx into the cortex with or without WS, promoting lactate uptake by neurons and astrocytes. This, in turn, induces MCT2 expression in neurons and activates hypoxia-inducible factor 1α (HIF1α) and VEGFa expression in astrocytes. Together, these findings uncover a previously unrecognized role for neuronal MCT2 in regulating lactate flux, signaling, and vascular remodeling, thereby linking neural activity to metabolic adaptation and vascular development in the neonatal mouse neocortex.
Language
English
Publication Title
Cell Death and Differentiation
Grant
RF1 AG045781to W.C.X
Rights
© The Author(s) 2025. This is an Open Access work distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Lee, D., Wu, A., Yao, L. et al. Neuronal MCT2 promotes angiogenesis via lactate in the developing mouse neocortex. Cell Death Differ 33, 539–556 (2026). https://doi.org/10.1038/s41418-025-01581-w
Manuscript Version
Final Publisher Version