Endothelial Cells Mediated by UCP2 Control the Neurogenic-to-Astrogenic Neural Stem Cells Fate Switch During Brain Development

During mammalian cortical development, neural stem/progenitor cells (NSCs) gradually alter their characteristics, and the timing of generation of neurons and glial cells is strictly regulated by internal and external factors. However, whether the blood vessels located near NSCs affect the neurogenic-to-gliogenic transition remain unknown. Here, it is demonstrated that endothelial uncoupling protein 2 (UCP2) deletion reduces blood vessel diameter and affects the transition timing of neurogenesis and gliogenesis. Deletion of endothelial UCP2 results in a persistent increase in astrocyte production at the postnatal stage. Mechanistically, the endothelial UCP2/ROS/ERK1/2 pathway increases chymase-1 expression to enhance angiotensin II (AngII) secretion outside the brain endothelium. The endotheliocyte-driven AngII-gp130-JAK-STAT pathway also regulates gliogenesis initiation. Moreover, endothelial UCP2 knockdown decreases human neural precursor cell (hNPC) differentiation into neurons and accelerates hNPC differentiation into astrocytes. Altogether, this work provides mechanistic insights into how endothelial UCP2 regulates the neurogenic-to-gliogenic fate switch in the developing neocortex.