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

Abstract

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.

Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice

“…As a mitochondrial protein, UCP2 plays a critical role in mitochondrial function, including separating oxidative phosphorylation from ATP synthesis and controlling proton reentry into the mitochondrial matrix 29 . Sustained UCP2-mediated uncoupling reduces mitochondrial ROS production to protect neurons 30 . UCP2 is involved in the regulation of the activity of neurons and astrocytes (glial cells) in several brain areas 30 , 31 .…”

Microvascular endothelial cells derived from spinal cord promote spinal cord injury repair

“…In embryonic and adult stages [ 61 ], a phenomenon called neurovascular congruence showing functionally and physically interdependent in the vascular and nervous systems is widespread, suggesting close association of vascular system with neural microenvironment. Moreover, it was reported that endothelial cells direct axon growth in SCI model and improve neurogenesis; In the brain, BMECs were found to regulate NSC differentiation fate by secreting bioactive factors [ 62 ] and provide trans -differentiation signals to reprogram astrocytes into NSC [ 63 ]. In addition, influence of endothelial cells on NSC have been reported [ 21 , 56 , 64 ], and the proliferation and differentiation of neural progenitor cells is accompanied by vascularization of the central nervous system to meet the increasing demand for nutrients and oxygen, suggesting a close relationship between neovascularization and neurogenesis [ 65 ].…”

Mitochondrial redox stress based treatment of hepatic encephalopathy

“…In neurons, sustained UCP2 mediated uncoupling leads to increased mitochondrial proliferation and greater ATP production, making neurons more adaptive to dynamic uctuations in neuronal activity 21,22 . UCP2 has been implicated in the regulation of the activity of neurons and Astrocytes (glial cells) in several brain areas 17,[23][24][25] . Western Blot results in the present study showed TAA induced Ucp2 increase in SNr (Fig.…”