• Yue Li, Yuming Zhao, Chong Gao, Meiling Wu, Kwok-Fai So, Yao Tong, and Jiangang Shen.
• School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region; State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
• Neuroscience. 2020 Nov 10; 448: 172-190.

AbstractCaveolin-1 (Cav-1) is an important modulator for adult neurogenesis in post stroke brain repair but its underlying mechanisms are largely unknown. In the present study, we report that endothelial Cav-1 inhibits neuronal differentiation of neural stem/progenitor cells (NSCs/NPCs) in post ischemic brain via regulating vascular endothelial growth factor (VEGF) and NeuroD1 signaling pathway. We first investigated the dynamic change of Cav-1 and its impact on neuronal differentiation in rat and mouse models of 2 h transient middle cerebral artery occlusion (MCAO) plus 1, 7, 14, 21 and 28 day of reperfusion. We then studied the roles of endothelial Cav-1 in modulating the neuronal differentiation of NPCs which were co-cultured with brain microvascular endothelial cells (BMVECs) under 2 h oxygen-glucose deprivation plus 5 days reoxygenation (OGD/R). The major discoveries include: (1) Cav-1 expression in the hippocampal dentate gyrus (DG) was down-regulated on day 1 after 2 h cerebral ischemia, and gradually recovered with reperfusion time, accompanied with transient increased but gradually reduced neuronal differentiation of NPCs marked by doublecortin (DCX). (2) Cav-1 knockout mice exhibited the increased DCX and VEGF at the granular cell layers of hippocampal DG in post-ischemic brains. (3) Co-cultured with BMVECs, NPCs had remarkably decreased neuronal differentiation under OGD/R. Knockdown of Cav-1 in the BMVECs increased VEGF secretion into the medium and NeuroD1+ cells, and rescued the neuronal differentiation of NPCs without affecting astroglial and oligodendroglial differentiation. (4) Cav-1 exosomes released from BMVECs inhibited neuronal differentiation of NPCs via decreasing the expression of VEGF, p44/42MAPK phosphorylation and NeuronD1 upon OGD/R insults. Taken together, endothelial Cav-1 serves as a niche regulator to inhibit neuronal differentiation via negatively modulating VEGF, p44/42MAPK phosphorylation and NeuronD1 signaling pathway.Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

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