VPS28 regulates brain vasculature by controlling neuronal VEGF trafficking through extracellular vesicle secretion
Xiaohua Dong,
Dongya Jiang,
Long Wang,
Jing Zhao,
Lingling Yu,
Yun Huang,
Xiaohui Wu,
Yanqing Zhu,
Yingmin Zhao,
Qingshun Zhao,
Guangming Zhang,
Xinyuan Li
Affiliations
Xiaohua Dong
Department of Neurosurgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 20033, China; Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 20033, China; Department of Pediatric, Jingjiang People’s Hospital Affiliated to Yangzhou University, Jingjiang 214500, China; Corresponding author
Dongya Jiang
Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Long Wang
Department of Cardiology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, the Affiliated Hangzhou First People's Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Jing Zhao
Department of Neurosurgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 20033, China
Lingling Yu
Department of Pediatric, Jingjiang People’s Hospital Affiliated to Yangzhou University, Jingjiang 214500, China
Yun Huang
Department of Pediatric, Jingjiang People’s Hospital Affiliated to Yangzhou University, Jingjiang 214500, China
Xiaohui Wu
Department of Pediatric, Jingjiang People’s Hospital Affiliated to Yangzhou University, Jingjiang 214500, China
Yanqing Zhu
Department of Pediatric, Jingjiang People’s Hospital Affiliated to Yangzhou University, Jingjiang 214500, China
Yingmin Zhao
Department of Pediatric, Jingjiang People’s Hospital Affiliated to Yangzhou University, Jingjiang 214500, China; Corresponding author
Qingshun Zhao
Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China; Corresponding author
Guangming Zhang
Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 20033, China; Corresponding author
Xinyuan Li
Department of Neurosurgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 20033, China; Corresponding author
Summary: Extracellular vesicles (EVs) participate in intercellular communication and contribute to the angiogenesis. However, the understanding of the mechanisms underlying EVs secretion by neurons and their action on the vascular system of the central nervous system (CNS) remain rudimentary. Here, we show that vacuolar protein sorting 28 (Vps28) is essential for the sprouting of brain central arteries (CtAs) and for the integrity of blood-brain barrier (BBB) in zebrafish. Disruption of neuron-enriched Vps28 significantly decreased EVs secretion by regulating the formation of intracellular multivesicular bodies (MVBs). EVs derived from zebrafish embryos or mouse cortical neurons partially rescued the brain vasculature defect and brain leakage. Further investigations revealed that neuronal EVs containing vascular endothelial growth factor A (VEGF-A) are key regulators in neurovascular communication. Our results indicate that Vps28 acts as an intercellular endosomal regulator mediating the secretion of neuronal EVs, which in turn communicate with endothelial cells to mediate angiogenesis through VEGF-A trafficking.
