Dong Xiaohua, Jiang Dongya, Wang Long, Zhao Jing, Yu Lingling, Huang Yun, Wu Xiaohui, Zhu Yanqing, Zhao Yingmin, Zhao Qingshun, Zhang Guangming, Li Xinyuan
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.
iScience. 2022 Mar 9;25(4):104042. doi: 10.1016/j.isci.2022.104042. eCollection 2022 Apr 15.
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.
细胞外囊泡（EVs）参与细胞间通讯并促进血管生成。然而，对于神经元分泌EVs的潜在机制及其对中枢神经系统（CNS）血管系统的作用的理解仍很初步。在此，我们表明液泡蛋白分选28（Vps28）对于斑马鱼脑中央动脉（CtAs）的出芽和血脑屏障（BBB）的完整性至关重要。富含神经元的Vps28的破坏通过调节细胞内多囊泡体（MVBs）的形成显著降低了EVs的分泌。源自斑马鱼胚胎或小鼠皮质神经元的EVs部分挽救了脑血管系统缺陷和脑渗漏。进一步的研究表明，含有血管内皮生长因子A（VEGF-A）的神经元EVs是神经血管通讯中的关键调节因子。我们的结果表明，Vps28作为一种细胞间内体调节剂，介导神经元EVs的分泌，进而通过VEGF-A转运与内皮细胞通讯以介导血管生成。
