MicroRNA-126 Regulates Angiogenesis and Neurogenesis in a Mouse Model of Focal Cerebral Ischemia

Meijie Qu; Jiaji Pan; Liping Wang; Panting Zhou; Yaying Song; Shuhong Wang; Lu Jiang; Jieli Geng; Zhijun Zhang; Yongting Wang; Yaohui Tang; Guo-Yuan Yang

doi:10.1016/j.omtn.2019.02.002

MicroRNA-126 Regulates Angiogenesis and Neurogenesis in a Mouse Model of Focal Cerebral Ischemia

Mol Ther Nucleic Acids. 2019 Jun 7:16:15-25. doi: 10.1016/j.omtn.2019.02.002. Epub 2019 Feb 11.

Authors

Meijie Qu¹, Jiaji Pan², Liping Wang¹, Panting Zhou², Yaying Song¹, Shuhong Wang³, Lu Jiang², Jieli Geng⁴, Zhijun Zhang², Yongting Wang², Yaohui Tang⁵, Guo-Yuan Yang⁶

Affiliations

¹ Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
² Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
³ Department of Geriatrics, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
⁴ Department of Neurology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
⁵ Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: yaohuitang@sjtu.edu.cn.
⁶ Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China; Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: gyyang@sjtu.edu.cn.

Abstract

Studies demonstrate that microRNA-126 plays a critical role in promoting angiogenesis. However, its effects on angiogenesis following ischemic stroke are unclear. Here, we explored the effect of microRNA-126-3p and microRNA-126-5p on angiogenesis and neurogenesis after brain ischemia. We demonstrated that both microRNA (miRNA)-126-3p and microRNA-126-5p increased the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) compared with the scrambled miRNA control (p < 0.05). Transferring microRNA-126 into a mouse middle cerebral artery occlusion model via lentivirus, we found that microRNA-126 overexpression increased the number of CD31⁺/BrdU⁺ (5-bromo-2'-deoxyuridine-positive) proliferating endothelial cells and DCX⁺/BrdU⁺ neuroblasts in the ischemic mouse brain, improved neurobehavioral outcomes (p < 0.05), and reduced brain atrophy volume (p < 0.05) compared with control mice. Western blot results showed that AKT and ERK signaling pathways were activated in the lentiviral-microRNA-126-treated group (p < 0.05). Both PCR and western blot results demonstrated that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) was decreased in the lentiviral-microRNA-126-treated group (p < 0.05). Dual-luciferase gene reporter assay also showed that PTPN9 was the direct target of microRNA-126-3p and microRNA-126-5p in the ischemic brain. We demonstrated that microRNA-126-3p and microRNA-126-5p promoted angiogenesis and neurogenesis in ischemic mouse brain, and further improved neurobehavioral outcomes. Our mechanistic study further showed that microRNA-126 mediated angiogenesis through directly inhibiting its target PTPN9 and activating AKT and ERK signaling pathways.

Keywords: PTPN9; angiogenesis; ischemic stroke; microRNA; neurogenesis.