Electroacupuncture improves ischemic stroke by intervening in neurovascular remodeling via miR-210-mediated regulation of the Wnt/HIF1A/netrin-1 signaling axis

Abstract

Objective: Cerebral infarction (stroke) is a major global public health issue. This study explores the mechanisms by which electroacupuncture affects motor function after cerebral infarction by combining complementary experimental approaches in middle cerebral artery occlusion mice. The work focuses particularly on the Wnt/hypoxia-inducible factor-1 alpha (HIF1A)/netrin-1 signaling axis and downstream targets, including netrin-1 and vascular endothelial growth factor (VEGF), to provide a comprehensive understanding of the mechanisms that underpin electroacupuncture stimulation after stroke.

Methods: The middle cerebral artery occlusion model was established with electroacupuncture intervention. The cerebral cortex of mice was collected for detections, including RNA sequencing, western blot, immunofluorescence, quantitative PCR, and so forth. HIF1A-overexpressing and knockdown cell lines in SH-SY5Y cells were used for further verification.

Results: Exosome and RNA sequencing identified the key microRNA mir-210 and the Wnt/HIF1A/netrin-1 signaling axis after electroacupuncture treatment at head acupoints in the murine model. In addition, the HIF1A transcription factor was upregulated and bound to promoters of genes for netrin-1 and VEGF thereby activating transcription of these loci. Dual luciferase reporter assays revealed that mir-210 targets the gene for the tumor suppressor adenomatous polyposis coli, thereby stimulating the Wnt-signaling pathway. Furthermore, behavioral experiments demonstrated that electroacupuncture intervention in the Wnt/HIF1A/netrin-1 signaling axis improved motor function in middle cerebral artery occlusion mice.

Conclusion: The study reveals that electroacupuncture stimulation promotes angiogenesis and neural reconstruction after cerebral infarction by regulating the Wnt/HIF1A/netrin-1 signaling axis through mir-210, and suggests novel therapeutic targets for the treatment of cerebral infarction with electroacupuncture.

Keywords: HIFA; Wnt; electroacupuncture; miR-210; middle cerebral artery occlusion; neurovascular remodeling.