Circulating exo-miR-154-5p regulates vascular dementia through endothelial progenitor cell-mediated angiogenesis

Xue Han; Li Zhou; Yu Tu; Jiajia Wei; Jiajia Zhang; Guojun Jiang; Qiaojuan Shi; Huazhong Ying

doi:10.3389/fncel.2022.881175

Circulating exo-miR-154-5p regulates vascular dementia through endothelial progenitor cell-mediated angiogenesis

Front Cell Neurosci. 2022 Jul 29:16:881175. doi: 10.3389/fncel.2022.881175. eCollection 2022.

Authors

Xue Han¹, Li Zhou², Yu Tu¹, Jiajia Wei¹, Jiajia Zhang¹, Guojun Jiang³, Qiaojuan Shi¹, Huazhong Ying^{1

2}

Affiliations

¹ Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou, China.
² School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
³ Department of Pharmacy, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China.

Abstract

Background: Vascular dementia (VaD) mainly results from cerebral vascular lesions and tissue changes, which contribute to neurodegenerative processes. Effective therapeutic approaches to targeting angiogenesis may reduce mortality of VaD. Endothelial progenitor cells (EPCs) play a key role in postnatal angiogenesis. Many exosomal microRNAs (exo-miRNAs) have been reported to involve in the development of dementia. The present study was designed to investigate whether the expression profile of the exo-miRNAs is significantly altered in patients with VaD and to reveal the function of differentially expressed miRNAs and the relevant mechanisms in EPC-mediated angiogenesis in VaD rat model.

Results: Exosomes isolated from serum of patients with VaD (n = 7) and age-matched control subjects (n = 7), and miRNA sequencing and bioinformatics analysis found that circulating exosome miRNA-155-5p, miRNA-154-5p, miR-132-5p, and miR-1294 were upregulated in patients with VaD. The expression of miRNA-154-5p was further verified to be upregulated in clinical samples (n = 23) and 2-vessel occlusion-induced VaD rat model by reverse transcription quantitative PCR (RT-qPCR). Notably, miRNA-154-5p inhibition in bone marrow-EPCs (BM-EPCs) from VaD rats improved EPC functions, including tube formation, migration, and adhesion, and elevated concentrations of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α). The mRNA levels of ICAM-1, VCAM-1, and MCP-1 were reduced in miRNA-154-5p-inhibited EPCs. In addition, miRNA-154-5p inhibition increased the level of superoxide dismutase (SOD), and decreased reactive oxygen species (ROS) in EPCs. PRKAA2 was chosen as a promising target gene of miR-154-5p, and miRNA-154-5p inhibition upregulated the protein expression of AMPKα2. Furthermore, upregulation of miR-154-5p markedly diminished EPC functions and inhibited angiogenesis following EPC transplantation in VaD rats.

Conclusion: Circulating exo-miR-154-5p was upregulated in patients with VaD, and miR-154-5p upregulation was associated with impaired EPC functions and angiogenesis in VaD rat model. Therefore, miR-154-5p is a promising biomarker and therapeutic strategy for VaD.

Keywords: angiogenesis; endothelial progenitor cells; exosome; miR-154-5p; vascular dementia.