Endothelial cell-derived exosomal circHIPK3 promotes the proliferation of vascular smooth muscle cells induced by high glucose via the miR-106a-5p/Foxo1/Vcam1 pathway.

Shaohua Wang,Yuanyuan Zhang,Jiao Li,Wenjing Wang,Yongjun Li,Min Shi,Peixin Xu

doi:10.18632/aging.203742

Shaohua Wang, Yuanyuan Zhang + Show 5 more

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https://doi.org/10.18632/aging.203742

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Abstract

The abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development and progression of diabetic vascular complications. In high-glucose (HG) conditions, endothelial cells (ECs) act as the first barrier to damaging stimuli and trigger a multi-response, including EC and VSMC crosstalk. However, the crosstalk pathways between ECs and VSMCs under HG conditions remain unclear. This study aimed to explore the roles and underlying mechanism of exosomes derived from ECs in the crosstalk between ECs and VSMCs. Our results showed that mouse aortic endothelial cell (MAEC)–secreted exosomes could promote the proliferation and inhibit the apoptosis of VSMCs induced by HG. Furthermore, we isolated the exosomes secreted by MAECs and found that exosomes derived from MAECs that were exposed to HG could transfer circHIPK3, which is enriched in MAEC-derived exosomes, to VSMCs. Exosomal circHIPK3 promoted the proliferation and inhibited the apoptosis of VSMCs. circHIPK3 sponged miR-106a-5p to relieve its repression of forkhead box O1 (Foxo1) expression. The increased expression of Foxo1 acted as a transcription factor to promote Vcam1 expression, thus facilitating the uptake of MAEC-derived exosomes by VSMCs. The results of this study suggested that exosomal circHIPK3 derived from MAECs promotes the proliferation of VSMCs induced by HG via the miR-106a-5p/Foxo1/Vcam1 pathway.

Highlights

Vascular complications are the major causes related to morbidity and mortality in patients with type 2 diabetes mellitus
To understand whether crosstalk occurs between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) under an HG condition, we co-cultured mouse aortic endothelial cell (MAEC) and VSMCs in normal glucose (NG; 5.5 mM) or HG (25 mM) with a transwell system
After using the nanoparticle tracking analysis (NTA) assay, we did not observe any differences related to the concentration of exosomes from HG (HG-Exo) and NG (NG-Exo) conditions, but the size peak of the exosomes was at 59.25 nm for NG-Exo and 69.25 nm for HG-Exo (Figure 1C)

Summary

Introduction

Vascular complications are the major causes related to morbidity and mortality in patients with type 2 diabetes mellitus. Considering that continuous high-glucose (HG) conditions can lead to vascular dysfunction, multiple types of cells are involved in this process, such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages [1]. Glucose at high levels can penetrate ECs by passive diffusion, which induces endothelial dysfunction via oxidative stress, inflammation, and apoptosis [2]. Endothelial dysfunction can lead to VSMC activation, which induces altered proliferation and migration [3]. The crosstalk and interaction between ECs and VSMCs play an essential part in regulating diabetic vascular disease progression; the underlying mechanisms of this interaction have not been comprehensively studied and remain unclear

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