Abstract
Exosomes play critical roles in mediating cell-to-cell communication by delivering noncoding RNAs (including miRNAs, lncRNAs, and circRNAs). Our previous study found that cardiomyocytes (CMs) subjected to hypoxia released circHIPK3-rich exosomes to regulate oxidative stress damage in cardiac endothelial cells. However, the role of exosomes in regulating angiogenesis after myocardial infarction (MI) remains unknown. The aim of this study was to establish the effects of exosomes derived from hypoxia-induced CMs on the migration and angiogenic tube formation of cardiac endothelial cells. Here, we reported that hypoxic exosomes (HPC-exos) can effectively reduce the infarct area and promote angiogenesis in the border surrounding the infarcted area. HPC-exos can also promote cardiac endothelial cell migration, proliferation, and tube formation in vitro. However, these effects were weakened after silencing circHIPK3 in hypoxia-induced CMs. We further verified that silencing and overexpressing circHIPK3 changed cardiac endothelial cell proliferation, migration, and tube formation in vitro by regulating the miR-29a expression. In addition, exosomal circHIPK3 derived from hypoxia-induced CMs first led to increased VEGFA expression by inhibiting miR-29a activity and then promoted accelerated cell cycle progression and proliferation in cardiac endothelial cells. Overexpression of miR-29a mimicked the effect of silencing circHIPK3 on cardiac endothelial cell activity in vitro. Thus, our study provides a novel mechanism by which exosomal circRNAs are involved in the communication between CMs and cardiac endothelial cells.
Highlights
It is important to regulate and maintain cardiac function by ensuring sufficient blood supply to deprived areas after myocardial infarction (MI) [1]
Exosomes secreted by CMs subjected to ischemia promote cardiac angiogenesis by delivering miRNA-222 and miRNA-143 [10]
We revealed that the exogenous delivery of exosomes secreted by CMs subjected to hypoxia can play an important role in promoting angiogenesis after MI in vitro and in vivo
Summary
It is important to regulate and maintain cardiac function by ensuring sufficient blood supply to deprived areas after myocardial infarction (MI) [1]. The maintenance of anatomic and functional integrity of the microvasculature after MI is dependent on the proliferation and migration of cardiac endothelial cells and neovascularization. We and others have observed that exosomes derived from CMs contain a variety of miRNAs, circRNAs and proteins, which may be transferred to adjacent endothelial cells and regulate their function [3, 4]. Exosomes are involved in regulating the function of target cells by releasing their contents into the target cells [5]. CM-derived exosomes were found to promote angiogenesis by delivering miR-222 under ischemic conditions [10]. In this context, we demonstrated that exosomes derived from CMs cultured under
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