Endothelial colony-forming cell-derived exosomal miR-21-5p regulates autophagic flux to promote vascular endothelial repair by inhibiting SIPL1A2 in atherosclerosis

Abstract

Background Percutaneous transluminal coronary angioplasty (PTCA) represents an efficient therapeutic method for atherosclerosis but conveys a risk of causing restenosis. Endothelial colony-forming cell-derived exosomes (ECFC-exosomes) are important mediators during vascular repair. This study aimed to investigate the therapeutic effects of ECFC-exosomes in a rat model of atherosclerosis and to explore the molecular mechanisms underlying the ECFC-exosome-mediated effects on ox-LDL-induced endothelial injury. Methods The effect of ECFC-exosome-mediated autophagy on ox-LDL-induced human microvascular endothelial cell (HMEC) injury was examined by cell counting kit-8 assay, scratch wound assay, tube formation assay, western blot and the Ad-mCherry-GFP-LC3B system. RNA-sequencing assays, bioinformatic analysis and dual-luciferase reporter assays were performed to confirm the interaction between the miR-21-5p abundance of ECFC-exosomes and SIPA1L2 in HMECs. The role and underlying mechanism of ECFC-exosomes in endothelial repair were explored using a high-fat diet combined with balloon injury to establish an atherosclerotic rat model of vascular injury. Evans blue staining, haematoxylin and eosin staining and western blotting were used to evaluate vascular injury. Results ECFC-exosomes were incorporated into HMECs and promoted HMEC proliferation, migration and tube formation by repairing autophagic flux and enhancing autophagic activity. Subsequently, we demonstrated that miR-21-5p, which is abundant in ECFC-exosomes, binds to the 3’ untranslated region of SIPA1L2 to inhibit its expression, and knockout of miR-21-5p in ECFC-exosomes reversed ECFC-exosome-decreased SIPA1L2 expression in ox-LDL-induced HMEC injury. Knockdown of SIPA1L2 repaired autophagic flux and enhanced autophagic activity to promote cell proliferation in ox-LDL-treated HMECs. ECFC-exosome treatment attenuated vascular endothelial injury, regulated lipid balance and activated autophagy in an atherogenic rat model of vascular injury, whereas these effects were eliminated with ECFC-exosomes with knockdown of miR-21-5p. Conclusions Our study demonstrated that ECFC-exosomes protect against atherosclerosis- or PTCA-induced vascular injury by rescuing autophagic flux and inhibiting SIAP1L2 expression through delivery of miR-21-5p.

ECFC-derived exosomal THBS1 mediates angiogenesis and osteogenesis in distraction osteogenesis via the PI3K/AKT/ERK pathway

“…Our previous investigation revealed that ECFCs are an important angiogenic mediator involved in DO [ 29 ]. It was confirmed that ECFCs-derived exosomes serve as important mediators during vascular repair and angiogenesis [ 30 , 31 ]. Several reports raised the possibility that ECFCs do not directly incorporate into newly developed vasculature, instead they stimulate the proliferation and migration of tissue-resident endothelial cells (ECs), using paracrine networks [ [32] , [33] , [34] ].…”

miR-21-5p promotes osteogenic differentiation and calcification of valvular interstitial cells by targeting TGFBI in calcific aortic valve disease

“…And recent omics-based studies on normal vs. CAVD tissues built molecular interaction networks and the key factors and disease association were identi ed 22,25 . Previous studies have MiR-21-5p has been identi ed as a key regulator in chronic heart failure and atherosclerosis 12,13 , which implied the role of miR-21-5p in cardiovascular diseases. Additionally, miR-21-5p has been reported to regulate extracellular matrix degradation and angiogenesis of condylar chondrocytes in temporomandibular joint osteoarthritis, which suggested miR-21-5p involving in osteogenic pathologies.…”

“…In the past few years, the important roles of miRNAs in diagnosis and treatment of cardiovascular diseases, including atherosclerosis, hear failure, cardiac hypertrophy and so on, were revealed in numerous research [9][10][11] . In particular, miR-21-5p has been recently validated its role in chronic heart failure 12 and atherosclerosis 13 . Additionally, miR-21-5p was identi ed as key factor in pathological mechanism of temporomandibular joint osteoarthritis mediated by its action on extracellular matrix degradation and angiogenesis 14 .…”

Exosomes: mediators regulating the phenotypic transition of vascular smooth muscle cells in atherosclerosis

“…In addition to the studies described above, two recent studies have suggested the therapeutic potential of exosomes. Ke et al suggested that endothelial colony-forming cell-derived exosomes regulate lipid homeostasis, activate autophagy, attenuate vascular endothelial injury, and play a protective role in AS [ 90 ]. Zhang et al reported that mesenchymal stem cell-derived exosomes fight against damaged ECs induced by ox-LDL and restore vascular activity by fetal-lethal non-coding developmental regulatory RNA [ 91 ].…”