Human Pericardial Fluid Contains Exosomes Enriched with Cardiovascular-Expressed MicroRNAs and Promotes Therapeutic Angiogenesis

Abstract

The pericardial fluid (PF) is contained in the pericardial sac surrounding the heart. MicroRNA (miRNA) exchange via exosomes (endogenous nanoparticles) contributes to cell-to-cell communication. We investigated the hypotheses that the PF is enriched with miRNAs secreted by the heart and that it mediates vascular responses through exosome exchange of miRNAs. The study was developed using leftover material from aortic valve surgery. We found that in comparison with peripheral plasma, the PF contains exosomes enriched with miRNAs co-expressed in patients’ myocardium and vasculature. At a functional level, PF exosomes improved survival, proliferation, and networking of cultured endothelial cells (ECs) and restored the angiogenic capacity of ECs depleted (via Dicer silencing) of their endogenous miRNA content. Moreover, PF exosomes improved post-ischemic blood flow recovery and angiogenesis in mice. Mechanistically, (1) let-7b-5p is proangiogenic and inhibits its target gene, TGFBR1, in ECs; (2) PF exosomes transfer a functional let-7b-5p to ECs, thus reducing their TGFBR1 expression; and (3) let-7b-5p depletion in PF exosomes impairs the angiogenic response to these nanoparticles. Collectively, our data support the concept that PF exosomes orchestrate vascular repair via miRNA transfer.

Pericardial Fluid Exosomes: A New Material to Treat Cardiovascular Disease

“…Beltrami et al 4 . addressed one such challenge by investigating PF obtained from patients undergoing AVR surgery.…”

“…The study by Beltrami et al 4 presents evidence for the complexity of the cargo carried by patient-derived PF exosomes. Nevertheless, the authors do not completely address the supplemental role of exosome-free PF in angiogenesis.…”

“…[1][2][3] To date, exosomes secreted by stem and progenitor cells in the myocardium have shown promising therapeutic benefits, although their precise cellular origin and mechanism(s) of action remain poorly characterized. In this issue of Molecular Therapy, Beltrami et al 4 report that exosomes present in the pericardial fluid (PF) of patients undergoing aortic valve replacement (AVR) are enriched with microRNAs (miRNAs) co-expressed in patients' myocardium and vasculature. The authors further report that PF exosomes enhanced angiogenesis in cultured endothelial cells, improved blood flow recovery and capillary density, and reduced necrosis in mouse models of unilateral limb ischemia.…”

“…The authors further report that PF exosomes enhanced angiogenesis in cultured endothelial cells, improved blood flow recovery and capillary density, and reduced necrosis in mouse models of unilateral limb ischemia. The Beltrami et al 4 study presents molecular evidence by studying one of the well-known let-7 family of miRNAs, miR-let-7b-5p, which is present at high levels within PF exosomes. The authors demonstrate that miR-let-7b-5p partially mediates the angiogenic potential of PF exosomes, which supports the conclusion that PF exosomes may have therapeutic potential for the treatment of vascular diseases.…”

“…Moreover, while there is increasing evidence for a strong role for exosomal miRNAs in promoting angiogenesis, any significant contributions made by exosomal proteins are often overlooked. Beltrami et al 4 investigated in detail the miRNA content of PF exosomes, but determining the protein content and its role in promoting angiogenesis should strengthen the current understanding of PF-exosomes particularly toward clinical translation. This should be interesting, because the authors report that proangiogenic let-7b-5p is only partially responsible for mediating the observed angiogenic potential of PF exosomes.…”