Journal
MOLECULAR THERAPY
Volume 25, Issue 3, Pages 679-693Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2016.12.022
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Funding
- British Heart Foundation (BHF) [RG/15/5/31446]
- BHF Regenerative Medicine Centers [RM/13/2/30158]
- Leducq Transatlantic Network MIRVAD [13 CVD 02]
- National Institute of Heath Research (NIHR) through the Bristol Biomedical Research Unit (BRU)
- MRC [MC_U120097112] Funding Source: UKRI
- British Heart Foundation [RG/15/5/31446, FS/10/61/28566] Funding Source: researchfish
- Medical Research Council [MC_U120097112] Funding Source: researchfish
- National Institute for Health Research [CL-2016-11-502] Funding Source: researchfish
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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 nanopartides. Collectively, our data support the concept that PF exosomes orchestrate vascular repair via miRNA transfer.
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