Human Pericardial Fluid Contains Exosomes Enriched with Cardiovascular-Expressed MicroRNAs and Promotes Therapeutic Angiogenesis.
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.
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK; National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.
Cristina
C
Beltrami
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK.
Marie
M
Besnier
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK.
Saran
S
Shantikumar
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK.
Andrew I U
AI
Shearn
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK.
Cha
C
Rajakaruna
National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.
Abas
A
Laftah
Circolo Research Hospital, 57 21100 Varese, Italy.
Fausto
F
Sessa
IRCCS MultiMedica, 20099 Milan, Italy.
Gaia
G
Spinetti
National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK; Duke-NUS Medical School, Singapore 169857, Singapore.
Enrico
E
Petretto
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK; National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.
Gianni D
GD
Angelini
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK; National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK. Electronic address: costanza.emanueli@bristol.ac.uk.
Costanza
C
Emanueli
D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics; D002319:Cardiovascular System / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D000069236:Pericardial Fluid / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics
D060565:Argonaute Proteins; D035683:MicroRNAs; D043244:Ribonuclease III
angiogenesis; clinical samples; exosomes; extracellular vesicles; human; ischemia; let-7b; microRNAs; pericardial fluid