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

Cristina Beltrami,Marie Besnier,Saran Shantikumar,Andrew I.U Shearn,Cha Rajakaruna,Abas Laftah,Fausto Sessa,Gaia Spinetti,Enrico Petretto,Gianni D Angelini,Costanza Emanueli

doi:10.1016/j.ymthe.2016.12.022

Cristina Beltrami, Marie Besnier + Show 9 more

Open Access

PDF Available

https://doi.org/10.1016/j.ymthe.2016.12.022

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

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.

Highlights

The pericardial fluid (PF) is an ultrafiltrate of plasma contained within the double-walled pericardial sac that surrounds the heart and the roots of the great vessels bringing blood to and from the heart cells.[1]
Several miRNAs of putative cardiovascular origin appear to be relatively highly expressed. Fifteen of these miRNAs were rationally selected for further analyses, together with miR-208 and the liver-enriched miR-122
These data align with our hypothesis that the PF represents a liquid compartment in which expressional information and executive command from the heart and thoracic vessels are released in the form of miRNAs

Summary

Introduction

The pericardial fluid (PF) is an ultrafiltrate of plasma contained within the double-walled pericardial sac ( known as pericardium) that surrounds the heart and the roots of the great vessels (ascending aorta, superior and inferior vena cavae, pulmonary arteries and pulmonary veins) bringing blood to and from the heart cells (see Figure S1).[1]. Molecules can be transported from the pericardial cavity to the peripheral circulation by the thoracic duct via the parietal pericardium, by the right lymphatic duct via the right pleural cavity,[5] or through the capillary network and the venous system.[6,7] Cardiac enzymes and troponins are present at higher levels in the PF than the peripheral blood, and increased levels of these molecules are used to aid the diagnosis of fatal myocardial infarct postmortem.[8,9] the PF contains biologically active factors and components, of possible myocardial origin, including atrial and brain natriuretic peptides and endothelin-1.10 From the above, the myocardial contribution to PF content is apparent, and we reasoned that the PF composition might reflect, at least in part, the myocardium expression profile in health and disease

Methods

Results

Conclusion