Extracellular vesicles transfer of microRNAs and atherosclerosis – EXTREMA
Despite a better management of risk factors, cardiovascular diseases (CVD) remain the principal cause of deaths worldwide. So far, efficient treatments to treat CVD are lacking. Atherosclerosis represents the common feature of CVD. Atherosclerosis initiates at endothelial level and is characterized by an accumulation of lipids within the intima at specific areas where blood flow is low and disturbed contributing to the recruitment of inflammatory cells. Atherosclerosis involved various cell types that communicate with each other through different mechanisms. Such communication affects cells and contributes to major phenotypical changes contributing to disease. Among gene expression regulators it appears that short non-coding RNAs, microRNAs (miR), play a crucial role in the development of atherosclerosis. Recently, extracellular vesicles (EVs) emerged as new mediators of intercellular crosstalk taking place either locally or remotely.
Upon different stimuli, cells release EVs in the extracellular space. To date, 2 types of EVs have been described: 1- microvesicles (MVs -also microparticles) and 2- exosomes (Exos). These EVs differ from each other by their size, composition and mechanisms leading to their formation. MVs (100nm-1µm diameter) are released from the plasma membrane and express surface antigens from the originating cell. Exosomes (40nm-100nm) are released from multivesicular bodies and express specific markers enriched in those unique organelles.
EVs have been considered as interesting potential biomarkers of CVD, as is the case for endothelial-derived MVs. Recent evidences indicate that EVs are not only biomarkers but also real biological effectors capable of transmitting information to remote cells. During their formation, EVs package and carry some material, especially miRs, from originating cells to recipient cells, in which they contribute to specific phenotypical changes through regulation of gene expression. To date, mechanisms linking EV-mediated miRs transfer to the development of atherosclerosis have not been characterized so far.
We hypothesize that circulating endothelial-derived EVs control gene expression, cellular phenotypic changes and disease processes by selectively transferring miRs to remote target cells in atherosclerosis.
We obtained preliminary results supporting this hypothesis. Indeed, we identified 2 sets of miRs preferentially expressed into MVs (MV-miR) and Exos (Exo-miR) as function of hemodynamic conditions (shear stress) and proatherogneic conditions (oxLDL stimulation) in vitro. We further investigated and selected miRNAs candidates that are also found as circulating MV-miR and Exo-miR in both experimental and clinical atherosclerosis EVs in vivo. Moreover, we identified recipient cells for MVs and Exos into the spleen. Interestingly, these cells express low amount of miRs which are contained into EVs targeting them. These findings suggest that EVs mediated miRs transfer could affect their phenotype by targeting specific genes. Furthermore, these miRs candidates target genes have been associated with atherosclerosis development.
This proposal includes 3 specific aims.
(1) To profile the miRNA content of endothelial EVs as a function of hemodynamic and proatherogenic conditions and to determine mechanisms involved in miRNA sorting into EVs.
(2) To analyze the biodistribution and functional effects of transferred EVs both in vivo and in vitro
(3) To highlight the consequences of the EV-mediated miRNA transfer in atherosclerosis and its involvement in inflammation associated. In particular, we will assess in vivo how EVs mediated miRNAs transfer contribute to atherosclerosis development and inflammation by quantifying atherosclerotic lesions and immune profile in EVs treated mice.
The Principal Investigator has extensive expertise in vascular biology, miRNAs and in atherosclerosis disease. Preliminary results have been obtained attesting the feasibility of this project.
Monsieur Xavier Loyer (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Help of the ANR 353,665 euros
Beginning and duration of the scientific project: September 2016 - 36 Months