Extracellular vesicles from monocyte/platelet aggregates modulate human atherosclerotic plaque reactivity.

Silvia Oggero,Simone Marcone,Thomas Burgoyne,Trinidad Montero‐Melendez,Mary Barry,Andreia L Pinto,Lucy V Norling,David Burke,Stephen Fitzsimons,Catherine Godson,Mauro Perretti,Dinara Ikramova,Orina Belton,Monica Gaetano,Dianne Cooper,Eoin P Brennan

doi:10.1002/jev2.12084

Abstract

Extracellular vesicles (EVs) are emerging as key players in different stages of atherosclerosis. Here we provide evidence that EVs released by mixed aggregates of monocytes and platelets in response to TNF‐α display pro‐inflammatory actions on endothelial cells and atherosclerotic plaques. Tempering platelet activation with Iloprost, Aspirin or a P2Y12 inhibitor impacted quantity and phenotype of EV produced. Proteomics of EVs from cells activated with TNF‐α alone or in the presence of Iloprost revealed a distinct composition, with interesting hits like annexin‐A1 and gelsolin. When added to human atherosclerotic plaque explants, EVs from TNF‐α stimulated monocytes augmented release of cytokines. In contrast, EVs generated by TNF‐α together with Iloprost produced minimal plaque activation. Notably, patients with coronary artery disease that required percutaneous coronary intervention had elevated plasma numbers of monocyte, platelet as well as double positive EV subsets. In conclusion, EVs released following monocyte/platelet activation may play a potential role in the development and progression of atherosclerosis. Whereas attenuating platelet activation modifies EV composition released from monocyte/platelet aggregates, curbing their pro‐inflammatory actions may offer therapeutic avenues for the treatment of atherosclerosis.

Highlights

Extracellular vesicles (EVs) are cell-borne particles that contain a complex biological cargo composed of nucleic acids, proteins and lipids
Flow cytometry analysis demonstrated a high degree of monocyte/platelet aggregates whereby 56.5±5.1% of CD14+ events were positive for the platelet marker CD41 (n = 10; Figure 1a and 1b)
In this study we provide evidence that monocyte/platelet-derived EVs are pro-inflammatory and activate endothelial cells and the human atherosclerotic plaque

Summary

Introduction

Extracellular vesicles (EVs) are cell-borne particles that contain a complex biological cargo composed of nucleic acids, proteins and lipids. Increased numbers of monocyte/platelet aggregates are reported in patients with atherosclerosis (Furman et al, 1998, 2001) or atherothrombosis (Neumann et al, 1999), and animal models have unravelled some of the molecular mechanisms underlying this inter-cellular interaction (Del Conde et al, 2005; Patko et al, 2012). While presence of these aggregates has been used as a possible biomarker, there is lack of investigation about their possible function especially in relation to the EVs which they can release. This could be relevant, since EVs can cause endothelial dysfunction, vascular calcification, unstable plaque progression, rupture and thrombus formation (Jansen et al, 2017)

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