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

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.

Role of Extracellular Vesicles in the Pathogenesis of Vascular Damage

“…63 These effects can be blunted by the inhibition of platelet activation with acetylsalicylic acid, P2Y12 inhibitor, and iloprost. 63…”

“…64,65 Under inflammatory stimuli, their interaction promotes the release of EVs with proatherogenic properties and long-lasting effects at vascular levels. 63 These effects can be blunted by the inhibition of platelet activation with acetylsalicylic acid, P2Y12 inhibitor, and iloprost. 63 Endothelial EVs are crucial in the development of the atherosclerotic processes, and local proatherogenic stimuli can alter endothelial EV release, regulating endothelial and macrophage function locally and at distant sites.…”

“…63 These effects can be blunted by the inhibition of platelet activation with acetylsalicylic acid, P2Y12 inhibitor, and iloprost. 63 Endothelial EVs are crucial in the development of the atherosclerotic processes, and local proatherogenic stimuli can alter endothelial EV release, regulating endothelial and macrophage function locally and at distant sites. In vitro, Ox-LDL and IL-6 increase packaging of miR-92a-3p in EVs secreted by endothelial cells, which in turn activates endothelial proliferation and angiogenesis.…”

Cellular Chitchatting: Exploring the Role of Exosomes as Cardiovascular Risk Factors

“…In particular, the platelet’s activation status plays a pivotal role in the small EVs pro inflammatory content. Inhibition of platelets activation leads to a milder inflammatory phenotype, suggesting a synergistic role of monocyte/platelet aggregates in releasing functional EVs ( Oggero et al, 2021 ).…”

Thrombo-Inflammation: A Focus on NTPDase1/CD39

“…In recent years, much attention has been given to atherosclerosis as a chronic inflammatory disease characterized by vascular infiltration of innate immune cells. On this respect, it is worth noting that P2Y12 receptor is also involved in platelet/monocyte aggregate formation, an event linking thrombosis with vascular inflammation and atherosclerosis [ 59 , 61 ]. Such evidence further strengthens the importance of CD39 in atherogenesis [ 62 , 63 ].…”