Horizontal RNA transfer goes deep: platelet consumption and microRNA utilization by vascular smooth muscle cells

Abstract

| INTRODUC TI ON MicroRNAs (miRNAs), which are short non-coding RNAs that repress translation of cognate sequence-matched mRNAs through multiple mechanisms, have been established as both important regulators and key biomarkers of cardiovascular function. miRNAs have been shown to modulate gene expression, resulting in altered development and/or functional responses, in every type of vascular cell. miRNAs also circulate in plasma, either complexed to lipoproteins or contained within extracellular vesicles (EVs). Circulation of miRNAs enables their functionality both as biomarkers for altered gene expression to indicate and describe pathologic conditions, and as mediators of horizontal gene transfer between vascular cells in an autocrine or a paracrine fashion. miRNAs are well suited to these roles, owing to their relatively long half-life (approximately 5 days), which can support long-term gene regulation in distal cells. Horizontal transfer of intercellular RNA extends the reach of miR-NAs beyond their cell of origin, and adds new dimensions to gene regulation in vivo. Horizontal miRNA transfer may be of particular relevance in postmitotic and senescent vascular cells, in which modulation of gene expression by miRNAs can affect cellular activation in acute or chronic settings. In particular, platelets are highly enriched in miRNAs, and platelets are emerging as major sources and transfer hubs mediating miRNA exchange in blood. Platelet-derived microvesicles (PMVs) constitute a major proportion of plasma microvesicles (MVs), and these structures have been shown to deliver platelet miR-NAs to other vascular and extravascular cells in multiple contexts. Moreover, phagocytosis of intact platelets has been demonstrated in several vascular cell types, including endothelial cells, neutrophils, and monocytes, providing yet another opportunity for miRNA exchange by engulfment of whole platelets. The mechanisms, cellular and molecular targets, and functional outcomes of horizontal transfer of platelet miRNAs are active areas of investigation. Most recently, Zeng et al reported a new cellular target of platelet miR-NAs: vascular smooth muscle cells (VSMCs) in vitro following coincubation with platelets, and in vivo following wire injury to the femoral artery in mice, with effects on the VSMC injury response. 1Even more surprising is the apparent engulfment of intact platelets by VSMCs, representing not only exchange of genetic material, but exchange of complex cellular content between these vascular cells.In this Neighborhood Watch, we discuss the background, implications, unanswered questions, and future perspectives of this study. | PL ATELE T RNA TR AN S FERThe recent report by Zeng et al 1 builds upon an exciting area of research in the cardiovascular field: the ability of platelets to modulate the gene expression in other cells in contact with the blood by transferring (mi)RNAs, which then alters the physiology of the recipient cells. This ability to transfer RNAs was first reported in 2012, when the delivery of mRNAs ...