Lipoxin A₄ stimulates endothelial miR-126-5p expression and its transfer via microvesicles

The proresolution lipid mediator lipoxin (LX)A₄ bestows protective bioactions on endothelial cells. We examined the impact of LXA₄ on transcellular endothelial signaling via microRNA (miR)-containing microvesicles. We report LXA₄ inhibition of MV release by TNF-α-treated HUVECs, associated with the down-regulation of 18 miR in endothelial microvesicles (EMVs) and the up-regulation of miR-126-5p, both in HUVECs and in EMVs. LXA₄ up-regulated miR-126-5p by ∼5-fold in HUVECs and promoted a release of microvesicles (LXA₄-EMVs) that enhanced miR-126-5p by ∼7-fold in recipient HUVECs. In these cells, LXA₄-EMVs abrogated the up-regulation of VCAM-1, induced in recipient HUVECs by EMVs released by untreated or TNF-α-treated HUVECs. LXA₄-EMVs also reduced by ∼40% the expression of SPRED1, which we validated as an miR-126-5p target, whereas they stimulated monolayer repair in an in vitro wound assay. This effect was lost when the EMVs were depleted of miR-126-5p. These results provide evidence that changes in miR expression and microvesicle packaging and transfer represent a mechanism of action of LXA₄, which may be relevant in vascular biology and inflammation.-Codagnone, M., Recchiuti, A., Lanuti, P., Pierdomenico, A. M., Cianci, E., Patruno, S., Mari, V. C., Simiele, F., Di Tomo, P., Pandolfi, A., Romano, M. Lipoxin A₄ stimulates endothelial miR-126-5p expression and its transfer via microvesicles.