Adenosine-to-Inosine editing of vasoactive microRNAs alters their targetome and function in ischemia Van der Kwast. Post-ischemic microRNA A-to-I editing

Abstract Adenosine-to-Inosine (A-to-I) editing in the seed-sequence of microRNAs can shift the microRNAs’ targetomes and thus their function. Using public RNA-sequencing data, we identified 35 vasoactive microRNAs that are A-to-I edited. We quantified A-to-I editing of the primary-microRNAs in vascular fibroblasts and endothelial cells. Nine primary-microRNAs were indeed edited and editing consistently increased under ischemia. We determined mature microRNA-editing for the highest expressed microRNAs: miR-376a-3p, miR-376c-3p, miR-381-3p and miR-411-5p. All four mature microRNAs were edited in their seed-sequence. We show that both ADAR1 and ADAR2 can edit pri-microRNAs, in a microRNA-specific manner. MicroRNA-editing also increased under ischemia in vivo in a murine hindlimb ischemia model and ex vivo in human veins. For each edited microRNA, we confirmed a shift in targetome. Expression of the edited microRNA targetomes, not the wildtype targetomes, was downregulated under ischemia in vivo. Furthermore, microRNA-editing enhanced angiogenesis in vitro and ex vivo. In conclusion, we show that microRNA A-to-I editing is a widespread phenomenon, induced by ischemia. Each editing event results in a novel microRNA with a unique targetome, leading to increased angiogenesis.