FTO-dependent m⁶A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke.

Abstract

Vascular repair is considered a key restorative measure to improve long-term outcomes after ischemic stroke. N⁶-methyladenosine (m⁶A), the most prevalent internal modification in eukaryotic mRNAs, functionally mediates vascular repair. However, whether circular RNA SCMH1 (circSCMH1) promotes vascular repair by m⁶A methylation after stroke remains to be elucidated. Here, we identify the role of circSCMH1 in promoting vascular repair in peri-infarct cortex of male mice and male monkeys after photothrombotic (PT) stroke, and attenuating the ischemia-induced m⁶A methylation in peri-infarct cortex of male mice after PT stroke. Mechanically, circSCMH1 increased the translocation of ubiquitination-modified fat mass and obesity-associated protein (FTO) into nucleus of endothelial cells (ECs), leading to m⁶A demethylation of phospholipid phosphatase 3 (Plpp3) mRNA and subsequently the increase of Plpp3 expression in ECs. Our data demonstrate that circSCMH1 enhances vascular repair via FTO-regulated m⁶A methylation after stroke, providing insights into the mechanism of circSCMH1 in promoting stroke recovery.