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

The mechanisms behind how vascular repair is regulated after ischemic stroke are yet to be elucidated. Here, the authors describe that a circular RNA interacts with FTO to promote vascular repair following stroke in mice and primates via mediating m6 A modification. Vascular repair is considered a key restorative measure to improve long-term outcomes after ischemic stroke. N-6-methyladenosine (m(6)A), the most prevalent internal modification in eukaryotic mRNAs, functionally mediates vascular repair. However, whether circular RNA SCMH1 (circSCMH1) promotes vascular repair by m(6)A 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 m(6)A 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 m(6)A 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 m(6)A methylation after stroke, providing insights into the mechanism of circSCMH1 in promoting stroke recovery.

Automated summary

This study reveals that circular RNA SCMH1 promotes vascular repair after ischemic stroke by mediating m6A methylation. It is found that SCMH1 interacts with FTO and regulates m6A modification to enhance vascular repair following ischemic stroke. This finding provides important insights into the mechanism of vascular repair.