Role of METTL3-Dependent N-Methyladenosine mRNA Modification in the Promotion of Angiogenesis.

Epigenetic alterations occur in many physiological and pathological processes. N-methyladenosine (mA) modification is the most prevalent modification in eukaryotic mRNAs. However, the role of mA modification in pathological angiogenesis remains elusive. In this study, we showed that the level of mA modification was significantly upregulated in endothelial cells and mouse retinas following hypoxic stress, which was caused by increased METTL3 levels. METTL3 silencing or METTL3 overexpression altered endothelial cell viability, proliferation, migration, and tube formation in vitro. METTL3 knockout in vivo decreased avascular area and pathological neovascular tufts in an oxygen-induced retinopathy model and inhibited alkali burn-induced corneal neovascularization. Mechanistically, METTL3 exerted its angiogenic role by regulating Wnt signaling through the mA modification of target genes (e.g., LRP6 and dishevelled 1 [DVL1]). METTL3 enhanced the translation of LRP6 and DVL1 in an YTH mA RNA-binding protein 1 (YTHDF1)-dependent manner. Collectively, this study suggests that METTL3-mediated mA modification is an important hypoxic stress-response mechanism. The targeting of mA through its writer enzyme METTL3 is a promising strategy for the treatment of angiogenic diseases.