Role of METTL3-Dependent N6-Methyladenosine mRNA Modification in the Promotion of Angiogenesis

Epigenetic alterations occur in many physiological and pathological processes. N-6-methyladenosine (m(6)A) modification is the most prevalent modification in eukaryotic mRNAs. However, the role of m(6)A modification in pathological angiogenesis remains elusive. In this study, we showed that the level of m(6)A 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 m(6)A modification of target genes (e.g., LRP6 and dishevelled 1 [DVL1]). METTL3 enhanced the translation of LRP6 and DVL1 in an YTH m(6)A RNA-binding protein 1 (YTHDF1)-dependent manner. Collectively, this study suggests that METTL3-mediated m(6)A modification is an important hypoxic stress-response mechanism. The targeting of m(6)A through its writer enzyme METTL3 is a promising strategy for the treatment of angiogenic diseases.