Retinal ischemia and hypoxia can induce neovascularization accompanied by upregulation of multiple angiogenesis-related factors, including vascular endothelial growth factor, erythropoietin, and angiopoietins (Ang-1 and Ang-2), and more.
1 In addition, epigenetic mechanisms, including DNA methylation,
4 histone modifications,
5 and noncoding RNAs,
6 are increasingly recognized as critical regulators of retinal EC (REC) proliferation, migration, and angiogenesis. RNA
N6-methyladenosine (m
6A) is the most widely occurring and reversible epigenetic modification of mRNAs in mammalian cells, characterized by a methylation at the
N6 position of adenosine.
7 It has been shown that m
6A modification regulates multiple biological processes by affecting RNA stability, mRNA degradation, and translation.
8,9 The m
6A modification status is controlled by methyltransferase complexes known as “m
6A writers,” including methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), Wilms tumor 1 associated protein (WTAP), as well as newly discovered m
6A writers, involving Vir-like m
6A methyltransferase associated,
10 zinc finger CCCH-type containing 13 (ZC3H13),
11 and RNA binding motif protein 15/15B (RBM15/15B).
12 The demethylation of m
6A can be accomplished by the presence of alkylation repair homolog protein 5 (ALKBH5), as well as fat mass and obesity-associated protein (FTO), which are recognized as “m
6A erasers.” In addition, m
6A modification is recognized by “m
6A readers” such as YTH
N6-methyladenosine RNA binding proteins (YTHDF), comprising cytoplasmic protein YTHDF1, YTHDF2, and YTHDF3 and nuclear protein YTHDC1.
7 METTL3 is the primary component of the methyltransferase complex and has been implicated in various biological processes, including the self-renewal and differentiation of stem cells,
13,14 cardiac homeostasis,
15 cerebellar development,
16 neurogenesis,
17 and cancers.
18 In particular, loss of METTL3 function in mice leads to embryonic lethality because of immature vascularization.
13 Furthermore, endothelial-specific deletion of METTL3 inhibits Notch signaling, thereby affecting the functions of hematopoietic stem and progenitor cells.
19 Additionally, the ablation of METTL3 leads to a notable suppression of both corneal and retinal neovascularization, attributed to its impact on low-density lipoprotein receptor–related protein 6 (LRP6) and disheveled (DVL1).
20 However, the precise mechanism underlying METTL3-mediated m
6A modification in regulating retinal angiogenesis remains unclear.