Methyltransferase-like 14 suppresses the retinal neovascularization by reducing HIF-1α in proliferative retinopathy

Proliferative retinopathy (PR), a leading cause of visual impairment, is characterized by pathological retinal neovascularization. As an important methyltransferase, methyltransferase-like 14 (METTL14) plays a key role in the N6-methyladenosine (m⁶A) modification, which is the most widespread modification in mRNA and has been defined as a critical regulator in retinal diseases.

This study aims to clarify the mechanisms by which METTL14 regulates pathological retinal neovascularization in PR. The m⁶A levels were determined by m⁶A RNA colorimetric quantification in mice retinas and endothelial cells. The METTL14 levels in mice retinas and endothelial cells were detected by qPCR, western blotting and immunofluorescence assays. Retinal flat mounts from the oxygen-induced retinopathy (OIR) mice were used to assess the effects of METTL14 on retinal neovascularization. The effects of METTL14 on angiogenic functions of endothelial cells were measured by cell counting kit-8 (CCK-8), wound healing and tube formation assays. Mechanistically, we used the sequence-based RNA adenosine methylation site predictor (SRAMP) system to predict the target genes of METTL14 and performed qPCR, western blotting and RNA immunoprecipitation assays to validate their interactions. Statistical analyses were performed using Student's t test or one-way ANOVA.

The levels of m⁶A and METTL14 were reduced in the retinas of OIR mice and in cobalt chloride (CoCl₂)-induced endothelial cells. METTL14 overexpression increased the m⁶A levels in mice retinas and endothelial cells. METTL14 overexpression in the OIR mice decreased the retinal neovascularization and vaso-obliteration. In CoCl₂-induced endothelial cells, METTL14 overexpression enhanced cells viability and reduced cells migration and tube formation. Mechanistically, METTL14 bound to hypoxia-inducible factor 1-alpha (HIF-1α) and suppressed HIF-1α levels.

This study suggests that METTL14-mediated m⁶A modification is a pivotal step in regulating the pathogenesis of retinal neovascularization. Therefore, METTL14 might be introduced as a promising therapeutic strategy for the management of PR. However, our findings are limited by the types of clinical samples, and further validation in larger clinical cohorts is required.