FTO regulates ocular angiogenesis via m⁶A-YTHDF2-dependent mechanism

Area of Science:

• Ophthalmology
• Molecular Biology
• Epigenetics

Background:

• Pathological ocular angiogenesis leads to vision loss.
• Understanding its mechanisms is key for developing treatments.
• N⁶-methyladenosine (m⁶A) modification plays a role in cellular processes.

Purpose of the Study:

• Investigate the role of FTO-mediated m⁶A demethylation in pathological ocular angiogenesis.
• Determine FTO's impact on endothelial cell function and corneal neovascularization (CNV).

Main Methods:

• Utilized a corneal neovascularization (CNV) mouse model.
• Performed in vitro experiments involving endothelial cell (EC) FTO silencing.
• Assessed EC proliferation, migration, and tube formation.
• Analyzed m⁶A levels, RNA stability, and gene expression (e.g., FAK).

Main Results:

• FTO levels were elevated in neovascularized corneas and ECs.
• FTO silencing reduced EC proliferation, migration, and tube formation.
• In vivo FTO silencing attenuated CNV.
• FTO inhibition increased m⁶A methylation of pro-angiogenic genes (e.g., FAK), enhancing RNA decay via YTHDF2.

Conclusions:

• FTO promotes pathological ocular angiogenesis by regulating EC function.
• The mechanism involves m⁶A demethylation and the YTHDF2 reader.
• FTO is a potential therapeutic target for ocular angiogenesis disorders.