CircSlc17a5 controlled by VLDLR/QKI pathway regulated the choroidal angiogenesis

Area of Science:

• Ophthalmology
• Molecular Biology
• Genetics

Background:

• Ocular neovascularization, a significant cause of vision loss, is linked to Very-low-density lipoprotein receptor (VLDLR).
• The precise molecular mechanisms governing VLDLR's role in ocular neovascularization remain incompletely understood.
• Circular RNAs (circRNAs) are emerging as critical regulators in various biological processes, including neovascularization.

Purpose of the Study:

• To investigate the role of circRNAs in Very-low-density lipoprotein receptor (VLDLR)-associated ocular neovascularization.
• To elucidate the molecular pathways involving VLDLR, Quaking (QKI), and circRNAs in the context of choroidal angiogenesis.

Main Methods:

• Utilized Vldlr knockout (Vldlr-/-), Robo4 knockout (Robo4-/-), and wild-type (WT) mice.
• Employed oxygen-induced retinopathy (OIR) mouse model and high-throughput sequencing to profile circRNA and transcript expression.
• Validated candidate circRNAs using RNase R treatment, Sanger sequencing, and quantitative polymerase chain reaction (qPCR).
• Assessed choroidal neovascularization using ex vivo choroidal sprouting assays and laser-induced choroidal neovascularization models.

Main Results:

• Quaking (QKI) expression was significantly downregulated in Vldlr-deficient mice compared to WT and Robo4-deficient mice.
• VLDLR expression or Reelin stimulation led to increased QKI expression in bEnd.3 cells.
• Circular RNA sequencing identified circSlc17a5 as a VLDLR-regulated circRNA, with increased circRNA numbers observed in OIR mice.
• QKI was found to mediate the biogenesis of circSlc17a5, which significantly regulated choroidal angiogenesis.

Conclusions:

• CircSlc17a5, regulated by the VLDLR/QKI pathway, is a crucial regulator of choroidal angiogenesis.
• This study identifies a novel molecular mechanism involving VLDLR, QKI, and circSlc17a5 in the pathogenesis of ocular neovascularization.