Background: Type 3 macular neovascularization (MNV3) is an important subtype of neovascular age-related macular degeneration. Previously, we established an advanced MNV3-like mouse model by knocking out the Vhl, Rb1, and p107 genes in the retinal progenitors (Rb1/p107/Vhl TKO model). This study investigates the role of the p107 protein (also called Rb transcriptional corepressor like 1, Rbl1) on retinal blood vessels in the VhlKO retina. Methods: By breeding the retinal-specific alpha-Cre mice with Vhl floxed mice and p107 -/-mice, we got VhlKO, p107KO, and p107/VhlDKO mice. Whole mount retinal IB4 staining, and fundus fluorescein angiography (FFA) were performed to evaluate the retinal vascular vessels. Immunofluorescence staining studied retinal cell types, cell proliferation, and cell death. RNA sequencing, chromatin immunoprecipitation (CHIP), and dual luciferase reporter assay were also performed to study the retinal transcriptome, the binding of p107 protein to the promoter region of Hif target genes, and the effect of the p107 protein on the transcriptional activity of the Hif target genes. Results: p107/VhlDKO mice have delayed regression of hyaloid vessels, retinal degeneration, and retinal neovascularization. The p107 protein significantly inhibits the Hif pathway activity in VhlKO retinas. It can also bind to the promoter regions and suppress the transcriptional activity of several Hif target genes, including Vegfa, Kdr, and Tek. Conclusions:The p107 protein inhibits angiogenesis in the VhlKO retina, as it can bind and inhibit Hif target genes related to retinal angiogenesis.
