Investigative ophthalmology & visual science · 2013
SRPK1 inhibition modulates VEGF splicing to reduce pathological neovascularization in a rat model of retinopathy of prematurity.
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Gammons Melissa V R, Dick Andrew D, Harper Steven J, Bates David O
Аннотация
PURPOSE: We tested the hypothesis that recombinant human VEGF-A165b and the serine arginine protein kinase (SRPK) inhibitor, SRPIN340, which controls splicing of the VEGF-A pre-mRNA, prevent neovascularization in a rodent model of retinopathy of prematurity (ROP).
METHODS: In the 50/10 oxygen-induced retinopathy (50/10 OIR) model that exposes newborn rats to repeated cycles of 24 hours of 50% oxygen alternating with 24 hours of 10% oxygen, pups received intraocular injections of SRPIN340, vehicle, VEGF165b, anti-VEGF antibody, or saline. Whole mounts of retinas were prepared for isolectin immunohistochemistry, and preretinal or intravitreal neovascularization (PRNV) determined by clock hour analysis.
RESULTS: The anti-VEGF antibody (P < 0.04), rhVEGF165b (P < 0.001), and SRPIN340 (P < 0.05) significantly reduced PRNV compared with control eyes. SRPIN340 reduced the expression of proangiogenic VEGF165 without affecting VEGF165b expression.
CONCLUSIONS: These results suggest that splicing regulation through selective downregulation of proangiogenic VEGF isoforms (via SRPK1 inhibition) or competitive inhibition of VEGF signaling by rhVEGF165b has the potential to be an effective alternative to potential cyto- and neurotoxic anti-VEGF agents in the treatment of pathological neovascularization in the eye.
METHODS: In the 50/10 oxygen-induced retinopathy (50/10 OIR) model that exposes newborn rats to repeated cycles of 24 hours of 50% oxygen alternating with 24 hours of 10% oxygen, pups received intraocular injections of SRPIN340, vehicle, VEGF165b, anti-VEGF antibody, or saline. Whole mounts of retinas were prepared for isolectin immunohistochemistry, and preretinal or intravitreal neovascularization (PRNV) determined by clock hour analysis.
RESULTS: The anti-VEGF antibody (P < 0.04), rhVEGF165b (P < 0.001), and SRPIN340 (P < 0.05) significantly reduced PRNV compared with control eyes. SRPIN340 reduced the expression of proangiogenic VEGF165 without affecting VEGF165b expression.
CONCLUSIONS: These results suggest that splicing regulation through selective downregulation of proangiogenic VEGF isoforms (via SRPK1 inhibition) or competitive inhibition of VEGF signaling by rhVEGF165b has the potential to be an effective alternative to potential cyto- and neurotoxic anti-VEGF agents in the treatment of pathological neovascularization in the eye.
Предметные рубрики MeSH
AnimalsBlotting, WesternCells, CulturedDisease Models, AnimalEnzyme-Linked Immunosorbent AssayFemaleHumansInfant, NewbornInjections, IntraocularNiacinamidePiperidinesProtein Kinase InhibitorsProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyRetinal NeovascularizationRetinopathy of PrematurityVascular Endothelial Growth Factor A