Abstract
Purpose :
Insulin like growth factor binding protein 2 (IGFBP2) belongs to a highly conserved family of insulin-like growth factor (IGF) binding proteins that modulate IGF-1 actions. IGFBP2 locus 2q33-q34 is linked to glaucoma related traits. In addition, elevated levels of IGFBP2 have been detected in the vitreous and aqueous humor of neovascular eye diseases. Here, we performed in vivo imaging, histological and functional analysis of a transgenic mouse line (TgIgfbp2) overexpressing Igfbp2.
Methods :
TgIgfbp2 mice overexpressing a mouse Igfbp2 cDNA driven by CMV promoter were obtained from Jackson Laboratory. Twenty TgIgfbp2 mice (3-14 months) and 10 littermate controls were examined by fluorescein angiography (FA), indocyanine green angiography (ICGA), fundus and optical coherence tomography (OCT). Histology and electroretinogram (ERG, focal and full-field) were performed at the age of 12-14 months.
Results :
TgIgfbp2 mice have normal choroidal and retinal vasculature by FA and ICGA. Fundus showed hyperfluorescence of optic disc and severe RPE degeneration. Richardson staining revealed wide spread vacuoles in RPE. Large lysosomal vesicles containing pigment granules, hypopigmentation and photoreceptor degeneration were located close to the optic disc. Scotopic focal ERG close to the optic disc showed 1.6 (p<0.05) and 2.3 (p<0.01) times decrease of B-wave amplitude in TgIgfbp2 mice (N=7) than controls (N=5) at lower (-0.93 log cd s/m2) and higher (3.58 log cd s/m2) intensities, respectively, indicating impaired rod function. At high intensity (3.58 log cd s/m2), scotopic A-wave amplitude was 2.0 times (p<0.05) lower than controls, indicating both rod and cone functions were affected. At 3.58 log cd s/m2 intensity, photopic full-field ERG showed lower A-wave amplitude for M-cone (2.7 times, p<0.01, N=10) and S-cone (1.5 times, non-significant, N=10) compared to controls (N=6), indicating M-cones are more sensitive to the damage. B-wave amplitude for M and S cones was decreased 1.5 times (p<0.05) compared to controls, suggesting that downstream cone-related pathways are also compromised.
Conclusions :
Elevated Igfbp2 induces RPE and optic disc abnormalities which further exacerbate rod and cone functions around the optic disc at senescence. Our results suggest that TgIgfbp2 mouse may provide opportunities to address the underlying pathological mechanisms related to abnormal optic disc diseases like Glaucoma.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.