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Y. Bai, M. Zhu, Y.-Z. Le; Temporal Requirement of the RPE-Produced VEGF in Choroidal Development. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5902.
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Previous studies demonstrate that the RPE-produced vascular endothelial growth factor (VEGF) is required for choroidal development. To determine the temporal requirement of VEGF in choroidal development, we determined choroidal density, and photoreceptor function and morphology in mice that had inducible RPE-specific VEGF knockout at various time during development, using the inducible gene knockout system established in our laboaratory.
The inducible RPE-specific VEGF knockout mice were generated by breeding our tetracycline inducible RPE-specific Cre mice with the floxed VEGF mice. RPE-specific VEGF disruption was achieved by doxycycline induction at various time during development. Loss of the RPE-produced VEGF was confirmed with Western blot analysis and immunohistochemistry. Choroidal density was determined by a computer-assisted assay using anti-CD31 antibody stained choroidal flat-mounts. Retinal function was measured with electroretinography and retinal morphology was examined in H&E staining retinal sections.
A computer-assisted semi-quantitative assay was developed to determine choroidal density using anti-CD31 antibody stained choroidal flat-mounts. Induction of RPE-specific VEGF disruption any time from embryonic day 9 (E9) to E13 caused a decrease in choroidal density, photoreceptor function, and photoreceptor outer nuclear layer thickness. However, no apparent defects were observed in mice with inducible VEGF knockout after E13.
Our results demonstrate that the RPE-produced VEGF was required for choroidal development up to E13. Although choroidal vasculature continues to develop/differentiate after birth, the loss of the RPE-produced VEGF after E13 did not cause apparent defects, suggesting that the RPE-produced VEGF was no longer required for choroidal development at this time. Our results also suggest that the inducible RPE-specific VEGF knockout mice may be a useful model for the study of post-developmental function of VEGF, which is related to the pathogenesis of diabetic retinopathy and age-related macular degeneration, leading causes of blindness.
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