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Stacey L. Hose, Laura Asnaghi, Cheng Zhang, Marisol Cano, Morton F. Goldberg, Charles G. Eberhart, Eric F. Wawrousek, J. S. Zigler, Jr., Debasish Sinha; Defects in Optic Nerve Glia and in the Lens During Embryonic Development May Cause Persistent Fetal Vasculature (PFV) Disease. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2356.
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© ARVO (1962-2015); The Authors (2016-present)
To use animal models to investigate the cellular basis of abnormal remodeling of the fetal vasculature in PFV disease.
Sprague-Dawley rats with the Nuc1 and/or frogleg mutations, transgenic mice with abnormal astrocyte development, and age-matched wild type rats and mice were used. Paraffin sections of human eyes from PFV patients and normal donors were obtained from the Eye Pathology Laboratory, Wilmer Eye Institute. For immunohistochemistry with single or double labeling, frozen sections were incubated with primary antibodies, and then with fluorescent secondary antibodies conjugated with either Cy-2 or Cy-3. The primary antibodies used were a monoclonal to AQP4 and polyclonals to GFAP and VEGF. Real-time PCR and western blot analysis were used to quantify AQP4 and VEGF mRNA and protein expression. VEGF protein concentrations in the vitreous were determined by ELISA. Migration of wild type and Nuc1 optic nerve astrocytes were analyzed by transwell assay.
As we reported previously, Nuc1 homozygous rats, which express the mutant protein (βA3/A1-crystallin) in astrocytes, exhibit PFV; we now report that when Nuc1 homozygous rats also are homozygous for the frogleg mutation, PFV is more severe. In both rat models the lens ruptures shortly before birth. In the double mutant, the glial populations of the optic nerve, both astrocytes and oligodendrocytes, are severely abnormal. Astrocytes from the optic nerve of Nuc1 rats have higher expression of AQP4 and migrate faster than normal astrocytes, perhaps accounting for their moving into the vitreous and ensheathing the hyaloid artery. VEGF is increased in the vitreous and lenses of the Nuc1 rat. The severity of PFV in the rat models is in contrast to the transgenic mice, where the astrocytes are abnormal, but the lens is completely normal. Both the frequency and the severity of PFV are markedly reduced in the mice.
Human PFV disease is a very complex and heterogeneous condition, and multiple factors may be involved in its etiology. Our data indicate that defects in the lens and in optic nerve glia during embryonic eye development can contribute to PFV disease in rodents. We hypothesize that the degree of completeness and severity of the disease depends, at least in part, on the lens phenotype.
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