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S. L. Hose, R. Grebe, M. Cano, M. F. Goldberg, G. A. Lutty, W.-K. Lo, J. S. Zigler, Jr., D. Sinha; Role of Astrocytes in Persistent Fetal Vasculature: Insights From a Novel Crystallin Mutation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4087.
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We demonstrated in the Nuc1 rat, a mutant in which the hyaloid vascular system fails to regress normally, and in human PFV disease, where the hyaloid vasculature abnormally persists after birth, that astrocytes expressing Vascular Endothelial Growth Factor (VEGF) and crystallins surround the retained vessels. The presence of astrocytes in these pathological conditions is in contrast to the normal eye, where astrocytes are not associated with the hyaloid vasculature. The Nuc1 phenotype results from mutation of the βA3/A1-crystallin gene, which, in the neural retina, is expressed only in astrocytes. We have investigated the role of astrocytes in PFV.
Expression of VEGF in the lens and vitreous of Nuc1 and wildtype (WT) rats was assessed by western blotting and ELISA. Sections through the optic nerve head from Nuc1 were compared to WT rats by transmission electron microscopy (TEM). Also cryosections were used for localization of GFAP and crystallins by immunofluorescence.
TEM studies show intact capillaries in WT rats on the third postnatal day, but clear hallmarks of involution by day 14. In contrast, capillaries impinging on the posterior lens capsule of a 29 day-old Nuc1 rat appear to be normal. We also demonstrate that astrocytes in the Nuc1 rat cover the hyaloid vessels of the developing eye. However, in the normal eye, astrocytes are not associated with the hyaloid vasculature. The VEGF concentration in the Nuc1 vitreous was nearly 5 fold higher than in the vitreous from normal rats. In addition to astrocytes, the lens also is a possible source of VEGF in the vitreous since VEGF164 was increased in the Nuc1 lens relative to WT. Both lens fibers and astrocytes from Nuc1 show striking structural abnormalities with profound effects on the expression and organization of intermediate filaments. Furthermore, GFAP-immunopositive astrocytes in the retained vessels of PFV patients express VEGF and crystallins.
These data for the first time suggest that astrocytes are involved in PFV. In addition, the involvement of βA3/A1-crystallin in normal astrocyte function and subsequent hyaloid vascular regression suggests a previously unknown non-lens function for β/γ-crystallins. The possibility that βA3/A1-crystallin may have a role in vascular remodeling is important, because such remodeling is fundamental to normal ocular development and to the pathogenesis of ocular diseases.
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