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R Lund, S Wang, T Holmes, JM Lawrence, M Vidal-Sanz, N Hurtado-Montalbán, MP Villegas-Pérez; Evolving Neurovascular Relationships in the RCS Rat with Age . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2719.
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Purpose: We have found previously that the progressive loss of photoreceptors that occurs in the Royal College of Surgeons (RCS) rat leads in time to axonal dystrophy in the optic fiber layer and to subsequent retinal ganglion cell loss. It appears that changes in the retinal vascular are responsible for the neuronal changes; here we examine how they develop and suggest mechanisms whereby the axonal loss occurs. Methods: Both dystrophic and congenic RCS rats (2-24month old) were used in this study. Animals were anesthetized and perfused intracardially. Whole-mount retinae were first stained for neurofilament protein (RT97), and then were transferred to an incubation medium for NADPH-diaphorase staining. A separate group of dystrophic rats were injected with Type II Peroxidase into the femoral vein; the whole-mount retinae were processed for HRP histochemistry. Results: The first changes are seen in the deep vascular plexus, as the photoreceptors are lost, this plexus comes into close proximity to the retinal pigment epithelial (RPE) cell layer. RPE cells are attracted to vessels of the plexus by an as yet unknown mechanism and this leads to a series of progressive changes in which the vessels form focal complexes including dilated or convoluted vessels associated with RPE cells. These complexes become more elaborate with many small vessels radiating from them. Vessels arising from the inner retinal circulation that supply the complexes must cross nerve fiber bundles before they plunge into the retina. With time, they appear to come under tension, pulling the optic axons that they cross into the retina. At these tension points, axons are ligated, and this leads to retinal ganglion cell (RGC) loss by retrograde degeneration. The vascular events begin in the ventral retina around the optic nerve head at around 3 months eventually extending into the dorsal retina. Axonal dystrophy similarly begins ventrally at between 5 and 6 months and spreads over much of the retinal area with age. Conclusions: These observations show a complex series of events whereby vascular changes can have secondary repercussions for neurons distant from the primary lesion.
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