Retinal Vascular Degeneration in the Transgenic P23H Rat Model of Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases involving a progressive degeneration of photoreceptor cells. Following the loss of photoreceptors, retinal vascularization tends to decrease, which seems to play a role in the degenerative process of retinal cells. This study reports changes in retinal vascular network architecture in the P23H rat model of RP at different stages of retinal degeneration. Homozygous P23H line-3 rats of ages ranging from 18 days to 16 months were used in this study. Age-matched Sprague-Dawley (SD) rats were used as control animals. Vertical sections and wholemount retinas were immunolabeled for type IV collagen or stained using NADPH diaphorase histochemistry, and retinal vascular networks were drawn using a camera lucida. The superficial and deep capillary plexus (DCP) were fully developed at P18 in P23H rat retinas and showed no differences from the control animals. In 4-month-old P23H rat retinas, the superficial and intermediate capillary plexus were similar to those observed in age-matched SD rats, but a reduction in the DCP could be observed in these animals, with a significant decrease in both capillary density and capillary loops. At 16 months, the DCP was completely lost, and only vessels exhibiting an abnormal, tortuous dead-end could be observed. The middle capillary plexus had virtually disappeared at this age. Only perpendicular vessels connecting the superficial and DCP were found. The superficial plexus showed no changes in the vascular surface with age. In RP, photoreceptor loss is accompanied by degenerative changes in the retinal vascular network. The disruption of the capillary plexus, with loss of capillary density and capillary loops, can hamper the normal supply of oxygen and nutrients to retinal cells, thus accelerating retinal degeneration. Therefore, changes in retinal vascularization must be taken into account in the design of therapies targeting retinal degenerative diseases.

Retinal Ganglion Cell Death as a Late Remodeling Effect of Photoreceptor Degeneration

“…The migration of the RPE cells on the retinal vessels causes vessel displacement, formation of “subretinal vascular complexes” and axonal strangulation by the inner displaced retinal vessels which is ultimately responsible for RGC death [4,5,9,10]. It is important to note that vascular changes will not occur until severe photoreceptor death has occurred [4,5,9,10,11,13,81] and is prevented if a significant number of photoreceptors remain alive [82].…”

“…Thus, to understand the causes of RGC death during retinal remodeling, it is important to know the progressive sequence of changes in the vascular supply to the retina that occurs secondary to photoreceptor loss [81]. As a consequence of photoreceptor loss, there are various changes that will precipitate the vascular changes: (i) an increase in retinal hyperoxia, which presumably suppresses the expression of different growth factors such as vascular endothelial growth factor (VEGF) [24,82,83]; (ii) a breakdown of the blood–retinal barrier [6,10]; (iii) the outer vascular plexus approaches the RPE cell layer [5].…”

Olfactory Ensheathing Cells Grafted Into the Retina of RCS Rats Suppress Inflammation by Down-Regulating the JAK/STAT Pathway

“…Resident microglia have been reported to be rapidly activated and migrate toward the inflamed lesion under pathological conditions in the retina (Akhtar-Schäfer et al, 2018; Szepesi et al, 2018). In RCS rats with Mertk gene mutation, BRB disruption results in the recruitment of blood-borne macrophages to help phagocytosis the apoptotic photoreceptors (Fernández-Sánchez et al, 2018). In our study, TMEM119 was applied to distinguish resident microglia and infiltrating macrophages.…”

Targeting Neurovascular Interaction in Retinal Disorders

“…In retinitis pigmentosa patients, the severity of visual field loss is correlated with retinal vessel attenuation [68,69]. In retinitis pigmentosa animal models, progressive loss of retinal blood vessels is also observed and a significant decrease in capillary density and capillary loop is found particularly in the deep (close to photoreceptors), but not in the superficial and intermediate capillary plexus [70,71]. In ROP mouse models, hyperoxia causes reduced density of retinal astrocytes in the avascular zone and maintaining retinal astrocytes normalizes revascularization [72,73].…”