sodium-iodate and Atrophy

Sodium iodate (NaIO3) induces retinal pigment epithelium (RPE) dysfunction, which leads to photoreceptor degeneration. Previously, we used electron microscopy to show that the administration of NaIO3 resulted in the accumulation of cell debris in the subretinal space, which was thought to be caused by failed phagocytosis in the outer segment of the photoreceptor due to RPE dysfunction. We further analyzed the pathological changes in the retina and choroid of NaIO3-injected mice, and found that the expression of OTX2, an RPE marker, disappeared from central part of the RPE 1 day after NaIO3 administration. Furthermore, fenestrated capillaries (choriocapillaris, CC) adjacent to the RPE could not be identified only 2 days after NaIO3 administration. An examination of the expression of the CC-specific protein plasmalemma vesicle-associated protein (PLVAP), in sections and flat-mount retina/choroid specimens showed destruction of the CC, and complete disappearance of the PLVAP signal 7 days after NaIO3 administration. In contrast, CD31 flat-mount immunohistochemistry of the retina indicated no difference in retinal vessels between NaIO3-treated mice and controls. Electron microscopy showed that the fenestrated capillaries in the kidney and duodenum were morphologically indistinguishable between control and NaIO3-treated mice. We examined cytokine production in the retina and RPE, and found that the Vegfa transcript level in the RPE decreased starting 1 day after NaIO3 administration. Taken together, these observations show that NaIO3 reduces the CC in the early stages of the pathology, which is accompanied by a rapid decrease in Vegfa expression in the RPE.

Topics: Animals; Atrophy; Choroid; Down-Regulation; Iodates; Mice; Retinal Degeneration; Retinal Pigment Epithelium; Vascular Endothelial Growth Factor A

Geographic atrophy (GA) is the late stage of non-neovascular age-related macular degeneration. A lack of animal models for GA has hampered treatment efforts. Presented herein is a rat model for GA using subretinal injection of sodium iodate (NaIO3).. Rats were given subretinal injections of NaIO3 (5 μg/μL) using a pico-injector. Fundus photographs and spectral domain optical coherent tomography scans were collected at 1, 3, 7, 14, and 28 days after injection, at which time rats were euthanized and eyes were enucleated. Eyes were either cryopreserved or dissected into retinal and choroidal flatmounts. Fluorescence immunohistochemistry was performed for retinal glial fibrillary acidic protein (activated Müller cells and astrocytes) and vimentin (Müller cells), as well as peanut agglutin lectin (photoreceptors) labeling. RPE/choroids were labeled for RPE65 and CD34. Images were collected on Zeiss confocal microscopes.. Fundus photos, spectral domain optical coherent tomography, and RPE65 staining revealed well-demarcated areas with focal loss of RPE and photoreceptors in NaIO3-treated rats. At 1 day after injection, RPE cells appeared normal. By 3 days, there was patchy RPE and photoreceptor loss in the injected area. RPE and photoreceptors were completely degenerated in the injected area by 7 days. A large subretinal glial membrane occupied the degenerated area. Choriocapillaris was highly attenuated in the injected area at 14 and 28 days.. The rat model reported herein mimics the photoreceptor cell loss, RPE atrophy, glial membrane formation, and choriocapillaris degeneration seen in GA. This model will be valuable for developing and testing drugs and progenitor cell regenerative therapies for GA.

Topics: Animals; Atrophy; cis-trans-Isomerases; Disease Models, Animal; Fluorescein Angiography; Geographic Atrophy; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Intraocular; Iodates; Male; Microscopy, Confocal; Phenotype; Rats; Rats, Inbred BN; Retina; Retinal Pigment Epithelium; Tomography, Optical Coherence; Vimentin

Topics: Animals; Atrophy; Capillaries; Choroid; Coloring Agents; Fluorescein Angiography; Indocyanine Green; Iodates; Rabbits; Retinal Vessels

Vascular casts were made of the choriocapillaris (CC) of rabbits that received sodium iodate intravenously 6-28 days prior to examination, in order to augment studies of CC regeneration in sectioned material. Regeneration of CC was evident 6 days after administration of iodate where zones of spared CC bordered zones of atrophic CC. Venular as well as capillary sprouts created foci of regenerating CC at this border. These foci to create an extended capillary plexus similar to mature CC. The observations corroborate those obtained in sectioned material as regards the geography of the CC response and the origins of new CC during the sodium iodate retinopathy, and provide new information on the way in which CC regenerates.

Topics: Animals; Atrophy; Capillaries; Iodates; Microscopy, Electron, Scanning; Pigment Epithelium of Eye; Rabbits; Regeneration

The rabbit and rat choriocapillaris atrophies in response to experimental destruction of the retinal pigment epithelium by intravenous injection of sodium iodate. This provides a convenient model of capillary atrophy. We have observed that pericytes are spared during this process; the atrophy is due to loss of endothelium only. Extensive examination of thin sections obtained 1 day to 11 weeks after administration of iodate showed that pericytes retained their normal relationship to the remnant capillary basement membrane left behind as the endothelial tube atrophied. This was most conspicuously manifested in their retention of processes longitudinally disposed along the sleeves of remnant basement membrane. The processes retained bundles of actin filaments that had dense regions along them and inserted into subplasmalemmal densities at basement membrane attachment sites, i.e. they had the characteristics of stress fibers. The pericytes did not phagocytose the debris of endothelial necrosis, in spite of their known phagocytic abilities. Necrotic endothelial cells were eliminated by sloughing into the capillary lumen. The observations support the idea that the function of pericytes in the choriocapillaris, the major source of nutrition for the retinal photoreceptors, resides in their contractility, and that pericytes do not remove necrotic endothelium during capillary atrophy.

Topics: Actins; Animals; Arteries; Arterioles; Atrophy; Basement Membrane; Capillaries; Choroid; Disease Models, Animal; Endothelium, Vascular; Iodates; Rabbits

The authors have obtained evidence that destruction of the retinal pigment epithelium (RPE) causes choriocapillaris (CC) atrophy. The observations led us to hypothesize that the RPE modulates CC structure and function. Rabbits received injections of sodium iodate, which selectively destroyed the RPE. The authors killed the rabbits at various times after iodate and examined the RPE and CC by fluorescein angiography, fundus photography, and light and electron microscopy. Fluorescein angiography and fundus photography revealed a pattern of retinopathy similar to that described by other investigators, eg, blood-retinal barrier breakdown and the patchy nature of the RPE/CC degeneration. One week after injection of iodate, the RPE transformed into a mixture of flattened, depigmented cells and plump, highly pigmented ones lying along Bruch's membrane. The CC appeared normal by light microscopy, but electron microscopy revealed changes indicating CC atrophy: degenerating endothelial cells (EC), EC that appeared normal but had reduced numbers of fenestrae, and pericapillary basal laminae that looped away from the endothelium, as if the latter had shrunk. One month after iodate, patches of Bruch's membrane were devoid of RPE, which was replaced by scar tissue. The CC was markedly atrophic over these patches, having reduced numbers of profiles and smaller lumina in those which remained. The CC appeared normal over areas where RPE remained. Eleven weeks after iodate, the light microscopic picture parallelled that seen 1 month after injection, but the patchy RPE degeneration was more extensive. By electron microscopy, the CC profiles over areas devoid of RPE showed severe atrophy. Degenerating EC were more numerous. EC adjacent to areas of RPE loss had few or no fenestrae. Here, capillaries were encased in dense, collagenous, connective tissue, unlike the CC of normal rabbits. These changes were not seen where the RPE still covered Bruch's membrane. These observations suggest that RPE modulates CC structure and function. The authors propose that a diffusible vascular modulating factor produced by RPE cells does this.

Topics: Animals; Atrophy; Capillaries; Choroid; Endothelium; Fibroblasts; Fluorescein Angiography; Iodates; Lysosomes; Pigment Epithelium of Eye; Rabbits; Retina; Retinal Degeneration; Time Factors