Characteristics of Eyes With CRB1-Associated EOSRD/LCA: Age-Related Changes.

PURPOSE: To evaluate ocular and retinal features of CRB1-associated early onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA) for age-related changes. DESIGN: Retrospective cohort study. METHODS: Sixteen pediatric patients with biallelic CRB1 EOSRD/LCA who had been followed for up to 18 years were reviewed. Results of comprehensive ophthalmic examinations-including visual acuity, refractive error, dark-adapted visual threshold, Goldmann perimetry, and macular optical coherence tomography (OCT)-were analyzed for significant age-related changes using mixed-effects models. RESULTS: Visual acuity dark-adapted visual sensitivity, and area of seeing visual field (all subnormal from the earliest ages recorded) declined with increasing age. Hyperopia was stable through childhood and adolescence. In CRB1 EOSRD/LCA, OCT extrafoveal inner and outer laminar thicknesses exceeded those in controls but varied little with age, and foveal metrics (depth, breadth, thickness at rim) differed significantly from those in controls, but variations in foveal metrics were not associated with declines in acuity. CONCLUSIONS: From the youngest ages, retinal and visual function is significantly subnormal and becomes progressively compromized. A goal of future therapies should be intervention at young ages, when there is more function to be rescued.

A Simplified Model of Activation and Deactivation of Human Rod Phototransduction-An Electroretinographic Study.

Purpose: To test the hypothesis that a simple model having properties consistent with activation and deactivation in the rod approximates the whole time course of the photoresponse. Methods: Routinely, an exponential of the form f = α·(1 - exp(-(τ·(t - teff)s-1))), with amplitude α, rate constant τ (often scaled by intensity), irreducible delay teff, and time exponent s-1, is fit to the early period of the flash electroretinogram. Notably, s (an integer) represents the three integrating stages in the rod amplification cascade (rhodopsin isomerization, transducin activation, and cGMP hydrolysis). The time course of the photoresponse to a 0.17 cd·s·m-2 conditioning flash (CF) was determined in 21 healthy eyes by presenting the CF plus a bright probe flash (PF) in tandem, separated by interstimulus intervals (ISIs) of 0.01 to 1.4 seconds, and calculating the proportion of the PF a-wave suppressed by the CF at each ISI. To test if similar kinetics describe deactivation, difference of exponential (DoE) functions with common α and teff parameters, respective rate constants for the initiation (I) and quenching (Q) phases of the response, and specified values of s (sI, sQ), were compared to the photoresponse time course. Results: As hypothesized, the optimal values of sI and sQ were 3 and 2, respectively. Mean ± SD α was 0.80 ± 0.066, I was 7700 ± 2400 m2·cd-1·s-3, and Q was 1.4 ± 0.47 s-1. Overall, r2 was 0.93. Conclusions: A method, including a DoE model with just three free parameters (α, I, Q), that robustly captures the magnitude and time-constants of the complete rod response, was produced. Only two steps integrate to quench the rod photoresponse.

The Development of Retinal Function and Refractive Error in Children With Retinopathy of Prematurity.

Purpose: The purpose of this study was to test the hypothesis that retinopathy of prematurity (ROP) prolongs development of rod-mediated thresholds for detection of stimuli at 10 degrees but not 30 degrees eccentricity. In addition, to evaluate the thresholds at each site for an association with visual acuity (VA) and spherical equivalent (SE). Methods: We estimated rod-mediated dark-adapted thresholds (DATs) for the detection of 2 degree diameter, 50 ms, blue (λ < 510 nm) flashes at 10 degrees and 30 degrees eccentric in former preterm subjects (n = 111), stratified by ROP severity: None (n = 32), Mild (n = 66), and Severe (n = 13). We also tested Term-born (n = 28) controls. To determine the age at half-maximal sensitivity (Agehalf) for each group and eccentricity, we fit DATs to logistic growth curves. We obtained VA and SE for Preterm subjects and evaluated the course of threshold development at 10 degrees and 30 degrees for significant association with VA and SE predicted at age 10 years. Results: DAT development at 10 degrees was significantly delayed in ROP (Mild and Severe); ROP did not significantly alter DAT development at 30 degrees. At age 10 years, among Preterm subjects, both VA and SE were significantly associated with group (None,Mild, and Severe). SE was predicted by the course of DAT development at 30 degrees. VA was not associated with the course of DAT development at 10 degrees. Conclusions: At 10 degrees, ROP-whether mild or severe-is associated with significant delays in DAT development, evidence that the late-maturing central retina is vulnerable to ROP. The association of 30 degree threshold and myopia are evidence that more peripheral retina is important to refractive development.

Non-Rigid Registration for High-Resolution Retinal Imaging.

Adaptive optics provides improved resolution in ophthalmic imaging when retinal microstructures need to be identified, counted, and mapped. In general, multiple images are averaged to improve the signal-to-noise ratio or analyzed for temporal dynamics. Image registration by cross-correlation is straightforward for small patches; however, larger images require more sophisticated registration techniques. Strip-based registration has been used successfully for photoreceptor mosaic alignment in small patches; however, if the deformations along strips are not simple displacements, averaging can degrade the final image. We have applied a non-rigid registration technique that improves the quality of processed images for mapping cones over large image patches. In this approach, correction of local deformations compensates for local image stretching, compressing, bending, and twisting due to a number of causes. The main result of this procedure is improved definition of retinal microstructures that can be better identified and segmented. Derived metrics such as cone density, wall-to-lumen ratio, and quantification of structural modification of blood vessel walls have diagnostic value in many retinal diseases, including diabetic retinopathy and age-related macular degeneration, and their improved evaluations may facilitate early diagnostics of retinal diseases.

Do the retinal abnormalities in X-linked juvenile retinoschisis include impaired phototransduction?

X-linked juvenile retinoschisis (XLRS), a hereditary retinal disorder primarily affecting males, is characterized by the formation of cystic spaces between the outer plexiform layer and outer nuclear layer of the retina. Mutations in the RS1 gene, which encodes the extracellular binding protein retinoschisin, are responsible for XLRS pathogenesis. While the role of retinoschisin in maintaining retinal integrity is well established, there is growing evidence suggesting compromised photoreceptor function in XLRS. To investigate the molecular pathways affected by RS1 deficiency, particularly in phototransduction, we performed electroretinographic (ERG) and proteomic analyses on retinae from Rs1 knockout mice, a model of human XLRS. The Rs1 knockout mice had reduced ERG a-wave amplitudes. Correspondingly, differential expression analysis revealed downregulation of proteins crucial for phototransduction, with Ingenuity Pathway Analysis (IPA) highlighting "phototransduction" as the most significantly downregulated biological theme. Compensatory mechanisms were also observed in the IPA, including upregulation of synaptic remodeling, inflammation, cell adhesion, and G-protein signaling. These findings strongly implicate an underrecognized role of photoreceptor dysfunction in XLRS pathology. We speculate that entrapment of mutant retinoschisin protein within photoreceptor inner segments as well as disrupted reciprocal regulation between L-type voltage-gated calcium channels and retinoschisin contribute to the dysfunction in photoreceptors.

Electroretinographic Responses in Retinopathy of Prematurity Treated Using Intravitreal Bevacizumab or Laser.

PURPOSE: Intravitreal injection of bevacizumab (IVB) offers advantages over laser photoablation for treatment of type 1 retinopathy of prematurity (ROP). However, retinal function has not, to date, been quantitatively compared following these interventions. Therefore, electroretinography (ERG) was used compare retinal function among eyes treated using IVB or laser, and control eyes. In addition, among the IVB-treated eyes, ERG was used to compare function in individuals in whom subsequent laser was and was not required. DESIGN: Prospective clinical cohort study. METHODS: ERG was used to record dark- and light-adapted stimulus/response functions in 21 children treated using IVB (12 of whom required subsequent laser in at least 1 eye for persistent avascular retina [PAR]). Sensitivity and amplitude parameters were derived from the a-wave, b-wave, and oscillatory potentials (OPs), representing activity in photoreceptor, postreceptor, and inner retinal cells, respectively. These parameters were then referenced to those of 76 healthy, term-born controls and compared to those of 10 children treated using laser only. RESULTS: In children with treated ROP, every ERG parameter was significantly below the mean in controls. However, these significant ERG deficits did not differ between IVB- and laser-treated eyes. Among children treated using IVB, no ERG parameter was significantly associated with dose or need for subsequent laser. CONCLUSION: Retinal function was significantly impaired in treated ROP eyes. Function in IVB-treated eyes did not differ from that in laser-treated eyes. Functional differences also did not distinguish those IVB-treated eyes that would subsequently need laser for PAR.

Microcephaly and chorioretinopathy associated with TUBGCP4: a case report and a review of the literature.

BACKGROUND: Microcephaly and chorioretinopathy (MCCRP) is a rare autosomal recessive (AR) disorder characterized by microcephaly, developmental delay, chorioretinopathy, and visual impairment. We characterized the long-term phenotype of an additional patient with MCCRP associated with TUBCGP4 pathogenic variants and analysed previously reported cases in the literature. MATERIALS AND METHODS: Analysis of clinical and genetic data of a patient with TUBGCP4-related MCCRP followed for more than 19 years and literature search for previously reported patients with TUBCGP4 variants using PubMed, Scopus, and Google Scholar. RESULTS: Molecular diagnosis using exome sequencing demonstrated two TUBCGP4 variants in trans: c.1669C>T (p.Arg557*) and c.1746 G>T (p.Leu582=). Clinical characteristics included microcephaly, microphthalmia, punched-out chorioretinal lesions, vision impairment, nystagmus, Tetralogy of Fallot and neurodevelopmental delay. Another six previously reported cases of TUBCGP4-related MCCRP were identified. Their clinical and genetic characteristics are compared. CONCLUSIONS: TUBCGP4-related microcephaly and chorioretinopathy, is a rare autosomal recessive neuro-ophthalmic disorder. Clinical characteristics in our proband have remained stable for two decades. The pathophysiology of this syndrome is not yet fully understood.

Modelling eye lengths and refractions in the periphery.

PURPOSE: To create a simplified model of the eye by which we can specify a key optical characteristic of the crystalline lens, namely its power. METHODS: Cycloplegic refraction and axial length were obtained in 60 eyes of 30 healthy subjects at eccentricities spanning 40° nasal to 40° temporal and were fitted with a three-dimensional parabolic model. Keratometric values and geometric distances to the cornea, lens and retina from 45 eyes supplied a numerical ray tracing model. Posterior lens curvature (PLC) was found by optimising the refractive data using a fixed lens equivalent refractive index ( n eq ). Then, n eq was found using a fixed PLC. RESULTS: Eccentric refractive errors were relatively hyperopic in eyes with central refractions ≤-1.44 D but relatively myopic in emmetropes and hyperopes. Posterior lens power, which cannot be measured directly, was derived from the optimised model lens. There was a weak, negative association between derived PLC and central spherical equivalent refraction. Regardless of refractive error, the posterior retinal curvature remained fixed. CONCLUSIONS: By combining both on- and off-axis refractions and eye length measurements, this simplified model enabled the specification of posterior lens power and captured off-axis lenticular characteristics. The broad distribution in off-axis lens power represents a notable contrast to the relative stability of retinal curvature.

The relation of the multifocal electroretinographic response to macular layer volume.

PURPOSE: To determine the association of the multifocal electroretinographic (mfERG) response amplitude with the volumes of the inner, postreceptor, and photoreceptor retinal layers in the region stimulated by each mfERG element. METHODS: Sixteen healthy, young adult control subjects were studied. Each of the 103 hexagonal elements of the standard, scaled mfERG were aligned, where possible, with patches of retina imaged using optical coherence tomography. Stimuli falling on the fovea and on the optic nerve head were excluded. Linear mixed-effects modeling was then used to derive estimated coefficients (voltage/volume) for the mfERG response throughout the full 80 ms standard epoch. The resulting predicted response amplitudes originating in each layer were then compared to pharmacologically "dissected" mfERGs obtained from other studies in monkey eyes. RESULTS: Across the duration of the response, the amplitude of the modeled contribution from (1) the inner retina was small-to-modest, (2) the postreceptor retina was larger and contained two prominent peaks, and (3) the photoreceptor response was the largest and most closely paralleled the overall (i.e., intact) response, including late-appearing oscillations. The significance of each layer's contribution was greatest when the absolute amplitude of that layer's response was largest. The contribution of the inner retina was maximally significant in the interval between the prominent troughs and peaks of the intact response. The contributions of the postreceptor and photoreceptor responses were maximally significant at the prominent troughs and peaks of the intact response. CONCLUSIONS: The results of the model were in good overall agreement with previous interpretations of the cellular contributions to the mfERG. There was also fair agreement with pharmacologically dissected monkey mfERG responses. Thus, the estimations of the contributions of the retinal layers to the mfERG so produced appeared plausible.

Longitudinal Change of Refractive Error in Retinopathy of Prematurity Treated With Intravitreal Bevacizumab or Laser Photocoagulation.

PURPOSE: To compare progression of myopia and refractive error in former premature infants with retinopathy of prematurity (ROP) treated using intravitreal bevacizumab (IVB) or laser. DESIGN: Retrospective clinical cohort study. METHODS: We identified premature infants with ROP treated using IVB from 2011 to 2020 and compared their longitudinal cycloplegic refraction data to that of infants with ROP treated using laser during the same timeframe. A subset of infants treated using IVB also underwent additional treatment using laser. We included cycloplegic refractions from 789 cumulative visits over a median 3.2 years. We used a linear mixed-effects model with a log decay function to evaluate how refraction changed with age after treatment. RESULTS: In aggregate, the model estimated a significant (P < .001) trend in refraction-from slight hyperopia to relatively more myopic states. However, progression in laser-treated eyes was significantly (P < .001) more rapid, regardless of treatment with IVB. The number of laser spots resulted in increased myopic progression by approximately 0.16 diopters per 100 laser spots. Both ROP stage and zone had a significant effect on myopic progression, with more severe disease resulting in faster myopic progression. Random effects, including individual subject variation with nested variance for left and right eye, accounted for 86.4% of the remaining variance not explained by age and treatment. CONCLUSIONS: Laser treatment for severe ROP increases the trend to severe myopia. In our sample, IVB did not affect myopic progression but did substantially reduce the amount of consequent laser required to treat ROP. The effect of laser persists after accounting for differences in ROP stage and zone.

Omega-3/Omega-6 Long-Chain Fatty Acid Imbalance in Phase I Retinopathy of Prematurity.

There is a gap in understanding the effect of the essential ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFA) on Phase I retinopathy of prematurity (ROP), which precipitates proliferative ROP. Postnatal hyperglycemia contributes to Phase I ROP by delaying retinal vascularization. In mouse neonates with hyperglycemia-associated Phase I retinopathy, dietary ω-3 (vs. ω-6 LCPUFA) supplementation promoted retinal vessel development. However, ω-6 (vs. ω-3 LCPUFA) was also developmentally essential, promoting neuronal growth and metabolism as suggested by a strong metabolic shift in almost all types of retinal neuronal and glial cells identified with single-cell transcriptomics. Loss of adiponectin (APN) in mice (mimicking the low APN levels in Phase I ROP) decreased LCPUFA levels (including ω-3 and ω-6) in retinas under normoglycemic and hyperglycemic conditions. ω-3 (vs. ω-6) LCPUFA activated the APN pathway by increasing the circulating APN levels and inducing expression of the retinal APN receptor. Our findings suggested that both ω-3 and ω-6 LCPUFA are crucial in protecting against retinal neurovascular dysfunction in a Phase I ROP model; adequate ω-6 LCPUFA levels must be maintained in addition to ω-3 supplementation to prevent retinopathy. Activation of the APN pathway may further enhance the ω-3 and ω-6 LCPUFA's protection against ROP.

Retinal glial remodeling by FGF21 preserves retinal function during photoreceptor degeneration.

The group of retinal degenerations, retinitis pigmentosa (RP), comprises more than 150 genetic abnormalities affecting photoreceptors. Finding degenerative pathways common to all genetic abnormalities may allow general treatment such as neuroprotection. Neuroprotection may include enhancing the function of cells that directly support photoreceptors, retinal pigment epithelial cells, and Müller glia. Treatment with fibroblast growth factor 21 (FGF21), a neuroprotectant, from postnatal week 4-10, during rod and cone loss in P23H mice (an RP model) with retinal degeneration, preserved photoreceptor function and normalized Müller glial cell morphology. Single-cell transcriptomics of retinal cells showed that FGF21 receptor Fgfr1 was specifically expressed in Müller glia/astrocytes. Of all retinal cells, FGF21 predominantly affected genes in Müller glia/astrocytes with increased expression of axon development and synapse formation pathway genes. Therefore, enhancing retinal glial axon and synapse formation with neurons may preserve retinal function in RP and may suggest a general therapeutic approach for retinal degenerative diseases.

Carbonic anhydrase inhibition in X-linked retinoschisis: An eye on the photoreceptors.

The retinoschisin protein is encoded on the short arm of the X-chromosome by RS1, is expressed abundantly in photoreceptor inner segments and in bipolar cells, and is secreted as an octamer that maintains the structural integrity of the retina. Mutations in RS1 lead to X-linked retinoschisis (XLRS), a disease characterized by the formation of cystic spaces between boys' retinal layers that frequently present in ophthalmoscopy as a "spoke-wheel" pattern on their maculae and by progressively worsening visual acuity (VA). There is no proven therapy for XLRS, but there is mixed evidence that carbonic anhydrase inhibitors (CAIs) produce multiple beneficial effects, including improved VA and decreased volume of cystic spaces. Consequently, linear mixed-effects (LME) models were used to evaluate the effects of CAI therapy on VA and central retinal thickness (CRT, a proxy for cystic cavity volume) in a review of 19 patients' records. The mechanism of action of action of CAIs is unclear but, given that misplaced retinoschisin might accumulate in the photoreceptors, it is possible-perhaps even likely-that CAIs act to benefit the function of photoreceptors and the neighboring retinal pigment epithelium by acidification of the extracellular milieu; patients on CAIs have among the most robust photoreceptor responses. Therefore, a small subset of five subjects were recruited for imaging on a custom multimodal adaptive optics retinal imager for inspection of their parafoveal cone photoreceptors. Those cones that were visible, which numbered far fewer than in controls, were enlarged, consistent with the retinoschisin accumulation hypothesis. Results of the LME modeling found that there is an initial benefit to both VA and CRT in CAI therapy, but these wane, in both cases, after roughly two years. That said, even a short beneficial effect of CAIs on the volume of the cystic spaces may give CAI therapy an important role as pretreatment before (or immediately following) administration of gene therapy.

The Fovea in Retinopathy of Prematurity.

Purpose: Because preterm birth and retinopathy of prematurity (ROP) are associated with poor visual acuity (VA) and altered foveal development, we evaluated relationships among the central retinal photoreceptors, postreceptor retinal neurons, overlying fovea, and VA in ROP. Methods: We obtained optical coherence tomograms (OCTs) in preterm born subjects with no history of ROP (none; n = 61), ROP that resolved spontaneously without treatment (mild; n = 51), and ROP that required treatment by laser ablation of the avascular peripheral retina (severe; n = 22), as well as in term born control subjects (term; n = 111). We obtained foveal shape descriptors, measured central retinal layer thicknesses, and demarcated the anatomic parafovea using automated routines. In subsets of these subjects, we obtained OCTs eccentrically through the pupil (n = 46) to reveal the fiber layer of Henle (FLH) and obtained adaptive optics scanning light ophthalmograms (AO-SLOs) of the parafoveal cones (n = 34) and measured their spacing and distribution. Results: Both VA and foveal depth decreased with increasing ROP severity (term, none, mild, severe). In severe subjects, foveae were broader than normal and the parafovea was significantly enlarged compared to every other group. The FLH was thinner than normal in mild (but not severe) subjects. VA was associated with foveal depth more than group. Density of parafoveal cones did not differ significantly among groups. Conclusions: Foveal structure is associated with loss of VA in ROP. The preserved FLH in severe (relative to mild) eyes suggests treatment may help cone axon development. The significantly larger parafovea and increased outer nuclear layer (ONL) thickness in ROP hint that some developmental process affecting the photoreceptors is not arrested in ROP but rather is supranormal.

Extracting the ON and OFF contributions to the full-field photopic flash electroretinogram using summed growth curves.

Under cone-mediated (photopic) conditions, an "instantaneous" flash of light, including both stimulus onset and offset, will simultaneously activate both "ON" and "OFF" bipolar cells, which either depolarize (ON) or hyperpolarize (OFF) in response and, respectively, produce positive-going and negative-going deflections in the electroretinogram (ERG). The stimulus-response (SR) relationship of the photopic ON response demonstrates logistic growth, like that manifested in the rod-mediated (scotopic) b-wave, which is driven by a single class of depolarizing bipolar cell. However, the photopic b-wave SR function is importantly shaped by OFF responses, leading to a "photopic hill." Furthermore, both on and off stimuli elicit activity in both ON and OFF bipolar cells. This has made it difficult to produce meaningful parameters for ready interpretation of the photopic b-wave SR relationship. Therefore, we evaluated whether the sum of sigmoidal SR functions, as descriptors of the depolarizing and hyperpolarizing components of the photopic flash ERG, could be used to elucidate and quantitate the mechanisms that produce the photopic hill. We used a novel fitting routine to optimize a sum of simple sigmoidal curves to SR data in five groups of subjects: Healthy adult, 10-week-old infant, congenital stationary night blindness (CSNB), X-linked juvenile retinoschisis (XJR), and preterm-born, both without and with a history of retinopathy of prematurity (ROP). Differences in ON and OFF amplitude, sensitivity, and implicit time among the groups were then compared using parameters extracted from these fits. We found that our modeling procedure enabled plausible derivations of ON and OFF pathway contributions to the ERG, and that the parameters produced appeared to have physiological relevance. In adult subjects, the ON and OFF amplitudes were similar in magnitude with respectively longer and shorter implicit times. Infant, CSNB, and XJR subjects showed significant ON pathway deficits. History of preterm-birth, without or with a diagnosis of ROP, did not much affect cone responses.

PR1P ameliorates neurodegeneration through activation of VEGF signaling pathway and remodeling of the extracellular environment.

Neurodegenerative diseases affect millions of people worldwide. Optic neuropathies are the most commonly occurring neurodegenerative diseases, characterized by progressive retinal ganglion cell (RGC) degeneration. We recently reported that Prominin-1, a protein found on the surface of stem cells, interacts with VEGF and enhances its activity. VEGF is known to have various protective roles in the nervous system. Subsequently, we have developed a 12-mer peptide derived from Prominin-1, named PR1P, and investigated its effects on neuronal survival of damaged RGCs in a rat model of optic nerve crush (ONC). PR1P prevented RGC apoptosis resulting in improvement of retinal function in the rat ONC model. PR1P treatment significantly increased phosphorylation of ERK and AKT and expression its downstream proteins c-fos and Egr-1 in the retina. Additionally, PR1P beneficially increased the MMP-9/TIMP-1 ratio and promoted glial activation in the retina of ONC rats. Thus, PR1P displayed neuroprotective effects through enhanced VEGF-driven neuronal survival and reconstruction of the extracellular environment in ONC model. Our data indicate that PR1P may be a promising new clinical candidate for the treatment of neurodegenerative diseases.

Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice.

Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1ß (IL-1ß) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1ß expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.

Photoreceptor glucose metabolism determines normal retinal vascular growth.

The neural cells and factors determining normal vascular growth are not well defined even though vision-threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet-derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon-induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia-associated retinal abnormalities and suppress phase I ROP in premature infants.

Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos.

Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases, such as age-related macular degeneration and macular telangiectasia. Ocular neovascularization is strongly associated with inflammation, but the source of inflammatory signals and the mechanisms by which these signals regulate the disruption of avascular privilege in photoreceptors are unknown. In this study, we found that c-Fos, a master inflammatory regulator, was increased in photoreceptors in a model of pathological blood vessels invading photoreceptors: the very low-density lipoprotein receptor-deficient (Vldlr-/- ) mouse. Increased c-Fos induced inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF), leading to activation of signal transducer and activator of transcription 3 (STAT3) and increased TNFα-induced protein 3 (TNFAIP3) in Vldlr-/- photoreceptors. IL-6 activated the STAT3/vascular endothelial growth factor A (VEGFA) pathway directly, and elevated TNFAIP3 suppressed SOCS3 (suppressor of cytokine signaling 3)-activated STAT3/VEGFA indirectly. Inhibition of c-Fos using photoreceptor-specific AAV (adeno-associated virus)-hRK (human rhodopsin kinase)-sh_c-fos or a chemical inhibitor substantially reduced the pathological neovascularization and rescued visual function in Vldlr-/- mice. These findings suggested that the photoreceptor c-Fos controls blood vessel growth into the normally avascular photoreceptor layer through the inflammatory signal-induced STAT3/VEGFA pathway.

The neural retina in retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a neurovascular disease that affects prematurely born infants and is known to have significant long term effects on vision. We conducted the studies described herein not only to learn more about vision but also about the pathogenesis of ROP. The coincidence of ROP onset and rapid developmental elongation of the rod photoreceptor outer segments motivated us to consider the role of the rods in this disease. We used noninvasive electroretinographic (ERG), psychophysical, and retinal imaging procedures to study the function and structure of the neurosensory retina. Rod photoreceptor and post-receptor responses are significantly altered years after the preterm days during which ROP is an active disease. The alterations include persistent rod dysfunction, and evidence of compensatory remodeling of the post-receptor retina is found in ERG responses to full-field stimuli and in psychophysical thresholds that probe small retinal regions. In the central retina, both Mild and Severe ROP delay maturation of parafoveal scotopic thresholds and are associated with attenuation of cone mediated multifocal ERG responses, significant thickening of post-receptor retinal laminae, and dysmorphic cone photoreceptors. These results have implications for vision and control of eye growth and refractive development and suggest future research directions. These results also lead to a proposal for noninvasive management using light that may add to the currently invasive therapeutic armamentarium against ROP.