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Photoreceptor glucose metabolism determines normal retinal vascular growth.

ABSTRACT: 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.

SUBMITTER: Fu Z

PROVIDER: S-EPMC5760850 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Photoreceptor glucose metabolism determines normal retinal vascular growth.

Fu Zhongjie Z Löfqvist Chatarina A CA Liegl Raffael R Wang Zhongxiao Z Sun Ye Y Gong Yan Y Liu Chi-Hsiu CH Meng Steven S SS Burnim Samuel B SB Arellano Ivana I Chouinard My T MT Duran Rubi R Poblete Alexander A Cho Steve S SS Akula James D JD Kinter Michael M Ley David D Pupp Ingrid Hansen IH Talukdar Saswata S Hellström Ann A Smith Lois Eh LE

EMBO molecular medicine 20180101 1

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 hyperg ...[more]

PMID: 29180355

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Project description:Retinal detachment is a sight-threatening disorder, which occurs when the photoreceptors are separated from their vascular supply. The aim of the present study was to shed light on photoreceptor energy metabolism during experimental detachment in rats. Retinal detachment was induced in the eyes of rats via subretinal injection of sodium hyaluronate. Initially, we investigated whether detachment caused hypoxia within photoreceptors, as evaluated by the exogenous and endogenous biomarkers pimonidazole and HIF-1α, as well as by qPCR analysis of HIF target genes. The results showed no unequivocal staining for pimonidazole or HIF-1α within any detached retina, nor upregulation of HIF target genes, suggesting that any reduction in pO2 is of insufficient magnitude to produce hypoxia-induced covalent protein adducts or HIF-1α stabilisation. Subsequently, we analysed expression of cellular bioenergetic enzymes in photoreceptors during detachment. We documented loss of mitochondrial, and downregulation of glycolytic enzymes during detachment, indicating that photoreceptors have reduced energetic requirements and/or capacity. Given that detachment did not cause widespread hypoxia, but did result in downregulated expression of bioenergetic enzymes, we hypothesised that substrate insufficiency may be critical in terms of pathogenesis, and that boosting metabolic inputs may preserve photoreceptor bioenergetic production and, protect against their degeneration. Thus, we tested whether supplementation with the bioavailable energy substrate pyruvate mitigated rod and cone injury and degeneration. Despite protecting photoreceptors in culture from nutrient deprivation, pyruvate failed to protect against apoptotic death of rods, loss of cone opsins, and loss of inner segment mitochondria, in situ, when evaluated at 3 days after detachment. The regimen was also ineffective against cumulative photoreceptor deconstruction and degeneration when evaluated after 4 weeks. Retinal metabolism, particularly the bioenergetic profiles and pathological responses of the various cellular subtypes still presents a considerable knowledge gap that has important clinical consequences. While our data do not support the use of pyruvate supplementation as a means of protecting detached photoreceptors, they do provide a foundation and motivation for future research in this area.

Project description:Pulse wave attenuation characteristics reflect compliance and resistance properties of the vessel wall as well as initial pulse generation factors. Recently, it has become possible to measure and map the retinal vessel wall pulse wave amplitudes. Predictable pulse wave amplitude distribution may allow inferences to be made concerning vascular compliance and resistance. Twenty-eight eyes from sixteen subjects (8 male and 8 female) were examined using modified retinal photoplethysmography with simultaneous ophthalmodynamometry. This allowed the assessment of vessel wall pulsation amplitudes under a dynamic range of intraocular pressures. Pulse amplitudes were calculated using harmonic regression analysis. The pulse wave attenuation was measured under different ranges of ophthalmodynamometric force (ODF) as a function of distance along the vessel (VDist), which in turn was calculated in disc diameters (DD) from the center of the optic disc. A linear mixed-effects model with randomized slopes and intercepts was used to estimate the correlations between the logarithmically transformed harmonic regression wave amplitude (HRWa) and the Fourier trigonometric coefficients with the predictors (VDist and ODF). The retinal venous harmonic regression wave attenuation (coefficient value±standard error) -0.40±0.065/DD, (p-value < 0.00001, 95% confidence interval (CI) -0.53 to -0.27), which was approximately twice that of the arterial -0.17±0.048/DD, (p-value < 0.0004, 95% CI = -0.27 to -0.08). There was a positive correlation between attenuation of the harmonic regression wave and ophthalmodynamometric force in both vascular systems. The attenuation of all but the sine coefficient of the second Fourier harmonic (bn2) achieved statistical significance in the correlation with VDist. The cosine coefficient of the first Fourier harmonic an1 was the only coefficient to achieve statistical significance in the correlation with the predictors VDist and ODF in both vascular systems. The an1 coefficient value in the correlation with VDist was -3.79±0.78 and -1.269±0.37 (p < 0.0006), while this coefficient value in the correlation with ODF was 0.026±0.0099 and 0.009±0.04 (p < 0.01) in both the retinal veins and arteries respectively. The predictable attenuation characteristics in normal subjects suggest that this technique may allow the non-invasive quantification of retinal vascular compliance and other hemodynamic parameters.

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Photoreceptor glucose metabolism determines normal retinal vascular growth.

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Photoreceptor glucose metabolism determines normal retinal vascular growth.

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