Ontology highlight
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PROVIDER: PRJNA941894 | ENA |
REPOSITORIES: ENA
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Project description:Pathological retinal angiogenesis with irregular and fragile vessels (also termed as neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups driven in part by unmet metabolic demand from retinal neurons. Sustaining neural retinal metabolism with an adequate nutrient supply may prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular telangiectasia and altered serine/glycine metabolism is suggested in retinopathy of prematurity. Here we assessed the role of serine metabolism in suppressing hypoxia-driven retinal neovascularization in mice. Systemic serine supplementation decreased, and dietary serine/glycine deficiency worsened retinal neovascularization. Fatty acid oxidation was essential in mediating serine protective effects and serine also increased the levels of phosphatidylcholine, the most abundant phospholipids in the retina. Exogenous serine increased abundance of proteins involved in oxidative phosphorylation in total retinas, as well as increased expression of mitochondrial respiration-related genes and decreased expression of pro-angiogenic genes in rod photoreceptor cluster. Pharmaceutical inhibition of mitochondrial energy production largely attenuated serine suppression of retinal neovascularization. Our data suggested that increasing serine is a potential therapeutic approach for neovascular eye diseases by enhancing retinal mitochondrial function and lipid metabolism to suppress driving factors for uncontrolled angiogenesis.
2025-05-07 | PXD056490 | Pride
Project description:Objective: Pathological retinal angiogenesis is vision threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and with hypoxia-induced neovascularization (NV), and test interventions to address those changes to prevent NV. Methods: OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome change and the ratio of mitochondrial/nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented in OIR mice either prior to or during neovessel formation. Results: In OIR vs. control retinas proteomics identified decreased retinal mitochondrial respiration and synaptic formation pathway proteins at peak neovascularization. mtDNA/nDNA was decreased during hypoxia-induced neovessel growth (as was OCR) suggesting impaired mitochondrial respiration. Pyruvate administration during but not prior to neovessel formation (in line with compromised mitochondrial activity) suppressed NV in vivo. Conclusions: Mitochondrial energetics are suppressed during retinal NV in OIR. Appropriately timed supplementation of energy substrates (pyruvate) may be a novel approach in neovascular retinal diseases.
2025-05-06 | PXD051410 | Pride
Project description:Purpose: To investigate the role of endothelial-mesenchymal transition (EndoMT) in pathological retinal angiogenesis and identify key molecular mediators in retina angiogenesis. Methods: RNA sequencing was performed on retinal tissue from oxygen-induced retinopathy (OIR) mouse model to analyze gene expression patterns. Gene Set Enrichment Analysis was used to examine the correlation between EMT and angiogenesis gene sets. Fibronectin (FN1) expression was evaluated in endothelial cells, and its function was assessed through siRNA mediated knockdown in both in vitro angiogenesis assays and the OIR model. Results: EndoMT occurred early in retinal angiogenesis development, with significant correlation between EMT and angiogenesis gene sets. FN1 was identified as the most significantly upregulated EMT-related gene in endothelial cells. siRNA-mediated inhibition of FN1 effectively prevented VEGF-induced angiogenesis in vitro and reduced pathological angiogenesis in the OIR model. Conclusions: EndoMT is a crucial early event in pathological retinal angiogenesis, with FN1 serving as a key mediator. Targeting FN1 may provide a novel therapeutic strategy that could synergize with anti-VEGF treatments to more effectively treat pathological angiogenesis in DR and ROP, particularly in cases of poor response to anti-VEGF therapy alone.
2025-03-19 | GSE289223 | GEO
Project description:We determined which metabolic pathways are activated by hypoxia-inducible factor 1-mediated (HIF-1-mediated) protection against oxygen-induced retinopathy (OIR) in newborn mice, the experimental correlate to retinopathy of prematurity, a leading cause of infant blindness. HIF-1 coordinates the change from oxidative to glycolytic metabolism and mediates flux through serine and 1-carbon metabolism (1CM) in hypoxic and cancer cells. We used untargeted metabolite profiling in vivo to demonstrate that hypoxia mimesis activates serine/1CM. Both [13C6] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [13C3] serine labeling of metabolites followed in liver lysates strongly suggest that retinal serine is primarily derived from hepatic glycolytic carbon and not from retinal glycolytic carbon in newborn pups. In HIF-1α2lox/2lox albumin-Cre-knockout mice, reduced or near-0 levels of serine/glycine further demonstrate the hepatic origin of retinal serine. Furthermore, inhibition of 1CM by methotrexate blocked HIF-mediated protection against OIR. This demonstrated that 1CM participates in protection induced by HIF-1 stabilization. The urea cycle also dominated pathway enrichment analyses of plasma samples. The dependence of retinal serine on hepatic HIF-1 and the upregulation of the urea cycle emphasize the importance of the liver to remote protection of the retina.
2019-07-05 | MTBLS856 | MetaboLights
Project description:Diabetic retinopathy (DR) causes vision loss due to sustained inflammation and vascular dam-age. The vascular damage is characterized fibrinogen leakage, angiogenesis, and hypoxia exac-erbating retinal damage. Neuronal regulation of microglia via the CX3CL1 (FKN)-CX3CR1 pathway also play a significant role in retinal pathology; here defects in the FKN-CX3CR1 pathway exacerbate inflammation, vascular damage and vision impairment. However, the con-tribution of hypoxic astrocytes to the pathological process of DR is unclear.
2025-02-17 | GSE276207 | GEO
Project description:We determined which metabolic pathways are activated by hypoxia-inducible factor 1-mediated (HIF-1-mediated) protection against oxygen-induced retinopathy (OIR) in newborn mice, the experimental correlate to retinopathy of prematurity, a leading cause of infant blindness. HIF-1 coordinates the change from oxidative to glycolytic metabolism and mediates flux through serine and 1-carbon metabolism (1CM) in hypoxic and cancer cells. We used untargeted metabolite profiling in vivo to demonstrate that hypoxia mimesis activates serine/1CM. Both [13C6] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [13C3] serine labeling of metabolites followed in liver lysates strongly suggest that retinal serine is primarily derived from hepatic glycolytic carbon and not from retinal glycolytic carbon in newborn pups. In HIF-1?2lox/2lox albumin-Cre-knockout mice, reduced or near-0 levels of serine/glycine further demonstrate the hepatic origin of retinal serine. Furthermore, inhibition of 1CM by methotrexate blocked HIF-mediated protection against OIR. This demonstrated that 1CM participates in protection induced by HIF-1 stabilization. The urea cycle also dominated pathway enrichment analyses of plasma samples. The dependence of retinal serine on hepatic HIF-1 and the upregulation of the urea cycle emphasize the importance of the liver to remote protection of the retina.
2020-06-30 | MSV000085654 | GNPS
Project description:Pathological retinal neovascularization is a common mechanism for leading causes of vision loss including retinopathy of prematurity (ROP), diabetic retinopathy, and wet age-related macular degeneration. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism controlled by the ER-resident proteins ATF6, IRE1, and PERK. In response to endoplasmic reticulum stress, UPR activates downstream transcriptional and translational programs that upregulate many proteins, including key angiogenesis factors like VEGF and HIF1a. This suggests an important role for UPR in developmental and pathologic retinal angiogenesis, but it is unclear which UPR regulatory genes are most important in these processes. Here, we focused on the role of Activating Transcription Factor 6 (ATF6) in pathologic and developmental retinal angiogenesis. We induced pathologic retinal neovascularization in Atf6-/- mice using the oxygen-induced retinopathy (OIR) model of ROP and examined functional, histologic, and molecular consequences in the retina. we found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR and angiogenesis transcriptional programs in Atf6-/- mice after OIR. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppression of UPR and angiogenesis gene expression. Last, we examined very young Atf6-/- mice when the inner retinal vasculature is developing and found a significant defect in pruning and blood vessel extension to the periphery at P7, but this delay was transient and Atf6-/- blood vessels fully recovered at older ages of development. Together, our results demonstrate ATF6’s critical role in developmental and pathological angiogenesis and highlight its potential as a therapeutic target to mitigate pathological retinal neovascularization.
2025-08-14 | GSE292097 | GEO
Project description:Müller cells play a critical role in retinal angiogenesis and inflammation, particularly in ischemic retinopathies such as oxygen-induced retinopathy (OIR). Here, we employed actively translating transcriptome profiling using RiboTag technology to selectively examine gene expression in Müller cells with and without Nrf2, a master regulator of oxidative stress responses, during OIR. Conditional deletion of Nrf2 in Müller cells exacerbated retinal avascular areas and pathological neovascularization in the OIR model, without altering Müller cell number or viability. RiboTag-based RNA sequencing and pathway analysis identified dysregulation of oxidative phosphorylation and acute phase signaling, along with suppression of pathways related to neuronal signaling. Müller cell Nrf2 deficiency resulted in dysregulation of multiple genes involved in acute-phase response, inflammation, and angiogenesis. These findings uncover a critical role for Nrf2 in maintaining Müller cell homeostasis and identify molecular signatures by which its loss amplifies retinal gliosis and pathological angiogenesis.
2025-09-18 | GSE304959 | GEO
Project description:Phlebotomy-induced-anemia (PIA), which induces tissue hypoxia and angiogenesis, occurs universally among infants at risk for severe retinopathy of prematurity (ROP). We hypothesized that PIA exacerbates pathologic retinal neovascularization in ROP. Methods: We induced PIA to a hematocrit of 18% among rats undergoing the established 50/10 oxygen-induced retinopathy (OIR) model. Rats were euthanized at P15 and P20, during the avascular and neovascular phases of OIR, respectively. Whole retinal transcriptomes were compared to non-PIA controls. Results: RNA sequencing showed dampened pathways of angiogenesis, inflammation, and neural development in anemic OIR females at P20. Conclusion: PIA dampened transcriptomic pathways central to retinal vascular and neural development in neonatal rats. These data suggest PIA provides a protective effect from ROP.
2024-09-04 | GSE272252 | GEO
Project description:Epithelial membrane protein 2 (EMP2) regulates hypoxia induced angiogenesis in retinal epithelial cells
| PRJNA636612 | ENA