Coviretinopathy: COVID-19-induced VEGF-dependent retinopathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315089 | GEO | 2026/01/26
REPOSITORIES: GEO
Dataset's files
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Project description:Pathologic retinal neovascularization is a potentially blinding consequence seen in many common diseases including diabetic retinopathy, retinopathy of prematurity, and retinal vascular occlusive diseases, among others. The use of therapeutics targeting pro-angiogenesis factors such as vascular endothelial growth factor (VEGF) has proven to be highly effective, however considerable side effects exist and serial anti-VEGF treatment has been shown to decrease effectiveness over time. Characterization of additional regulators of neovascularization is needed to further understand neovascular disease and identify possible new therapeutic targets. This study investigates epithelial membrane protein 2 (EMP2) and its role as a possible modulator of angiogenesis in human retinal pigment epithelium (RPE) under hypoxia. EMP2 is highly expressed in human RPE and RPE cell lines. Adult retinal pigment epithelial cell line-19 (ARPE-19) cells were genetically modified to either overexpress EMP2 (OE) or knock down EMP2 (KD) and expression at the RNA and protein level was evaluated using RNA sequencing and western blot respectively. Protein expression was evaluated under both normoxic conditions and conditions of hypoxic stress with 0.5% O2. EMP2 expression was found to positively correlate with expression of the pro-angiogenesis factors hypoxia inducible factor 1-alpha (HIF-1a) and VEGF for both RNA and protein. EMP2 mediated changes in ARPE-19 cells was also found to alter the secretion of a paracrine factor(s) in conditioned media that can regulate human umbilical vein endothelial cells (HUVEC) endothelial cell migration and capillary tube formation in in vitro functional angiogenesis assays. This study identifies EMP2 as a potentially important mediator of angiogenesis in the human RPE, a tissue involved in abnormal retinal neovascularization in a number of diseases. EMP2 levels positively correlate with those of the potent pro-angiogenesis mediators HIF-1a and VEGF, however the mechanism of this relationship remains to be clarified. This study supports further investigation of EMP2 as a promising novel target for therapeutic treatment of pathologic neovascularization in the retina.
2020-06-03 | GSE151610 | GEO
Project description:Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that vitreous levels of angiogenic proteins regulated by hypoxia-inducible factor (HIF)-1 and -2 (HIFs) remain elevated in diabetic eyes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs we normalized the expression of multiple vasoactive mediators – including VEGF – in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF-inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.
2023-04-18 | GSE229730 | GEO
Project description:Proliferative retinopathy is associated with abnormal vascular development (neovascularisation) of the retina. In mouse, the oxygen-induced retinopathy (OIR) model mimics the proliferative retinopathy found in extreme premature babies (Retinopathy of Prematurity) and in patients suffering from diabetic retinopathy. Using Drop-seq, we performed single-cell RNAseq analysis of mouse retina under physiological, normoxic (NORM) condition and retina under OIR condition, at postnatal day 14 and day 17, periods associated with a peak of neovascularisation. We used both whole retina cells or rod (CD73) depleted retina cells. Sorting conditions (whole vs. rod-depleted) derived count matrices were aligned with Seurat CCA and processed for dimensionality reduction and clustering.
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Project description:While quality of life compromising afflictions such as diabetic retinopathy (DR) are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the only influencer of vascular dysfunction within the retina. Activin A (activin), a ligand of the transforming growth factor β superfamily (TGF-β), attenuated VEGF-induced VE-cadherin disorganization, pore formation and permeability of primary human retinal endothelial cells (HRECs). Efforts to further investigate the mechanism of this phenomenon revealed that activin reduced expression of Rab11, which was required for the activin effect. The activin effect was not observed in cells with suppressed expression of the endosomally-localized protein tyrosine phosphatase, (PTP1b), whereas PTPs present on the plasma membrane were dispensable. Activin attenuated VEGF-mediated phosphorylation of VEGF receptor 2 (VEGFR2) at time points 30 min and longer post stimulation. Together these data support the concept that activin suppressed VEGF-induced barrier relaxation by perturbing trafficking of activated VEGFR2. This activin-based suppression of responsiveness to VEGF was compromised in the endothelium of pathological blood vessels from patients who developed end-stage proliferative diabetic retinopathy (PDR). This defect rendered HRECs hyper-responsive to VEGF and was not observed in retinal vessels of diabetic mice, which do not develop the angiogenic forms of DR. These data provide novel insights regarding the pathogenesis of PDR in patients.
2025-06-03 | GSE291008 | GEO
Project description:<p>The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients and dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export and lipid droplet formation. Noteworthy, it also shows profound changes in pathways for long-chain fatty acid production, vital for retina homeostasis. The net result is accumulation of large quantities of mead acid, a marker of essential fatty acid deficiency, and a potential marker for retinopathy severity. Thus, our lipid signature might contribute to better understand diseases of the retina that lead to vision impairment or blindness.</p>
2023-05-09 | MTBLS6965 | MetaboLights
Project description:Purpose: To investigate the expression and function of apolipoprotein C3 (APOC3) in diabetic retinopathy (DR). Methods: The quantitative expression of APOC3 in aqueous humor of patients with DR was detected using our proteomic datasets (PXD046630 and PXD053634). A multiplex immunoassay was used to examine the level of APOC3 in serum of patients with DR. Western blot, immunohistochemistry and enzyme-linked immunosorbent assays were used to measure APOC3 expression in liver, duodenum, retina and serum of db/db mice and oxygen induced retinopathy (OIR) mice, and in the human retinal microvascular endothelial cells (hRMECs) exposed to high glucose, hypoxia or both of them. Cell proliferation, migration and tube formation assays were used to assessed the phenotypic characteristics of hRMECs treated with recombinant APOC3 (r-APOC3), hypoxia and both of them. RNA sequence analysis and inhibition assay were conducted to explore the pathway in r-APOC3 and hypoxia stimulation. Results: APOC3 expression were significantly increased in aqueous humor and serum of patients with DR, as well as in liver, duodenum, serum, and retina of db/db mice and OIR mice, while did not markedly change in both hRMECs and their conditioned medium when exposed to high glucose, hypoxia or both of them. r-APOC3 combined with hypoxia significantly enhanced the proliferation, migration and tube formation of hRMECs, and promoted the upregulation of MYC, VEGF and IL6. Inhibition of MYC expression alleviated the phenotypic changes in hRMECs treated with r-APOC3 combined with hypoxia. Purpose: To investigate the expression and function of apolipoprotein C3 (APOC3) in diabetic retinopathy (DR). Methods: The quantitative expression of APOC3 in aqueous humor of patients with DR was detected using our proteomic datasets (PXD046630 and PXD053634). A multiplex immunoassay was used to examine the level of APOC3 in serum of patients with DR. Western blot, immunohistochemistry and enzyme-linked immunosorbent assays were used to measure APOC3 expression in liver, duodenum, retina and serum of db/db mice and oxygen induced retinopathy (OIR) mice, and in the human retinal microvascular endothelial cells (hRMECs) exposed to high glucose, hypoxia or both of them. Cell proliferation, migration and tube formation assays were used to assessed the phenotypic characteristics of hRMECs treated with recombinant APOC3 (r-APOC3), hypoxia and both of them. RNA sequence analysis and inhibition assay were conducted to explore the pathway in r-APOC3 and hypoxia stimulation. Results: APOC3 expression were significantly increased in aqueous humor and serum of patients with DR, as well as in liver, duodenum, serum, and retina of db/db mice and OIR mice, while did not markedly change in both hRMECs and their conditioned medium when exposed to high glucose, hypoxia or both of them. r-APOC3 combined with hypoxia significantly enhanced the proliferation, migration and tube formation of hRMECs, and promoted the upregulation of MYC, VEGF and IL6. Inhibition of MYC expression alleviated the phenotypic changes in hRMECs treated with r-APOC3 combined with hypoxia.
2024-12-09 | GSE283578 | GEO
Project description:Effects of Ischemic Preconditioning, Bevacizumab and Etanercept Ischemia and reperfusion injury provides an acute model of ischemic retinopathy that includes neurodegeneration and VEGF-dependent vascular permeability and is amenable to rapid drug testing. The distinct effects of ischemic preconditioning and bevacizumab demonstrate that the apoptotic and vascular responses to ischemia may be separated and that VEGF expression is not neuroprotective following ischemic-reperfusion. Using transient ischemia followed by reperfusion (IR) to model ischemic retinal disease, this study compares the effects of ischemic preconditioning (IPC) and therapies targeting vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNFα) on retinal apoptosis, vascular permeability and mRNA biomarker expression. Only the Ischemic Preconditioning (not Bevacizumab and Etanercept treated samples) were hybridized to arrays. Study contains 6 replicates of control and 6 IP treated retinal samples.
2010-05-31 | E-GEOD-20521 | biostudies-arrayexpress
Project description:Effects of Ischemic Preconditioning, Bevacizumab and Etanercept Ischemia and reperfusion injury provides an acute model of ischemic retinopathy that includes neurodegeneration and VEGF-dependent vascular permeability and is amenable to rapid drug testing. The distinct effects of ischemic preconditioning and bevacizumab demonstrate that the apoptotic and vascular responses to ischemia may be separated and that VEGF expression is not neuroprotective following ischemic-reperfusion.
2010-06-01 | GSE20521 | GEO
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2022-08-28 | GSE159585 | GEO
Project description:Diabetic retinopathy (DR) is one of the main causes of blindness in working age populations in industrialized countries. It is estimated that close to 100 million individuals worldwide suffer from DR. Regrettably, relatively little is known of the cellular processes at play during late stages of the disease, especially concerning diabetic macular edema (DME). Streptozotocin-induced diabetic retinopathy (STZ) allows to reproduce experimentally in the mouse retina the retina vascular leakage and neuroegeneration features observed in human pathological retina with non-proliferative DR. Using agnostic and orthogonal approaches, in our work we demonstrate that in contrast to healthy retina, the STZ diabetic retina engages pathways of cell cycle arrest, resulting in cellular senescence. These findings combined with further pharmacological approaches provide mechanistic evidence supporting that targeting selectively senescent vessels in DR represents a potential treatment for high vascular permeability in DME.
2023-12-19 | GSE211583 | GEO