Epithelial membrane protein-2 promotes VEGF signaling to promote pathological neovascular growth in retinopathy of prematurity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE123945 | GEO | 2021/12/17
REPOSITORIES: GEO
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Project description:To reveal the altered expression profiles of circular RNAs (circRNAs) in the peripheral blood mononuclear cells (PBMCs) of patients with retinopathy of prematurity (ROP), microarray analysis was conducted in the samples from ROP patients and controls.
2022-08-10 | GSE204780 | GEO
Project description:Retinopathy of prematurity (ROP), a blinding condition affecting preterm infants, accounts for up to 40% of all childhood blindness worldwide. ROP is an interruption of retinal vascular maturation, which is physiologically complete at full term and thus ongoing at the time of preterm birth. Although ROP demonstrates delayed onset following preterm birth, representing a window for therapeutic intervention, we cannot cure or prevent this disease. The in-utero environment, including placental function, is increasingly recognized for contributions to preterm infant disease risk. Herein, we examine the clinical associations between presence and severity of acute placental inflammation to ROP risk. Using logistic regression, we find a protective relationship between presence and severity of acute placental inflammation and preterm infant development of ROP. This is most significant for infants born in the absence of maternal preeclampsia. Further, we examine the underlying molecular mediators that may inform this protective paradigm. Adopting a candidate approach analyzing proteins with described ROP risk associations, we find that placental HTRA1 and FABP4 protein expression is significantly decreased within placental tissues characterized by acute inflammation. Additionally, HTRA1 and VEGFA demonstrate inverse longitudinal trends within the peripheral circulation for infants born in the presence compared to absence of acute placental inflammation. An agnostic approach, including whole transcriptome and differential methylation placental analysis, identifies novel mediators and pathways that may underly protection. Taken together, these data build on emerging literature showing disparate associations between acute placental inflammation and ROP development within preeclamptic or non-preeclamptic preterm infant populations and identifies novel placental mechanisms that may inform postnatal risk associations in preterm infants.
2023-01-01 | GSE218039 | GEO
Project description:The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects on intraretinal vascularization. In an experimental ROP model, VEGF receptor 2 (VEGFR2) knockdown in retinal endothelial cells reduced IVNV and promoted intraretinal vascularization, whereas knockdown of a downstream effector, signal transducer and activator of transcription 3 (STAT3) in retinal endothelial cells only reduced IVNV. In this study, we tested the hypothesis that the different pathways involved in VEGF-triggered VEGFR2 signaling and VEGF-triggered STAT3 signaling in retinal endothelial cells would allow us to delineate signaling pathways involved in IVNV from those involved in intraretinal vascularization in ROP. To address our hypothesis, we used RNA-sequencing and pathway enrichment analysis to determine changes in the transcriptome of cultured human retinal microvascular endothelial cells (HRMECs). Of the enriched pathways, inactivation of oncostatin M signaling was predicted by either KDR or STAT3 knockdown in the presence of VEGF. Activation of kinetochore metaphase signaling was predicted by KDR knockdown, whereas inactivation was predicted by STAT3 knockdown in the presence of VEGF. Inactivation of signaling by the Rho family of GTPases was predicted by KDR knockdown, but activation was predicted by STAT3 knockdown in the presence of VEGF. Taken together, our data identified unique signaling pathway differences between VEGF-triggered VEGFR2 and VEGF-triggered STAT3 in HRMECs that might have implications in ROP.
2022-12-29 | GSE221861 | GEO
Project description:The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects on intraretinal vascularization. In an experimental ROP model, VEGF receptor 2 (VEGFR2) knockdown in retinal endothelial cells reduced IVNV and promoted intraretinal vascularization, whereas knockdown of a downstream effector, signal transducer and activator of transcription 3 (STAT3) in retinal endothelial cells only reduced IVNV. In this study, we tested the hypothesis that the different pathways involved in VEGF-triggered VEGFR2 signaling and VEGF-triggered STAT3 signaling in retinal endothelial cells would allow us to delineate signaling pathways involved in IVNV from those involved in intraretinal vascularization in ROP. To address our hypothesis, we used RNA-sequencing and pathway enrichment analysis to determine changes in the transcriptome of cultured human retinal microvascular endothelial cells (HRMECs). Of the enriched pathways, inactivation of oncostatin M signaling was predicted by either KDR or STAT3 knockdown in the presence of VEGF. Activation of kinetochore metaphase signaling was predicted by KDR knockdown, whereas inactivation was predicted by STAT3 knockdown in the presence of VEGF. Inactivation of signaling by the Rho family of GTPases was predicted by KDR knockdown, but activation was predicted by STAT3 knockdown in the presence of VEGF. Taken together, our data identified unique signaling pathway differences between VEGF-triggered VEGFR2 and VEGF-triggered STAT3 in HRMECs that might have implications in ROP.
2022-12-29 | GSE221860 | GEO
Project description:Schemic retinopathies such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP), are the main causes of blindness in working age and pediatric populations in industrialized countries. It is estimated that close to 100 million individuals worldwide suffer from DR and 15 million preterm infants born each year are predisposed to ROP. Regrettably, relatively little is known of the cellular processes at play during late stages of pathological angiogenesis in these diseases and consequently current standards of care target all neovascularization. Oxygen-induced retinopathy (OIR) allows to reproduce experimentally in the mouse retina the pathological features observed in human pathological retina such as ischemic avascular regions as well as epi-retinal neovascularization. Using agnostic and orthogonal approaches, in our work we demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cell cycle arrest, resulting in cellular senescence. These findings combined with further genetic and pharmacological approaches provide mechanistic evidence supporting that targeting selectively senescent vessels in DR represents a potential treatment for neovascular retinal disease.
2021-02-22 | GSE158799 | GEO
Project description:Retinopathy of prematurity (ROP) is a disorder of the developing retina of preterm infants. ROP can lead to blindness due to abnormal angiogenesis that is the result of suspended vascular development and vaso-obliteration leading to severe retinal stress and hypoxia. We tested the hypothesis that a combined treatment with two human progenitor populations, the CD34+ cells, bone marrow-derived, and the endothelial colony-forming cells (ECFCs) synergistically protected the developing retinal vasculature in a murine model of ROP, the oxygen-induced retinopathy (OIR)., CD34+ cells alone, ECFCs alone, or a combination thereof were injected intravitreally at either P5 or P12 and pups were euthanized at P17. Retinas from OIR mice injected with ECFCs or the combined treatment revealed formation of the deep vascular plexus (DVP) while still in hyperoxia, with normal appearing connections between the superficial vascular plexus (SVP) and the DVP. The combination therapy prevented aberrant retinal neovascularization and was more effective anatomically and functionally at rescuing the ischemia phenotype than either cell type alone. The beneficial effect of the cell combination was the result of their ability to orchestrate an acceleration of vascular development and more rapid ensheathment of pericytes on the developing vessels.
2019-12-31 | GSE135844 | GEO
Project description:Retinopathy of prematurity (ROP) is the most common cause of childhood blindness worldwide and is caused by oxygen therapy necessary to prevent mortality after premature birth. We have previously demonstrated the efficacy of systemic hypoxia inducible factor (HIF) stabilization through HIF prolyl hydroxylase inhibition (HIF PHi) in protecting retinal vasculature from oxygen toxicity in a mouse model of ROP or oxygen induced retinopathy (OIR). We definitively demonstrated that hepatic HIF-1 can be activated to confer this protection using systemic dimethyloxalylglycine (DMOG) to prevent HIF-1α degradation. In this study we compare Roxadustat, a small molecule stabilizer of HIF-1 currently in phase 3 clinical trials for increasing erythropoiesis in adult patients with chronic kidney disease, to DMOG. We demonstrate that Roxadustat induces vascular protection during hyperoxia to induce the coordinated sequential growth of retinal vasculature with a 3-fold reduction in oxygen induced capillary loss (p-=0.001). In order to define the molecular mechanism of protection, we further compared the transcriptome of both liver and retina after systemic treatment with Roxadustat or DMOG. Similar gene expression profiles were identified in liver but very different effects on transcription were found in retinal tissues because Roxadustat, in contrast to DMOG, directly targets retina, confirmed by western blot and by rescue of the hepatic HIF-1 KO, two criteria that DMOG treatment is unable to fulfill. Systems pharmacologic analysis demonstrates that Roxadustat induces typical HIF regulated genes critical to aerobic glycolysis in liver and retinal tissues whereas DMOG, acting through either secreted hepatokines or by influence of systemic DMOG, downregulates cell adhesion/extracellular matrix interaction pathways while increasing expression of histone cluster genes. Stratification of liver transcriptomes to secreted gene products again shows close consensus of hepatic genes induced by both small molecules, and includes upregulation of a plethora of angiogenic proteins such as plasminogen activator inhibitor (PAI-1), erythropoietin (EPO), and orosomucosoid 2 (ORM2). Secondary validation of these transcripts by serum ELISA confirms secretion of EPO and PAI-1 into blood from liver. These findings definitively demonstrate that HIF stabilization can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect, hepatic HIF-1 stabilization and increased serum angiokines. Systems pharmacology analysis therefore explains why intermittent, low dosage of small molecule HIF stabilizers creates a profound protective phenotype, because both pathways can take advantage of cytoprotection induced by the liver and by retina synergistically. These data provide a rationale for considering low dose, intermittent systemic administration of Roxadustat, currently in phase 3 trials in adults with chronic kidney disease, to eradicate ROP in children.
2016-05-03 | GSE74170 | GEO
Project description:Oxygen-induced retinopathy (OIR) animal model is widely used for retinopathy of prematurity (ROP). The purpose of this project was to identify proteins and related pathways of OIR with or without anti-vascular endothelial growth factor (VEGF) treatment, for use as biomarkers in diagnosing and treating ROP.
2023-09-14 | PXD045378 |
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:Epithelial membrane protein-2 promotes VEGF signaling to promote pathological neovascular growth in retinopathy of prematurity
| PRJNA510363 | ENA