Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy

Inhibition of vascular endothelial growth factor (VEGF) in retinopathy of prematurity (ROP) raises concerns for premature infants because VEGF is essential for retinovascular development as well as neuronal and glial health. This study tested the hypothesis that endothelial cell-specific knockdown of VEGF receptor 2 (VEGFR2), or downstream STAT3, would inhibit VEGF-induced retinopathy without delaying physiologic retinal vascular development. We developed an endothelial cell-specific lentiviral vector that delivered shRNAs to VEGFR2 or STAT3 and a green fluorescent protein reporter under control of the VE-cadherin promoter. The specificity and efficacy of the lentiviral vector-driven shRNAs were validated in vitro and in vivo. In the rat oxygen-induced retinopathy model highly representative of human ROP, the effects of endothelial cell knockdown of VEGFR2 or STAT3 were determined on intravitreal neovascularization (IVNV), physiologic retinal vascular development [assessed as area of peripheral avascular/total retina (AVA)], retinal structure, and retinal function. Targeted knockdown of VEGFR2 or STAT3 specifically in retinal endothelial cells by subretinal injection of lentiviral vectors into postnatal day 8 rat pup eyes efficiently inhibited IVNV, and knockdown of VEGFR2 also reduced AVA and increased retinal thickness without altering retinal function. Taken together, our results support specific knockdown of VEGFR2 in retinal endothelial cells as a novel therapeutic method to treat retinopathy.

• Publication year

  2018

• Venue

  Angiogenesis

• Publication date

  2018-05-05

• Fields of study

  Medicine

• Identifiers
  DOI 10.1007/s10456-018-9618-5PMID 29730824PMCID 6203654
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Evolution of Intravitreal Therapy for Retinal Diseases-From CMV to CNV: The LXXIV Edward Jackson Memorial Lecture.

  2018cited by this paper
• Diabetic retinopathy, an overview.

  2017cited by this paper
• Assessment of Lower Doses of Intravitreous Bevacizumab for Retinopathy of Prematurity: A Phase 1 Dosing Study

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• Anti-Vascular Endothelial Growth Factor Therapy for Primary Treatment of Type 1 Retinopathy of Prematurity: A Report by the American Academy of Ophthalmology.

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• INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT FOR RETINOPATHY OF PREMATURITY: Comparison Between Ranibizumab and Bevacizumab

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• VEGFA activates erythropoietin receptor and enhances VEGFR2-mediated pathological angiogenesis.

  2014cited by this paper
• Quantitative analyses of retinal vascular area and density after different methods to reduce VEGF in a rat model of retinopathy of prematurity.

  2014cited by this paper
• VEGF-A Is Necessary and Sufficient for Retinal Neuroprotection in Models of Experimental Glaucoma

  2013cited by this paper
• Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of retinopathy of prematurity.

  2013cited by this paper
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  2013cited by this paper
• Serum concentrations of vascular endothelial growth factor in an infant treated with ranibizumab for retinopathy of prematurity

  2013cited by this paper
• VEGF-mediated STAT3 activation inhibits retinal vascularization by down-regulating local erythropoietin expression.

  2012cited by this paper
• Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity.

  2012cited by this paper
• Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.

  2011cited by this paper
• Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog.

  2011cited by this paper
• Reduction in endothelial tip cell filopodia corresponds to reduced intravitreous but not intraretinal vascularization in a model of ROP.

  2009cited by this paper
• The role of supplemental oxygen and JAK/STAT signaling in intravitreous neovascularization in a ROP rat model.

  2009cited by this paper
• Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic.

  2008cited by this paper
• Endogenous VEGF Is Required for Visual Function: Evidence for a Survival Role on Müller Cells and Photoreceptors

  2008cited by this paper
• Role of VEGF in organogenesis

  2008cited by this paper
• Neutralizing VEGF decreases tortuosity and alters endothelial cell division orientation in arterioles and veins in a rat model of ROP: relevance to plus disease.

  2008cited by this paper
• Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury.

  2007cited by this paper
• Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation.

  2007cited by this paper
• VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection

  2004cited by this paper
• VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia.

  2003cited by this paper
• Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

  1996cited by this paper
• The effect of postnatal growth retardation on abnormal neovascularization in the oxygen exposed neonatal rat.

  1996cited by this paper
• Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

  1996cited by this paper
• Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice

  1995cited by this paper
• Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity

  1995cited by this paper
• Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia

  1995cited by this paper
• Variable oxygen exposure causes preretinal neovascularization in the newborn rat.

  1993influential reference
• Diabetic retinopathy: an overview.

  1976cited by this paper

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• Hypoxia-driven Histone Modification Landscape and the Role of EZH2 in Retinal Neovascularization.

  2025cites this paper
• Association of the ADRB2 rs1042714 variant with retinopathy of prematurity highlights the importance of the renin-angiotensin-aldosterone system

  2025cites this paper
• Retinal vascularization rate predicts retinopathy of prematurity and remains unaffected by low-dose bevacizumab treatment

  2025cites this paper
• Endothelial MEMO1 Regulates Angiogenic Signaling in a Model of Retinopathy of Prematurity

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  2024cites this paper
• Aflibercept to treat retinopathy of prematurity: need for more research

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• Retinopathy of Prematurity—Targeting Hypoxic and Redox Signaling Pathways

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• Editorial: Identification of novel biomarkers for retinopathy of prematurity in preterm infants by use of innovative technologies and artificial intelligence

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• SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis

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• Acrizanib as a Novel Therapeutic Agent for Fundus Neovascularization via Inhibitory Phosphorylation of VEGFR2

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• Update on Management of Retinopathy of Prematurity: A Review

  2024cites this paper
• Müller cells and retinal angiogenesis: critical regulators in health and disease

  2024cites this paper
• Laser versus Anti-VEGF: A Paradigm Shift for Treatment-Warranted Retinopathy of Prematurity

  2023cites this paper
• Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy

  2023cites this paper
• Pathophysiology of Retinopathy of Prematurity.

  2023cites this paper
• Extending Peripheral Retinal Vascularization in Retinopathy of Prematurity (ROP) through Regulation of VEGF Signaling: Abbreviated title: VEGF regulation facilitates retinal vascularization in ROP.

  2023cites this paper
• A Literary Pediatric Retina Fellowship With Michael T. Trese, MD.

  2023cites this paper
• Evaluation of risk factors and assessment of socio-demographic factors affecting retinopathy of prematurity in a tertiary care centre of central India

  2023cites this paper
• SYVN1 Promotes STAT3 Protein Ubiquitination and Exerts Antiangiogenesis Effects in Retinopathy of Prematurity Development

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• Regulation of Long Noncoding RNA NEAT1/miR-320a/HIF-1α Competitive Endogenous RNA Regulatory Network in Diabetic Retinopathy

  2023cites this paper
• How can the safety of antibody therapy for retinopathy of prematurity be improved?

  2023cites this paper
• RNA-Seq Provides Insights into VEGF-Induced Signaling in Human Retinal Microvascular Endothelial Cells: Implications in Retinopathy of Prematurity

  2022influential citation
• Retinopathy of prematurity

  2022cites this paper
• Functional and Structural Findings in Infants Treated for Retinopathy of Prematurity Using Optical Coherence Tomography Angiography.

  2022cites this paper
• Experiment-Based Interventions to Diabetic Retinopathy: Present and Advances

  2022cites this paper
• Plasma Levels of Vascular Endothelial Growth Factor After Low-Dose Bevacizumab Treatment for Retinopathy of Prematurity Study-More Questions Than Answers?-Reply.

  2022cites this paper
• Retinopathy of Prematurity: A Global Perspective and Recent Developments.

  2022cites this paper
• Exploration of Hub Genes in Retinopathy of Prematurity Based on Bioinformatics Analysis of the Oxygen-Induced Retinopathy Model

  2022cites this paper
• A Narrative Review of STAT Proteins in Diabetic Retinopathy: From Mechanisms to Therapeutic Prospects

  2022cites this paper
• VEGF promotes diabetic retinopathy by upregulating the PKC/ET/NF-κB/ICAM-1 signaling pathway

  2022cites this paper
• The Effect of Intravitreal Bevacizumab Dose on Retinal Vascular Progression in Retinopathy of Prematurity

  2021cites this paper
• Therapeutic Efficacy of a Novel Acetylated Tetrapeptide in Animal Models of Age-Related Macular Degeneration

  2021cites this paper
• Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye

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  2021cites this paper
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  2021cites this paper
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  2020cites this paper
• 4-hydroxy-2-nonenal decreases coronary endothelial cell migration: Potentiation by aldehyde dehydrogenase 2 inhibition.

  2020cites this paper
• Strategies to Prevent Severe Retinopathy of Prematurity: A 2020 Update and Meta-analysis.

  2020cites this paper
• Retinopathy of Prematurity: Evolving Treatment with anti-Vascular Endothelial Growth Factor.

  2020cites this paper
• Viral-Vector Delivered anti-Angiogenic Therapies to the Eye

  2020influential citation
• Metabolic Dysregulation and Neurovascular Dysfunction in Diabetic Retinopathy

  2020cites this paper
• C-CBL is required for inhibition of angiogenesis through modulating JAK2/STAT3 activity in ROP development

  2020cites this paper
• Review on Mechanistic strategy of gene therapy in the treatment of disease.

  2020cites this paper
• Signaling Through the Erythropoietin Receptor Affects Angiogenesis in Retinovascular Disease

  2020cites this paper
• Experimental Evidence Behind Clinical Trial Outcomes in Retinopathy of Prematurity.

  2019cites this paper
• Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity

  2019cites this paper
• Recent Approaches for Angiogenesis in Search of Successful Tissue Engineering and Regeneration.

  2019cites this paper
• Relationship between Retinal Thickness Profiles and Visual Outcomes in Young Adults Born Extremely Preterm: The EPICure@19 Study.

  2019influential citation
• Endothelial Cell Isolation and Manipulation

  2019cites this paper
• GEP100/ARF6 regulates VEGFR2 signaling to facilitate high-glucose-induced epithelial-mesenchymal transition and cell permeability in retinal pigment epithelial cells.

  2019cites this paper
• Fundamentals of Vascular Biology

  2019cites this paper
• A review of treatment for retinopathy of prematurity

  2019cites this paper
• Discovering Mechanisms in the Changing and Diverse Pathology of Retinopathy of Prematurity: The Weisenfeld Award Lecture

  2019influential citation