ArticleThe American journal of pathology2013
Targeting the IRE1α/XBP1 and ATF6 arms of the unfolded protein response enhances VEGF blockade to prevent retinal and choroidal neovascularization.
Article in The American journal of pathology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 55 citations in OpenAlex.
- Altered IRE1α-Dependent Decidual Programming Links Impaired Inflammation and Angiogenesis in Recurrent Implantation Failure.Biology · 2026Article
- Single-Nucleus RNA Sequencing Highlights Endothelial and Müller Cell ER Stress During Retinal Neovascularization in Vldlr-/- Mouse.Investigative ophthalmology & visual science · 2026Article
- Failure of Hepatic Insulin Clearance via CEACAM1-Mediated Endocytosis: The Missing Physiological Link Between Proinsulin Misfolding, Hyperinsulinemia, and Metabolic Complications in Type 2 Diabetes, Obesity, and NAFLD.Problemy endokrinologii · 2026Review
- Endothelial IRE1 signaling maintains blood-brain barrier integrity and limits neuroinflammation after traumatic brain injury.Cell death & disease · 2026Article
- Targeting ATF6 reduces pathological neovascularization and improves visual outcomes in retinal disease models.Scientific reports · 2025Article
- Endoplasmic Reticulum Stress in Cancer Progression: A Comprehensive Review of Its Role and Mechanisms.International journal of medical sciences · 2025Review
- The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.Progress in retinal and eye research · 2024Review
- Biology and therapeutic targeting of vascular endothelial growth factor A.Nature reviews. Molecular cell biology · 2023Review
- PERK Inhibition Suppresses Neovascularization and Protects Neurons During Ischemia-Induced Retinopathy.Investigative ophthalmology & visual science · 2023Article
- Comparison between Cultivated Oral Mucosa and Ocular Surface Epithelia for COMET Patients Follow-Up.International journal of molecular sciences · 2023Article
- The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment.Cancers · 2022Review
- Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells.Biomedicines · 2022Article
- A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders.Frontiers in neuroscience · 2022Article
- ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model.Scientific reports · 2021Article
- Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy.Cell & bioscience · 2021Article
- Inhibition of retinal neovascularization by a PEDF-derived nonapeptide in newborn mice subjected to oxygen-induced ischemic retinopathy.Experimental eye research · 2020Article
- lncRNA H19 sponging miR-93 to regulate inflammation in retinal epithelial cells under hyperglycemia via XBP1s.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2020Article
- Development of Oxytolerant Salmonella typhimurium Using Radiation Mutation Technology (RMT) for Cancer Therapy.Scientific reports · 2020Article
- The Impacts of Unfolded Protein Response in the Retinal Cells During Diabetes: Possible Implications on Diabetic Retinopathy Development.Frontiers in cellular neuroscience · 2020Article
- Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia.Cellular & molecular biology letters · 2020Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Although anti-vascular endothelial growth factor (VEGF) treatments reduce pathological neovascularization in the eye and in tumors, the regression is often not sustainable or is incomplete. We investigated whether vascular endothelial cells circumvent anti-VEGF therapies by activating the unfolded protein response (UPR) to override the classic extracellular VEGF pathway. Exposure of endothelial cells to VEGF, high glucose, or H2O2 up-regulated the X-box binding protein-1/inositol-requiring protein-1 (IRE1) α and activating transcription factor 6 (ATF6) arms of the UPR compared with untreated cells. This was associated with increased expression in α-basic crystallin (CRYAB), which has previously bound VEGF. siRNA knockdown or pharmacological blockade of IRE1α, ATF6, or CRYAB increased intracellular VEGF degradation and decreased full-length intracellular VEGF. Inhibition of IRE1α, ATF6, or CRYAB resulted in an approximately 40% reduction of in vitro angiogenesis, which was further reduced in combination with a neutralizing antibody against extracellular VEGF. Blockade of IRE1α or ATF6 in the oxygen-induced retinopathy or choroidal neovascularization mouse models caused an approximately 35% reduction in angiogenesis. However, combination therapy of VEGF neutralizing antibody with UPR inhibitors or siRNAs reduced retinal/choroidal neovascularization by a further 25% to 40%, and this inhibition was significantly greater than either treatment alone. In conclusion, activation of the UPR sustains angiogenesis by preventing degradation of intracellular VEGF. The IRE1α/ATF6 arms of the UPR offer a potential therapeutic target in the treatment of pathological angiogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.