ArticleThe Journal of clinical investigation2021
HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 84 citations in OpenAlex.
- Identification of novel HIF2α inhibitors: a structure-based virtual screening approach.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Dopamine inhibits retinal pathological neovascularization in the oxygen-induced retinopathy mouse model.The Journal of pathology · 2026Article
- Yin and Yang of ginsenosides: Molecular mechanisms of bidirectional regulation of angiogenesis.Journal of ginseng research · 2026Review
- HIF inhibition: Current strategies and clinical challenges.Redox biology · 2026Review
- Pulmonary Hypertension Molecular Switch: HIF Signaling Pathway.Pulmonary circulation · 2026Review
- Suppression of Retinal Neovascularisation by Tetrahedral Framework Nucleic Acids-Resveratrol Via Dual Anti-Angiogenesis and Anti-Inflammation.Cell proliferation · 2026Article
- Nuclear translocation of SLC25A10 isoform 3 promotes chemoresistance in HCC cells via CEBPB/BCL2A1 signaling.Cell death & disease · 2026Article
- Molecular stress and neurovascular injury in the diabetic retina.The Journal of clinical investigation · 2026Review
- Nintedanib Eye Drops Inhibit Alkali Burn-Induced Corneal Neovascularization Via RAP1/MEK/ERK Signaling Pathway.Investigative ophthalmology & visual science · 2026Article
- Hypoxia, ROS, and HIF Signaling in I/R Injury: Implications and Future Prospects.Antioxidants (Basel, Switzerland) · 2026Review
- A Somatic Mutation in HIF-2α Affects Glucose and Lipid Metabolism via CD36 and Ceramide.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- The role and potential mechanism of PEST-containing nuclear protein (PCNP) in endothelial cell angiogenesis in vitro.Scientific reports · 2025Article
- Monocyte-derived exosomal periostin driven by histone lactylation contributes to retinal neovascularization.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mechanism of retinal angiogenesis induced by HIF-1α and HIF-2α under hyperoxic conditions.Scientific reports · 2025Article
- Dual VEGF-Targeting Strategy Via AAV2-Delivered sFLT-1 and shVEGF for Retinal Neovascularization Therapy.Investigative ophthalmology & visual science · 2025Article
- Chronic cerebral hypoperfusion induces venous dysfunction via EPAS1 regulation in mice.Nature communications · 2025Article
- Ref-1 redox activity modulates canonical Wnt signaling in endothelial cells.Redox biology · 2025Article
- Baicalin prevents experimental autoimmune uveitis by promoting macrophage polarization balance through inhibiting the HIF-1α signaling pathway.Scientific reports · 2025Article
- Peripheral blood HIF-1α levels: a study on their predictive ability for early-stage diabetic retinopathy.Endocrine connections · 2025Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 4 institutions in 2 countries.
Funding
Abstract
Therapies targeting VEGF have proven only modestly effective for the treatment of proliferative sickle cell retinopathy (PSR), the leading cause of blindness in patients with sickle cell disease. Here, we shift our attention upstream from the genes that promote retinal neovascularization (NV) to the transcription factors that regulate their expression. We demonstrated increased expression of HIF-1α and HIF-2α in the ischemic inner retina of PSR eyes. Although both HIFs participated in promoting VEGF expression by hypoxic retinal Müller cells, HIF-1 alone was sufficient to promote retinal NV in mice, suggesting that therapies targeting only HIF-2 would not be adequate to prevent PSR. Nonetheless, administration of a HIF-2-specific inhibitor currently in clinical trials (PT2385) inhibited NV in the oxygen-induced retinopathy (OIR) mouse model. To unravel these discordant observations, we examined the expression of HIFs in OIR mice and demonstrated rapid but transient accumulation of HIF-1α but delayed and sustained accumulation of HIF-2α; simultaneous expression of HIF-1α and HIF-2α was not observed. Staggered HIF expression was corroborated in hypoxic adult mouse retinal explants but not in human retinal organoids, suggesting that this phenomenon may be unique to mice. Using pharmacological inhibition or an in vivo nanoparticle-mediated RNAi approach, we demonstrated that inhibiting either HIF was effective for preventing NV in OIR mice. Collectively, these results explain why inhibition of either HIF-1α or HIF-2α is equally effective for preventing retinal NV in mice but suggest that therapies targeting both HIFs will be necessary to prevent NV in patients with PSR.
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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.