ArticleThe Journal of clinical investigation2019
Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 99 citations in OpenAlex.
- Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study.American journal of ophthalmology · 2021Trial
- Angiopoietin-Like 4 Induces Upregulation of VEGF and sVCAM1 Through JNK/c-Jun and JAK2/STAT5 Signaling Pathways.Investigative ophthalmology & visual science · 2026Article
- Synergistic inhibition of macular vascular permeability in diabetic edema: Ginsenoside Rg3 enhances ranibizumab efficacy by targeting angiopoietin-like protein 4 and vascular endothelial growth factor via neuropilin/RhoA signaling.Journal of diabetes investigation · 2026Article
- Targeting the ANGPTL4/NRP1/ABL1/RAD51 axis reverses cisplatin resistance by impairing DNA damage repair in head and neck cancer.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cis-regulatory evolution reveals sensory trade-offs as a genetic basis for temporal niche evolution in tapirs.Science advances · 2026Article
- Molecular stress and neurovascular injury in the diabetic retina.The Journal of clinical investigation · 2026Review
- Recent Investigations on Pathogenesis, Biomarkers, Epigenetics, and Emerging Therapeutic Strategies to Modulate Multiple Signaling Pathways in Diabetic Retinopathy.Journal of ophthalmology · 2026Review
- Proteome atlas for mechanistic discovery and risk prediction of diabetic retinopathy.Nature communications · 2025Article
- Integrative transcriptomic and metabolomic analysis explores mechanisms by which Astragalus membranaceus and Salvia miltiorrhiza ameliorates hypertensive renal damage.Scientific reports · 2025Article
- Somatic mutations in IRE1α regulate keratinocyte migration and survival by differentially activating Rho GTPases.Journal of cell science · 2025Article
- ANGPTL4: A Comprehensive Review of 25 Years of Research.Cancers · 2025Review
- Sexual dimorphism of lung immune-regulatory units imprint biased pulmonary fibrosis.Cellular & molecular immunology · 2025Article
- Recent Advancements in Understanding the Role and Mechanisms of Angiopoietin-like Proteins in Diabetic Retinopathy.Metabolites · 2025Review
- Article
- Emerging roles of angiopoietin‑like 4 in human tumors (Review).International journal of oncology · 2025Review
- ANGPTL4-the Link Binding Lipid Metabolism and Inflammation.Current medicinal chemistry · 2025Review
- Pemafibrate Induces a Low Level of PPARα Agonist-Stimulated mRNA Expression of ANGPTL4 in ARPE19 Cell.Bioengineering (Basel, Switzerland) · 2024Article
- ANGPTL4-mediated inflammation: A new mechanism of disease and therapeutic approach for rheumatoid arthritis.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- ANGPTL4 promotes choroidal neovascularization and subretinal fibrosis through the endothelial‒mesenchymal transition.International ophthalmology · 2024Article
- VEGF inhibition increases expression of HIF-regulated angiogenic genes by the RPE limiting the response of wet AMD eyes to aflibercept.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The majority of patients with diabetic macular edema (DME), the most common cause of vision loss in working-age Americans, do not respond adequately to current therapies targeting VEGFA. Here, we show that expression of angiopoietin-like 4 (ANGPTL4), a HIF-1-regulated gene product, is increased in the eyes of diabetic mice and patients with DME. We observed that ANGPTL4 and VEGF act synergistically to destabilize the retinal vascular barrier. Interestingly, while ANGPTL4 modestly enhanced tyrosine phosphorylation of VEGF receptor 2, promotion of vascular permeability by ANGPTL4 was independent of this receptor. Instead, we found that ANGPTL4 binds directly to neuropilin 1 (NRP1) and NRP2 on endothelial cells (ECs), leading to rapid activation of the RhoA/ROCK signaling pathway and breakdown of EC-EC junctions. Treatment with a soluble fragment of NRP1 (sNRP1) prevented ANGPTL4 from binding to NRP1 and blocked ANGPTL4-induced activation of RhoA as well as EC permeability in vitro and retinal vascular leakage in diabetic animals in vivo. In addition, sNRP1 reduced the stimulation of EC permeability by aqueous fluid from patients with DME. Collectively, these data identify the ANGPTL4/NRP/RhoA pathway as a therapeutic target for the treatment of DME.
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