ArticleProceedings of the National Academy of Sciences of the United States of America2008
Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 181 papers, 2 of them syntheses that pooled it.
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The trial behind it
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Who cites it
181 citing papers in PubMed, 2 syntheses or guidelines pooled it, 269 citations in OpenAlex.
- Kidney and endothelial injury biomarkers as predictors of complications and mortality in patients with malaria: a systematic review.Malaria journal · 2026Pooled it
- Systematic review of the role of angiopoietin-1 and angiopoietin-2 in Plasmodium species infections: biomarkers or therapeutic targets?Malaria journal · 2016Pooled it
- Tie2 protects the vasculature against thrombus formation in systemic inflammation.The Journal of clinical investigation · 2018Trial
- B-type natriuretic peptide and plasma hemoglobin levels following transfusion of shorter-storage versus longer-storage red blood cells: Results from the TOTAL randomized trial.American heart journal · 2017Trial
- Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial.Malaria journal · 2015Trial
- Trial
- Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity.PLoS pathogens · 2015Trial
- A randomized pilot study of L-arginine infusion in severe falciparum malaria: preliminary safety, efficacy and pharmacokinetics.PloS one · 2013Trial
- Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement.PLoS medicine · 2012Trial
- Inhaled nitric oxide for the adjunctive therapy of severe malaria: protocol for a randomized controlled trial.Trials · 2011Trial
- ETS-guided iPSC-endothelial models recapitulate malaria pathogenesis.EMBO molecular medicine · 2026Article
- The Role of Angiopoietin-2 in Post-Burn Pneumonia.European burn journal · 2025Article
- Plasmodium falciparum impairs Ang-1 secretion by pericytes in a 3D brain microvessel model.EMBO molecular medicine · 2025Article
- Evaluation of Endothelial Glycocalyx Damage in Neonatal Lambs With Diarrhoea: A Biomarker-Based Approach.Veterinary medicine and science · 2025Article
- Neurovascular Pathophysiology and Emerging Biomarkers in Cerebral Malaria: An Integrative Perspective.Neurology international · 2025Review
- Osteoprotegerin and its ligands RANKL and TRAIL in falciparum, vivax, and knowlesi malaria.iScience · 2025Article
- Elevated Levels of PDGF-BB and VEGF Are Associated With a Decreased Risk of Readmission or Death in Children With Severe Malarial Anemia.The Journal of infectious diseases · 2025Article
- Cathepsin K cleavage of angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis.The Journal of clinical investigation · 2025Article
- Neutrophil activation, acute lung injury and disease severity in Plasmodium knowlesi malaria.PLoS neglected tropical diseases · 2024Article
- Effects of switching from intravitreal injection of aflibercept to faricimab on ocular blood flow in patients with diabetic macular edema.Scientific reports · 2024Article
121 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 4 countries.
Funding
Abstract
Adherence of parasitized erythrocytes to activated endothelium causes microvascular obstruction, tissue ischemia, and clinical complications in severe malaria (SM); however, the mechanisms leading to endothelial activation remain unclear. The angiogenic factors, angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are modulators of endothelial activation, with Ang-2 release from Weibel-Palade bodies (WPBs) being regulated by endothelial nitric oxide (NO). We explored the relationships between endothelial NO bioavailability, Ang-2, VEGF, tissue perfusion, and clinical outcomes in SM. We measured plasma Ang-2 and VEGF, together with biomarkers of severity from 146 adults with and without SM, in parallel with longitudinal measures of endothelial function by using reactive hyperemia peripheral arterial tonometry (a measure of endothelial NO bioavailability). Regression was used to relate concentrations of Ang-2/VEGF with malaria disease severity, biomarkers of perfusion, endothelial activation, and parasite biomass. The longitudinal relationship between Ang-2 and endothelial function was assessed by using a mixed-effects model. Ang-2 concentrations were elevated in SM and associated with increased venous lactate, plasma intercellular cell adhesion molecule-1 concentrations, parasite biomass, and mortality. In contrast, VEGF concentrations were inversely associated with these biomarkers. Ang-2 concentrations were significantly better predictors of death than venous lactate (P = 0.03). Recovery of endothelial function was associated with falling concentrations of Ang-2. Ang-2 release from endothelial cells with reduced NO bioavailability is likely to contribute to endothelial activation, sequestered parasite biomass, impaired perfusion, and poor outcome in severe falciparum malaria. Agents that improve endothelial NO, reduce WPB exocytosis, and/or antagonize Ang-2 may have therapeutic roles in SM.
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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.