ArticleAntioxidants & redox signaling2015
Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase.
Article in Antioxidants & redox signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
55 citing papers in PubMed, 2 syntheses or guidelines pooled it, 89 citations in OpenAlex.
- The effects of folic acid supplementation on endothelial function in adults: a systematic review and dose-response meta-analysis of randomized controlled trials.Nutrition journal · 2023 · on this mapPooled it
- Association Between Folate and Health Outcomes: An Umbrella Review of Meta-Analyses.Frontiers in public health · 2020Pooled it
- Folic acid ingestion improves skeletal muscle blood flow during graded handgrip and plantar flexion exercise in aged humans.American journal of physiology. Heart and circulatory physiology · 2017Trial
- Shock Induced Endotheliopathy and High Trauma Mortality-Fight-or-Flight Response Revisited.International journal of molecular sciences · 2026Review
- Folic Acid and Endothelial Dysfunction in COVID-19.Life (Basel, Switzerland) · 2026Review
- B vitamins and cardiovascular health: mechanisms, clinical evidence, and precision prevention strategies.Nutrition & metabolism · 2026Review
- Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies.Current nutrition reports · 2026Review
- eNOS Uncoupling-ER Stress-Mitochondrial Dysfunction Axis in the Development of Pulmonary Hypertension.JACC. Basic to translational science · 2026Article
- Understanding the Impact of Hypoxia on Pulmonary Artery Endothelial Cells in Chronic Thromboembolic Pulmonary Hypertension Patients.International journal of molecular sciences · 2026Article
- Hypoxic Pulmonary Hypertension: Molecular Mechanisms and Clinical Research Advances.International journal of molecular sciences · 2026Review
- Research progress of ferroptosis in obesity and its complications.Journal of physiology and biochemistry · 2026Review
- Urate-lowering effect of delphinidin-3-glucoside in red kidney beans via binding to the FAD site of the XO enzyme.Journal of advanced research · 2026Article
- Intravascular ultrasound analysis of spontaneous pulmonary artery lumen enlargement after balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.Frontiers in medicine · 2026Article
- Periconceptional Folic Acid Supplementation and the Risk of Preeclampsia in Eastern Sudan: An Unmatched Case-Control Study.International journal of women's health · 2026Article
- Relation between Cerebrospinal Fluid Catecholamines and Vascular Risk Factors, Thyroid Function and Vitamins in Healthy Individuals and Patients with Neurodegenerative Diseases.Current Alzheimer research · 2026Observational
- Addressing micronutrient deficiencies and vitamin metabolism disorders in pediatric pulmonary hypertension: a strategic proposal for low- and middle-income countries.Frontiers in cardiovascular medicine · 2026Review
- Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy.Scientific reports · 2025Article
- Focusing on perihematomal hypoperfusion following intracerebral hemorrhage: from oxidative stress to prospective therapeutic approaches.Frontiers in physiology · 2025Article
- A specific folate activates serotonergic neurons to control C. elegans behavior.Nature communications · 2024Article
- Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.Circulation research · 2024Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsNitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8-tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling. However, the role of DHFR and eNOS recoupling in the response to hypoxia is not well understood. We hypothesized that increasing the capacity to recycle BH4 from BH2 would improve NO bioavailability as well as pulmonary vascular remodeling (PVR) and right ventricular hypertrophy (RVH) as indicators of pulmonary hypertension (PH) under hypoxic conditions.
resultsIn human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, eNOS was uncoupled as indicated by reduced superoxide production in the presence of the nitric oxide synthase inhibitor, L-(G)-nitro-L-arginine methyl ester (L-NAME). Concomitantly, NO levels, BH4 availability, and expression of DHFR were diminished under hypoxia. Application of folic acid (FA) restored DHFR levels, NO bioavailability, and BH4 levels under hypoxia. Importantly, FA prevented the development of hypoxia-induced PVR, right ventricular pressure increase, and RVH. INNOVATION: FA-induced upregulation of DHFR recouples eNOS under hypoxia by improving BH4 recycling, thus preventing hypoxia-induced PH.
conclusionFA might serve as a novel therapeutic option combating PH.
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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.