ArticleThe Journal of biological chemistry2013
Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 103 citations in OpenAlex.
- Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS).International journal of molecular sciences · 2017Trial
- Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia.Journal of applied physiology (Bethesda, Md. : 1985) · 2016Trial
- Association between the endothelial activation and stress index and 28-day all-cause mortality in critically ill patients with chronic obstructive pulmonary disease: a retrospective cohort study and predictive model establishment based on machine learning.BMC pulmonary medicine · 2026Article
- Oxidative Stress and Inflammation in Hypoxemic Respiratory Diseases and Their Comorbidities: Molecular Insights and Diagnostic Advances in Chronic Obstructive Pulmonary Disease and Sleep Apnea.Antioxidants (Basel, Switzerland) · 2025Review
- Association between single nucleotide polymorphisms inFrontiers in genetics · 2025Article
- Oxygen-sensing pathways and the pulmonary circulation.The Journal of physiology · 2024Review
- Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α.American journal of physiology. Lung cellular and molecular physiology · 2024Article
- Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.Nature reviews. Drug discovery · 2024Review
- Hypoxia Inducible Factor pathway proteins in high-altitude mammals.Trends in biochemical sciences · 2024Review
- Unraveling the role of HIF and epigenetic regulation in pulmonary arterial hypertension: implications for clinical research and its therapeutic approach.Frontiers in medicine · 2024Review
- High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.Molecular biology and evolution · 2023Article
- Vascular stiffening in aging females with a hypertension-induced HIF2A gain-of-function mutation.Bioengineering & translational medicine · 2023Article
- Personalized medicine using omics approaches in acute respiratory distress syndrome to identify biological phenotypes.Respiratory research · 2022Review
- Article
- The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure.Circulation research · 2022Review
- Transcription factors in the pathogenesis of pulmonary arterial hypertension-Current knowledge and therapeutic potential.Frontiers in cardiovascular medicine · 2022Review
- Hypoxia and the integrated stress response promote pulmonary hypertension and preeclampsia: Implications in drug development.Drug discovery today · 2021Review
- Erythrocytosis: genes and pathways involved in disease development.Blood transfusion = Trasfusione del sangue · 2021Review
- Endothelial cells in the pathogenesis of pulmonary arterial hypertension.The European respiratory journal · 2021Review
- Genetic Background of Congenital Erythrocytosis.Genes · 2021Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
Abstract
The central pathway for oxygen-dependent control of red cell mass is the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. PHD site specifically prolyl hydroxylates the transcription factor HIF-α, thereby targeting the latter for degradation. Under hypoxia, this modification is attenuated, allowing stabilized HIF-α to activate target genes, including that for erythropoietin (EPO). Studies employing genetically modified mice point to Hif-2α, one of two main Hif-α isoforms, as being the critical regulator of Epo in the adult mouse. More recently, erythrocytosis patients with heterozygous point mutations in the HIF2A gene have been identified; whether these mutations were polymorphisms unrelated to the phenotype could not be ruled out. In the present report, we characterize a mouse line bearing a G536W missense mutation in the Hif2a gene that corresponds to the first such human mutation identified (G537W). We obtained mice bearing both heterozygous and homozygous mutations at this locus. We find that these mice display, in a mutation dose-dependent manner, erythrocytosis and pulmonary hypertension with a high degree of penetrance. These findings firmly establish missense mutations in HIF-2α as a cause of erythrocytosis, highlight the importance of this HIF-α isoform in erythropoiesis, and point to physiologic consequences of HIF-2α dysregulation.
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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.