The von Hippel–Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice
Open Access
- 1 March 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (3), 827-839
- https://doi.org/10.1172/jci36362
Abstract
Mutation of the von Hippel–Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2α activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2α in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2α and suggest potential treatments for Chuvash patients.Keywords
This publication has 73 references indexed in Scilit:
- Adiponectin ameliorates hypoxia-induced pulmonary arterial remodelingBiochemical and Biophysical Research Communications, 2009
- von Hippel–Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α signaling and splenic erythropoiesisJCI Insight, 2007
- Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivoJCI Insight, 2007
- Acute postnatal ablation of Hif-2 α results in anemiaProceedings of the National Academy of Sciences of the United States of America, 2007
- Failure to prolyl hydroxylate hypoxia-inducible factor α phenocopies VHL inactivation in vivoThe EMBO Journal, 2006
- Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary PhysiologyPLoS Medicine, 2006
- Hypoxia, leukocytes, and the pulmonary circulationJournal of Applied Physiology, 2005
- Genetic Analysis of Pathways Regulated by the von Hippel-Lindau Tumor Suppressor in Caenorhabditis elegansPLoS Biology, 2004
- FIZZ1/RELMα, a Novel Hypoxia-Induced Mitogenic Factor in Lung With Vasoconstrictive and Angiogenic PropertiesCirculation Research, 2003
- Disruption of oxygen homeostasis underlies congenital Chuvash polycythemiaNature Genetics, 2002