The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice

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 (Vhl(R/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 Vhl(R/R) mice as a model for Chuvash disease. Lungs from Vhl(R/R) mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2 alpha activity was increased in lungs from Vhl(R/R) mice, and heterozygosity for Hif2 alpha, but not Hif1 alpha, generically suppressed both the polycythemia and pulmonary hypertension in the Vhl(R/R) mice. Furthermore, Hif2 alpha heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in Vhl(R/R) lungs, suggesting a selective role for HIF-2 alpha 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-2 alpha and suggest potential treatments for Chuvash patients.