The von Hippel–Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice
Michele M. Hickey, … , Melpo Christofidou-Solomidou, M. Celeste Simon
Michele M. Hickey, … , Melpo Christofidou-Solomidou, M. Celeste Simon
Published February 8, 2010
Citation Information: J Clin Invest. 2010;120(3):827-839. https://doi.org/10.1172/JCI36362.
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Research Article Hematology

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

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.

Authors

Michele M. Hickey, Theresa Richardson, Tao Wang, Matias Mosqueira, Evguenia Arguiri, Hongwei Yu, Qian-Chun Yu, Charalambos C. Solomides, Edward E. Morrisey, Tejvir S. Khurana, Melpo Christofidou-Solomidou, M. Celeste Simon

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Figure 8

Some, but not all, VhlR/R pulmonary phenotypes, are dependent on HIF-2α activity.

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Some, but not all, VhlR/R pulmonary phenotypes, are dependent on HIF-2α ...
(A) Representative lung images from each genotype suggest that neither Hif1a nor Hif2a heterozygosity completely restored WT pulmonary architecture (Masson’s trichrome staining). (B) Hydroxyproline content was decreased in both VhlR/R Hif1a+/– and VhlR/RHif2a+/– lungs compared with VhlR/R (n = 4–6 per genotype, *P < 0.02 compared with WT controls). (C) Macrophage infiltration was not significantly affected in either VhlR/R Hif1a+/– or VhlR/RHif2a+/– lungs (n = 5, **P < 0.007 compared with WT). (D) In contrast, only Hif2a heterozygosity resulted in a partial rescue of the hemorrhage phenotype, as quantitated by hemosiderin staining (n = 5–7, *P < 0.01 compared with WT controls). (E and F) Similarly, the number of cells in BAL from VhlR/RHif2a+/– lungs was restored to near WT levels, suggesting a rescue of edema (E, n = 5, *P < 0.05 compared with VhlR/R lungs). There was also a trend toward decreased BAL protein concentration in VhlR/RHif2a+/– lungs (F, n = 5, *P < 0.01, **P < 0.003 as compared with WT lungs). Scale bars: 20 μm.