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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 Article has an altmetric score of 3

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

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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 1

VhlR/R (R/R) mice develop pulmonary hypertension.

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VhlR/R (R/R) mice develop pulmonary hypertension.
   
(A) Systolic PA p...
(A) Systolic PA pressure was increased 1.5-fold in older, polycythemic VhlR/R mice (7 months of age) compared with WT controls (n = 12–13 per genotype). Elevated PA pressure was already present in 10-week-old VhlR/R mice (1.4-fold greater, n = 20–25), prior to any significant increase in hematocrit (HCT) levels and the onset of polycythemia (**P < 0.001, ***P < 0.0004). (B) VhlR/R hearts displayed RV hypertrophy (arrows) by 7 months of age. (C and D) Heart/body weight ratios (C, n = 18–21) and RV wall thickness (D, n = 11–17) were both significantly increased in older VhlR/R mice (1.2-fold and 1.5-fold greater, respectively, **P < 0.009). (E) The distribution of fully muscularized (F), partially muscularized (P), and nonmuscularized (N) vessels was shifted in VhlR/R lungs at both ages, with an increased proportion of fully muscularized vessels and a decrease in nonmuscularized vessels compared with WT animals (n = 4–5 per genotype at each age, **P < 0.006). Scale bars: 300 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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