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 (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-2α activity was increased in lungs from Vhl R/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the Vhl R/R mice. Furthermore, Hif2a 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-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.

Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia)

“…6,12,36,41 Decreased PHD activity could result in increased levels of erythropoietin as well as other HIF-controlled genes, as suggested by the report of exacerbation of high altitude C.a. sable et al…”

“…3 In keeping with this possibility, pulmonary hypertension in a murine model of Chuvash polycythemia seems to be mediated by elevated HIF-2. 6 Likewise, high altitude dwellers of Tibet 39 and the Andes mountains, 40 continuously exposed to high altitude hypoxia, may develop pulmonary hypertension, and the pulmonary hypertension appears to be mediated by elevated HIF-1 and HIF-2 levels. 6,41 Conversely, partial deficiency of HIF-2 expression protects against hypoxiainduced pulmonary hypertension in mice.…”

“…6 Likewise, high altitude dwellers of Tibet 39 and the Andes mountains, 40 continuously exposed to high altitude hypoxia, may develop pulmonary hypertension, and the pulmonary hypertension appears to be mediated by elevated HIF-1 and HIF-2 levels. 6,41 Conversely, partial deficiency of HIF-2 expression protects against hypoxiainduced pulmonary hypertension in mice. 9 It has recently been suggested that inactivation of PHDs may promote the detrimental effects of augmented HIF-1 and HIF-2 levels.…”

“…5 Data from cell lines and rodent models support the role of dysregulated HIF-1 and HIF-2 expression in the development of pulmonary hypertension. 6,7 Pulmonary hypertension develops in a murine model of Chuvash polycythemia, and this finding seems to be related specifically to increased HIF-2 activity. 2 Furthermore, lateonset pulmonary arterial hypertension has been reported in association with polycythemia due to an activating HIF-2A mutation, 8 and hif2+/-mice are protected from pulmonary hypertension during chronic hypoxia.…”

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

“…Importantly, two of these studies (3,5) demonstrated both a strong association between the Tibetan HIF2A haplotype and low hemoglobin concentration (which is controlled by the HIF-2␣ target gene, EPO (37)(38)(39)(40)), thereby providing compelling evidence that the HIF2A allele is a loss of function allele. Because HIF-2␣ also plays a central role in pulmonary hypertension (41)(42)(43)(44), the loss of function HIF2A allele would be predicted to blunt the erythrocytosis and pulmonary hypertension that might otherwise result from loss of PHD2 function (Fig. 4D, right panel).…”