Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia
Koen Brusselmans, Veerle Compernolle, Marc Tjwa, Michael S. Wiesener, Patrick H. Maxwell, Désiré Collen, Peter Carmeliet
Koen Brusselmans, Veerle Compernolle, Marc Tjwa, Michael S. Wiesener, Patrick H. Maxwell, Désiré Collen, Peter Carmeliet
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Article Vascular biology

Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia

Abstract

Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor–1α (HIF-1α), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2α is a homologue of HIF-1α and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2α–deficient (Hif2α+/–) mice after exposure to 10% O2 for 4 weeks. In contrast to WT mice, Hif2α+/– mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2α in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2α+/– mice after hypoxia, suggesting that HIF-2α–mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.

Authors

Koen Brusselmans, Veerle Compernolle, Marc Tjwa, Michael S. Wiesener, Patrick H. Maxwell, Désiré Collen, Peter Carmeliet

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(a) Western blot analysis showed that pulmonary HIF-2α protein levels we...
(a) Western blot analysis showed that pulmonary HIF-2α protein levels were decreased in Hif2α+/– mice compared with WT mice after normoxia (N) and after 1 week of hypoxia (H). Extracts from PC12 cells, exposed to normoxia or hypoxia (1% oxygen, 4 hours) as previously described (17, 26), were used as controls. (b) Systolic RV pressures in WT and Hif2α+/– mice under normoxia or after hypoxic exposure. Hemodynamic analysis revealed no differences in RV pressure under normoxia; however, WT mice showed increased RV pressure after 4 weeks of hypoxia, but Hif2α+/– mice did not. (c) RV hypertrophy analysis in WT and Hif2α+/– mice revealed no differences under normoxic conditions. After hypoxic exposure for 4 weeks, the ratio of the mass of the right ventricle to the mass of the left ventricle plus septum [RV/(LV+S)] was increased in WT mice but not in Hif2α+/– mice. (d) Pulmonary ET-1 transcript levels were increased in WT mice after exposure to chronic hypoxia for 6 days and were still elevated after 4 weeks of hypoxia. In contrast, chronic hypoxia failed to induce ET-1 expression in lungs of Hif2α+/– mice. Data represent means ± SEM of systolic RV pressure (mmHg; n = 4–7) (b), of the ratio of the mass of the right ventricle to the mass of the left ventricle plus septum [RV/(LV+S); n = 6–7] (c), and of the ET-1 mRNA copy number per 100 copies of HPRT (n = 5–6) (d). *Statistically significant (P < 0.05) vs. control (WT, normoxia).