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

Brusselmans, K; Compernolle, V; Tjwa, M; Wiesener, MS; Maxwell, PH; Collen, D; Carmeliet, P; (2003) Heterozygous deficiency of hypoxia-inducible factor-2 alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J CLIN INVEST , 111 (10) 1519 - 1527. 10.1172/JCI200315496.

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Abstract

Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor-la (HIF-1alpha), 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-2alpha is a homologue of HIF-1alpha 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-2alpha-deficient (Hif2alpha(+/-)) mice after exposure to 10% O-2 for 4 weeks. In contrast to WT mice, Hif2alpha(+/-) mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2a 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 Hif2alpha(+/-) mice after hypoxia, suggesting that HIF-2alpha-mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.

Type:Article
Title:Heterozygous deficiency of hypoxia-inducible factor-2 alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia
DOI:10.1172/JCI200315496
Keywords:ENDOTHELIAL GROWTH-FACTOR, NITRIC-OXIDE SYNTHASE, TRANSCRIPTION FACTOR, GENE-TRANSFER, VASCULAR DEVELOPMENT, FACTOR 1-ALPHA, LUNG, DISEASE, RAT, NOREPINEPHRINE
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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