HIF2α–arginase axis is essential for the development of pulmonary hypertension

Andrew S. Cowburn, Alexi Crosby, David Macias, Cristina Branco, Renato D. D. R. Colaço, Mark Southwood, Mark Toshner, Laura E. Crotty Alexander, Nicholas W. Morrell, Edwin R. Chilvers, Randall S. Johnson

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Abstract

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmo- nary endothelialHIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endo- thelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endotheliumafter exposure to hypoxia was not significantly different from normoxicWT mice andmuch lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also pro- tected mice fromhypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer newinsight into the role of pulmonary endothelialHIF-2α in regulating the pulmonary vascular response to hypoxia.
Original languageEnglish
Pages (from-to)8801-8806
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume113
Issue number31
Early online date18 Jul 2016
DOIs
Publication statusPublished - 02 Aug 2016

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    Cowburn, A. S., Crosby, A., Macias, D., Branco, C., Colaço, R. D. D. R., Southwood, M., Toshner, M., Crotty Alexander, L. E., Morrell, N. W., Chilvers, E. R., & Johnson, R. S. (2016). HIF2α–arginase axis is essential for the development of pulmonary hypertension. Proceedings of the National Academy of Sciences, 113(31), 8801-8806. https://doi.org/10.1073/pnas.1602978113, https://doi.org/10.1073/pnas.1602978113