Pulmonary endothelial HIF2$\alpha$-arginase axis plays an essential role in the development of hypoxia pulmonary hypertension

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Cowburn, Andrew S 
Crosby, Alexi 
Macias, David 
Branco, Cristina 
Colaço, Renato 

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodelling. The hypoxia-inducible transcription factors (HIFs), HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodelling; however, the specific role of pulmonary endothelial HIF 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 (PAH). The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic wild type (WT) mice and much 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 protected mice from hypoxia remodelling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with HPH. 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 new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.


This is the author accepted manuscript. The final version is available from the Proceedings of the National Academy of Sciences (PNAS) via https://doi.org/10.1073/pnas.1602978113

HIF2$\alpha$, arginase-1, pulmonary-endothelium, nitric oxide
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Proceedings of the National Academy of Sciences (PNAS)
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Proceedings of the National Academy of Sciences
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This study was funded by The Wellcome Trust, Papworth Hospital NIHR Cambridge Biomedical Research Centre.