HIF2α-arginase axis is essential for the development of pulmonary hypertension.

Change log
Cowburn, Andrew S 
Crosby, Alexi 
Macias, David 
Mendes Branco, Cristina Branco  ORCID logo  https://orcid.org/0000-0001-6953-4922
Colaço, Renato DDR 

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 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. 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 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 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 new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

HIF, hypertension, hypoxia, pulmonary, Animals, Arginase, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Cells, Cultured, Endothelium, Vascular, Humans, Hypertension, Pulmonary, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nitric Oxide, Ventricular Function, Right, Ventricular Pressure
Journal Title
Proc Natl Acad Sci U S A
Conference Name
Journal ISSN
Volume Title
Proceedings of the National Academy of Sciences
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (092738/Z/10/Z)
British Heart Foundation (None)
British Heart Foundation (None)