title: HIF2α-arginase axis is essential for the development of pulmonary hypertension.
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 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.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, United Kingdom; asc32@medschl.cam.ac.uk rsj33@cam.ac.uk.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cowburn
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, United Kingdom;
authors.forename: Alexi
authors.initials: A
authors.lastname: Crosby
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Macias
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
authors.forename: Cristina
authors.initials: C
authors.lastname: Branco
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
authors.forename: Renato D D R
authors.initials: RD
authors.lastname: Colaço
authors.affiliation: Department of Pathology, Papworth Hospital National Health Service Foundation Trust, Cambridge CB23 3RE, United Kingdom;
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, United Kingdom;
authors.forename: Mark
authors.initials: M
authors.lastname: Toshner
authors.affiliation: Division of Pulmonary and Critical Care, School of Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Laura E
authors.initials: LE
authors.lastname: Crotty Alexander
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, United Kingdom;
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, United Kingdom;
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm SE-171 77, Sweden asc32@medschl.cam.ac.uk rsj33@cam.ac.uk.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D016278:Ventricular Function, Right / Q000235:genetics / Q000502:physiology; D017725:Ventricular Pressure / Q000235:genetics / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D001119:Arginase; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide; D000099162:Endothelial PAS Domain-Containing Protein 1; C544448:Arg1 protein, mouse
keywords: HIF; hypertension; hypoxia; pulmonary