title: The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice.
abstract: Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (∼118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2α but not HIF-1α. Furthermore, endothelial HIF-2α was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.
authors.affiliation: Departments of Medicine, Anatomy, and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA pkapitsinou@kumc.edu.
authors.forename: Pinelopi P
authors.initials: PP
authors.lastname: Kapitsinou
authors.affiliation: Departments of Medicine, Anatomy, and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Ganeshkumar
authors.initials: G
authors.lastname: Rajendran
authors.affiliation: Departments of Medicine, Anatomy, and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Astleford
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Michael
authors.affiliation: Departments of Medicine, Anatomy, and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schonfeld
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fields
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shay
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Jaketa L
authors.initials: JL
authors.lastname: French
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: James
authors.initials: J
authors.lastname: West
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Medicine and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011651:Pulmonary Artery / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C485502:HIF-2 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases