title: Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension.
abstract: Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida andrew.bryant@medicine.ufl.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bryant
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Carrick
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Melinda E
authors.initials: ME
authors.lastname: McConaha
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Brittany R
authors.initials: BR
authors.lastname: Jones
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Sheila D
authors.initials: SD
authors.lastname: Shay
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Christy S
authors.initials: CS
authors.lastname: Moore
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Blackwell
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Santhi
authors.initials: S
authors.lastname: Gladson
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Niki L
authors.initials: NL
authors.lastname: Penner
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Ankita
authors.initials: A
authors.lastname: Burman
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tanjore
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Ayub K
authors.initials: AK
authors.lastname: Karwandyar
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Megha A
authors.initials: MA
authors.lastname: Talati
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Hui-Jia
authors.initials: HJ
authors.lastname: Dong
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Carrier
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Christa
authors.initials: C
authors.lastname: Gaskill
authors.affiliation: Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, Florida; and.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Scott
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Susan M
authors.initials: SM
authors.lastname: Majka
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Fessel
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Volker H
authors.identifier: http://orcid.org/0000-0002-7051-8994
authors.initials: VH
authors.lastname: Haase
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: James D
authors.initials: JD
authors.lastname: West
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Veterans Affairs Medical Center, Nashville, Tennessee; and.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Veterans Affairs Medical Center, Nashville, Tennessee; and.
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D066253:Vascular Remodeling / Q000502:physiology
chemical_list: D051793:Hypoxia-Inducible Factor 1
keywords: connective tissue growth factor; hypoxia-inducible factor; idiopathic pulmonary fibrosis; pulmonary hypertension; pulmonary vascular disease