title: Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α.
abstract: BACKGROUND
  Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1α allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified.
  
  
  OBJECTIVE
  We sought to determine the contribution of HIF-1α in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia.
  
  
  METHODS
  We used mice with homozygous conditional deletion of HIF-1α combined with tamoxifen-inducible smooth muscle-specific Cre recombinase expression. Mice received either tamoxifen or vehicle followed by exposure to either normoxia or chronic hypoxia (10% O2) for 30 days before measurement of cardiopulmonary responses.
  
  
  RESULTS
  Tamoxifen-induced smooth muscle-specific deletion of HIF-1α attenuated pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, right ventricular hypertrophy was unchanged despite attenuated pulmonary pressures.
  
  
  CONCLUSIONS
  These results indicate that HIF-1α in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.
authors.affiliation: 1 Department of Pediatrics and.
authors.forename: Molly K
authors.initials: MK
authors.lastname: Ball
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Waypa
authors.forename: Paul T
authors.initials: PT
authors.lastname: Mungai
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Nielsen
authors.forename: Lyubov
authors.initials: L
authors.lastname: Czech
authors.forename: V Joseph
authors.initials: VJ
authors.lastname: Dudley
authors.forename: Lauren
authors.initials: L
authors.lastname: Beussink
authors.forename: Robert W
authors.initials: RW
authors.lastname: Dettman
authors.forename: Sara K
authors.initials: SK
authors.lastname: Berkelhamer
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D002908:Chronic Disease; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit