title: Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation.
abstract: BACKGROUND
  Hypoxia-inducible factor-1α (HIF-1α), an oxygen (O2)-sensitive transcription factor, mediates transcriptional responses to low-O2 tension states. Although acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia can cause vascular remodeling and pulmonary hypertension, conflicting data exist on the role of HIF-1α in modulating pulmonary vascular tone.
  
  
  OBJECTIVE
  To investigate the role of smooth muscle cell (SMC)-specific HIF-1α in regulating pulmonary vascular tone.
  
  
  RESULTS
  Mice with an SMC-specific deletion of HIF-1α (SM22α-HIF-1α(-/-)) were created to test the hypothesis that pulmonary artery SMC (PASMC) HIF-1α modulates pulmonary vascular tone and the response to hypoxia. SM22α-HIF-1α(-/-) mice exhibited significantly higher right ventricular systolic pressure compared with wild-type littermates under normoxia and with exposure to either acute or chronic hypoxia in the absence of histological evidence of accentuated vascular remodeling. Moreover, myosin light chain phosphorylation, a determinant of SMC tone, was higher in PASMCs isolated from SM22α-HIF-1α(-/-) mice compared with wild-type PASMCs, during both normoxia and after acute hypoxia. Further, overexpression of HIF-1α decreased myosin light chain phosphorylation in HIF-1α-null SMCs.
  
  
  CONCLUSIONS
  In both normoxia and hypoxia, PASMC HIF-1α maintains low pulmonary vascular tone by decreasing myosin light chain phosphorylation. Compromised PASMC HIF-1α expression may contribute to the heightened vasoconstriction that characterizes pulmonary hypertension.
authors.affiliation: Department of Pediatrics, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Yu-Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Barnes
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alvira
authors.forename: Lihua
authors.initials: L
authors.lastname: Ying
authors.forename: Sushma
authors.initials: S
authors.lastname: Reddy
authors.forename: David N
authors.initials: DN
authors.lastname: Cornfield
mesh_terms: D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000378:metabolism*; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D014661:Vasoconstriction
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018994:Myosin Light Chains; C051615:transgelin