title: Hypoxia results in upregulation and de novo activation of von Willebrand factor expression in lung endothelial cells.
abstract: OBJECTIVE
  Increased von Willebrand factor (VWF) levels in lungs are associated with diseases such as pulmonary hypertension. The objective of our study was to determine the mechanism of increased VWF levels in conditions, such as hypoxia, which contribute to pulmonary hypertension.
  
  
  RESULTS
  We have previously reported generation of transgenic mice that express LacZ transgene under the regulation of lung- and brain-specific transcriptional regulatory elements of the VWF gene. Hypoxia exposure of these transgenic mice resulted in increased VWF and LacZ mRNA levels as well as redistribution of their expression from primarily larger vessels in the lungs to microvessels. Exposure of cultured lung microvascular endothelial cells to hypoxia demonstrated that VWF upregulation was accompanied by increased platelet binding. Transcription upregulation was mediated through inhibition of the repressor nuclear factor-IB association with the VWF promoter, and increased nuclear translocation of the transcription factor YY1 and association with its cognate binding site on the VWF gene. Knockdown of YY1 expression abolished the hypoxia-induced upregulation and reduced basal level of VWF.
  
  
  CONCLUSIONS
  These analyses demonstrate that hypoxia induces a phenotypic shift, accompanied by modulation of nuclear factor-IB and YY1 activities, in microvascular endothelial cells of the lungs to support VWF promoter activation.
authors.affiliation: Departments of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Anahita
authors.initials: A
authors.lastname: Mojiri
authors.forename: Maryam
authors.initials: M
authors.lastname: Nakhaii-Nejad
authors.forename: Wei-Lee
authors.initials: WL
authors.lastname: Phan
authors.forename: Stephen
authors.initials: S
authors.lastname: Kulak
authors.forename: Aneta
authors.initials: A
authors.lastname: Radziwon-Balicka
authors.forename: Paul
authors.initials: P
authors.lastname: Jurasz
authors.forename: Evangelos
authors.initials: E
authors.lastname: Michelakis
authors.forename: Nadia
authors.initials: N
authors.lastname: Jahroudi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics* / Q000503:physiopathology; D007763:Lac Operon / Q000235:genetics*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015854:Up-Regulation; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D014841:von Willebrand Factor
keywords: YY1; endothelial cell; hypoxia; nuclear factor-IB; von Willebrand factor