Hypoxia results in upregulation and de novo activation of von willebrand factor expression in lung endothelial cells

Anahita Mojiri, Maryam Nakhaii-Nejad, Wei Lee Phan, Stephen Kulak, Aneta Radziwon-Balicka, Paul Jurasz, Evangelos Michelakis, Nadia Jahroudi

Research output: Contribution to journalArticle

29 Scopus citations

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. Approach and 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.

Original languageEnglish (US)
Pages (from-to)1329-1338
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number6
DOIs
StatePublished - Jun 1 2013

Keywords

  • Endothelial cell
  • Hypoxia
  • Nuclear factor-IB
  • Von Willebrand factor
  • YY1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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