Hypoxia-induced activin A diminishes endothelial cell vasculogenic activity

Stephanie Merfeld-Clauss, Hongyan Lu, Xue Wu, Keith March, Dmitry O. Traktuev

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Acute ischaemia causes a significant loss of blood vessels leading to deterioration of organ function. Multiple ischaemic conditions are associated with up-regulation of activin A, but its effect on endothelial cells (EC) in the context of hypoxia is understudied. This study evaluated the role of activin A in vasculogenesis in hypoxia. An in vitro vasculogenesis model, in which EC were cocultured with adipose stromal cells (ASC), was used. Incubation of cocultures at 0.5% oxygen led to decrease in EC survival and vessel density. Hypoxia up-regulated inhibin BA (monomer of activin A) mRNA by 4.5-fold and activin A accumulation in EC-conditioned media by 10-fold, but down-regulated activin A inhibitor follistatin by twofold. Inhibin BA expression was also increased in human EC injected into ischaemic mouse muscles. Activin A secretion was positively modulated by hypoxia mimetics dimethyloxalylglycine and desferrioxamine. Silencing HIF1α or HIF2α expression decreased activin A secretion in EC exposed to hypoxia. Introduction of activin A to cocultures decreased EC number and vascular density by 40%; conversely, blockade of activin A expression in EC or its activity improved vasculogenesis in hypoxia. Activin A affected EC survival directly and by modulating ASC paracrine activity leading to diminished ability of the ASC secretome to support EC survival and vasculogenesis. In conclusion, hypoxia up-regulates EC secretion of activin A, which, by affecting both EC and adjacent mesenchymal cells, creates a micro-environment unfavourable for vasculogenesis. This finding suggests that blockade of activin A signalling in ischaemic tissue may improve preservation of the affected tissue.

Original languageEnglish (US)
Pages (from-to)173-184
Number of pages12
JournalJournal of Cellular and Molecular Medicine
Volume22
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • activin A
  • adipose stem/stromal cells
  • coculture
  • endothelial cells
  • hypoxia inducible factor
  • vasculogenesis

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Fingerprint Dive into the research topics of 'Hypoxia-induced activin A diminishes endothelial cell vasculogenic activity'. Together they form a unique fingerprint.

  • Cite this