Hypoxia-induced activin A diminishes endothelial cell vasculogenic activity

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 1 2018
Externally publishedYes

Fingerprint

Endothelial Cells
Stromal Cells
Cell Survival
Inhibins
Coculture Techniques
Blood Vessels
Hypoxia
activin A
Up-Regulation
Follistatin
Tissue Preservation
Deferoxamine
Conditioned Culture Medium
Ischemia
Cell Count
Oxygen
Muscles
Messenger RNA

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

Hypoxia-induced activin A diminishes endothelial cell vasculogenic activity. / Merfeld-Clauss, Stephanie; Lu, Hongyan; Wu, Xue; March, Keith L.; Traktuev, Dmitry.

In: Journal of Cellular and Molecular Medicine, Vol. 22, No. 1, 01.01.2018, p. 173-184.

Research output: Contribution to journalArticle

Merfeld-Clauss, Stephanie ; Lu, Hongyan ; Wu, Xue ; March, Keith L. ; Traktuev, Dmitry. / Hypoxia-induced activin A diminishes endothelial cell vasculogenic activity. In: Journal of Cellular and Molecular Medicine. 2018 ; Vol. 22, No. 1. pp. 173-184.
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