Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo

Tatyana N. Milovanova, Veena M. Bhopale, Elena M. Sorokina, Jonni S. Moore, Thomas K. Hunt, Martin Hauer-Jensen, Omaida C. Velazquez, Stephen R. Thom

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


We hypothesized that oxidative stress from hyperbaric oxygen (HBO 2, 2.8 ATA for 90 min daily) exerts a trophic effect on vasculogenic stem cells. In a mouse model, circulating stem/progenitor cell (SPC) recruitment and differentiation in subcutaneous Matrigel were stimulated by HBO2 and by a physiological oxidative stressor, lactate. In combination, HBO 2 and lactate had additive effects. Vascular channels lined by CD34+ SPCs were identified. HBO2 and lactate accelerated channel development, cell differentiation based on surface marker expression, and cell cycle entry. CD34+ SPCs exhibited increases in thioredoxin-1 (Trx1), Trx reductase, hypoxia-inducible factors (HIF)-1, -2, and -3, phosphorylated mitogen-activated protein kinases, vascular endothelial growth factor, and stromal cell-derived factor-1. Cell recruitment to Matrigel and protein synthesis responses were abrogated by N-acetyl cysteine, dithioerythritol, oxamate, apocynin, U-0126, neutralizing anti-vascular endothelial growth factor, or antistromal cell-derived factor-1 antibodies, and small inhibitory RNA to Trx reductase, lactate dehydrogenase, gp91 phox, HIF-1 or -2, and in mice conditionally null for HIF-1 in myeloid cells. By causing an oxidative stress, HBO2 activates a physiological redox-active autocrine loop in SPCs that stimulates vasculogenesis. Thioredoxin system activation leads to elevations in HIF-1 and -2, followed by synthesis of HIF-dependent growth factors. HIF-3 has a negative impact on SPCs.

Original languageEnglish (US)
Pages (from-to)711-728
Number of pages18
JournalJournal of applied physiology
Issue number2
StatePublished - Feb 2009


  • CD34
  • Hypoxia inducible factor-1
  • Hypoxia inducible factor-2
  • Hypoxia inducible factor-3
  • Mitogen-activated protein kinase
  • Stromal cell-derived factor-1
  • Thioredoxin
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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