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The Physiology and Pathophysiology of the Hyperbaric and Diving Environments

Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo

¹Institute for Environmental Medicine, Departments of ²Pathology and Laboratory Medicine and ⁶Emergency Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; ³Department of Surgery, University of California at San Francisco, San Francisco, California; ⁴Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and ⁵Department of Surgery, University of Miami, Miami, Florida

Submitted 5 August 2008 ; accepted in final form 14 November 2008

We hypothesized that oxidative stress from hyperbaric oxygen (HBO₂, 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, HBO₂ 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 anti-stromal 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.

CD34; thioredoxin; hypoxia inducible factor-1; hypoxia inducible factor-2; hypoxia inducible factor-3; mitogen-activated protein kinase; vascular endothelial growth factor; stromal cell-derived factor-1