Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo.
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 HBO(2) and by a physiological oxidative stressor, lactate. In combination, HBO(2) and lactate had additive effects. Vascular channels lined by CD34(+) SPCs were identified. HBO(2) 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, HBO(2) 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.
Milovanova
Tatyana N
TN
Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6068, USA.
Bhopale
Veena M
VM
Sorokina
Elena M
EM
Moore
Jonni S
JS
Hunt
Thomas K
TK
Hauer-Jensen
Martin
M
Velazquez
Omaida C
OC
Thom
Stephen R
SR
D043924:Angiogenesis Modulating Agents / Q000494:pharmacology; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019898:Autocrine Communication; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005978:Glutathione / Q000378:metabolism; D006931:Hyperbaric Oxygenation; D051793:Hypoxia-Inducible Factor 1 / Q000172:deficiency / Q000235:genetics; D019344:Lactic Acid / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000098:blood supply*; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors
D043924:Angiogenesis Modulating Agents; D042501:Angiogenic Proteins; D000975:Antioxidants; D015415:Biomarkers; D004338:Drug Combinations; D051793:Hypoxia-Inducible Factor 1; D007797:Laminin; D011509:Proteoglycans; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C059485:matrigel; D019344:Lactic Acid; D013879:Thioredoxins; D003094:Collagen; D005978:Glutathione