Endothelial Progenitor Cell Release into Circulation Is Triggered by Hyperoxia‐Induced Increases in Bone Marrow Nitric Oxide

Abstract

Endothelial progenitor cells (EPC) are known to contribute to wound healing, but the physiologic triggers for their mobilization are often insufficient to induce complete wound healing in the presence of severe ischemia. EPC trafficking is known to be regulated by hypoxic gradients and induced by vascular endothelial growth factor-mediated increases in bone marrow nitric oxide (NO). Hyperbaric oxygen (HBO) enhances wound healing, although the mechanisms for its therapeutic effects are incompletely understood. It is known that HBO increases nitric oxide levels in perivascular tissues via stimulation of nitric oxide synthase (NOS). Here we show that HBO increases bone marrow NO in vivo thereby increasing release of EPC into circulation. These effects are inhibited by pretreatment with the NOS inhibitor L-nitroarginine methyl ester (L-NAME). HBO-mediated mobilization of EPC is associated with increased lower limb spontaneous circulatory recovery after femoral ligation and enhanced closure of ischemic wounds, and these effects on limb perfusion and wound healing are also inhibited by L-NAME pretreatment. These data show that EPC mobilization into circulation is triggered by hyperoxia through induction of bone marrow NO with resulting enhancement in ischemic limb perfusion and wound healing. STEM CELLS 2006;24:2309 -2318

Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo

“…Our laboratory has reported that HBO 2 stimulates SPC mobilization by activating bone marrow nitric oxide synthase (15,60). The CD34 ϩ blood cell counts (Table 4) are consistent with this observation.…”

“…In animal models, mobilized SPCs are recruited to wounds and accelerate healing (13,15). While this response may arise because of the increased numbers of circulating SPCs, cell number alone does not necessarily reflect increased cell recruitment and vasculogenesis at peripheral sites (42).…”

“…These growth factors, and others, are synthesized by local endothelial cells, perivascular myofibroblasts, keratinocytes, macrophages, bone marrow-derived hemangiocytes, and endothelial progenitor cells recruited to peripheral sites (17,25,39,54,56). Growth factors influence the efficiency of new blood vessel growth by angiogenesis involving local endothelial cells, and they stimulate the recruitment and differentiation of circulating SPCs to form vessels by de novo vasculogenesis (15,22,50,57,62,70).…”

Lactate Stimulates Vasculogenic Stem Cells via the Thioredoxin System and Engages an Autocrine Activation Loop Involving Hypoxia-Inducible Factor 1

“…These growth factors, and others, are synthesized by local endothelial cells, perivascular myofibroblasts, keratinocytes, macrophages, bone marrow-derived hemangiocytes, and endothelial progenitor cells (EPCs) recruited to the wound site (18,25,33,43,45). Growth factors influence the efficiency of new blood vessel growth by angiogenesis involving local endothelial cells, and they stimulate the recruitment and differentiation of circulating SPCs to form vessels by vasculogenesis (15,22,39,46,50,58). Endothelial cells respond to lactate by increasing the synthesis of VEGF in a process that may involve the stabilization of HIF-1 (23).…”

Oxygen: Implications for Wound Healing

“…NO subsequently enhances the mobilization of EPCs, which home to the wound and contribute to the formation of neovessels. 15 Further, HBOT is involved in fibroblast activation, the up-regulation of growth factors, the reduction of the inflammatory response, and wound disinfection. 6 It is these data that that lend support to the utilization of HBOT as an adjunctive care measure for diabetic lower extremity ulcers.…”