NADPH Oxidase Nox2 Is Required for Hypoxia-Induced Mobilization of Endothelial Progenitor Cells

Abstract

Key Words: oxidative stress Ⅲ superoxide Ⅲ NADPH oxidase L ocal hypoxia is a phenomenon observed in several disease processes. 1 Hypoxia stabilizes the transcription factor Hif-1 and thereby induces and promotes the expression of several genes containing hypoxia responsive elements in their regulatory region: proangiogenic factors like vascular endothelial growth factor (VEGF) or stromal-cell derived factor-1␣ (SDF-1␣, CXCL12), 2 vasoconstrictors like endothelin-1 as well as inflammation-associated genes such as inducible NO synthase 3 and Cox2. Many of these factors promote angiogenesis and wound healing and are thus critical for the response to local hypoxia and injury. 1 The Hif-1 system is also used to measure the systemic oxygen supply and to control the formation of red blood cells. This effect is mediated by the glycoprotein erythropoietin (EPO) which is mainly produced in the kidney and secreted into the blood, from where it reaches the bone marrow and supports the maturation of red blood cells. 4 EPO binds to a cytokine receptor which does not contain an intrinsic kinase domain. Rather, its signal transduction is mediated by JAK2 (Janus kinase) which phosphorylates tyrosine residues and thereby generates SH2 recognition sites at the EPO-receptor. Via these structures, among others, the signal transducer and activator of transcription 5 (STAT5) is recruited and activated. STAT5 subsequently dimerizes, translocates into the nucleus, and induces transcription. 5 Through this signaling pathway, EPO elicits a plethora of effects that are not just restricted to hematopoesis. EPO has strong organ-protective effects in the heart, the brain, and the kidney, it promotes reendothelialization, 6 and induces the mobilization of endothelial progenitor cells (EPCs). 7 EPCs are bone marrow-derived mononuclear cells which are lineage negative and express the surface markers stem cell antigen (sca-1) or CD34 and endothelial markers like the VEGF-receptor 2 (flk-1 in mice). Additionally, EPCs take up low-density lipoprotein and bind lectin. EPCs are known to contribute to vascular repair, although the exact mechanisms of the action of these cells are still under controversial discussion. Most likely EPCs enhance the reparative capacity of the endothelium adjacent to the injury by releasing paracrine factors. 8,9 Thus, the label EPCs is misleading. An exact denomination of EPC as sca-1ϩ flk-1ϩ, lineage negative monocytic mononuclear cells with vasculogenic potential and reparative capacity might be more appropriate-also to better acknowledge the complex role of these cells in the vasculature. However, as such a term would largely reduce the readability of the manuscript, we refer to these cells as EPCs in the present study. Before homing to sites of injury, EPCs have to be mobilized from the bone marrow into the peripheral blood, a process which often involves factors locally produced in the injured tissue like SDF-1␣, granulocyte colony stimulating factor, and VEGF. 10 Importantly, many of these factors are also hypoxia-...

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“…HIF-1 activates the transcription of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), and erythropoietin (EPO), which are important molecules inducing EPC mobilization (6,24). Beside these humoral factors it is reasonable to assume that reactive oxygen species generated by the NAD(P)H oxidase are essential for hypoxia or EPO-induced mobilization of EPCs (72). The exposure of C57Bl6 wild-type mice or Nox2 knockout (Nox2 Ϫ/Ϫ ) mice to hypoxia or EPO resulted in a significant mobilization in the wild-type animals but failed in the Nox2 Ϫ/Ϫ mice.…”

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“…Altro meccanismo importante nella mobilizzazione delle CEP dopo un singolo episodio di esercizio fisico massimale è quello rivestito dalle specie reattive dell'ossigeno generate dalla NADPH ossidasi in seguito all'ipossia [22].…”

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“…ROS regulated both angiogenic gene expression in ECs and vasculogenic gene expression in EPC [51]. Understanding these mechanisms may provide insight into NADPH oxidase and its mediators as potential therapeutic targets for chronic inflammatory disease.…”

“…It seems that this is required for preserving stemness, such as undifferentiated, self-renewal state [49]. It seems that oxidative stress increases circulating cytokine levels, thereby stimulating NADPH oxidase dependent ROS production in BM, which may promote reparative mobilization of EPC from BM and the resulting revascularization of synovial tissue [50,51].…”

“…Moreover there is strong evidence that EPC express eNOS-enzyme generating NO. The activity of this enzyme is regulated under inflamed conditions [51]. Compounds or molecules that increase eNOS expression improve EPC function, contrary to that the eNOS inhibitory substances have deleterious effects on EPC activity.…”