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-...
Hepatocyte growth factor (HGF) promotes angiogenesis and prevents senescence of endothelial cells. Reactive oxygen species (ROS) play an essential role in angiogenesis. One of the most important sources of acutely induced ROS‐production are the members of the NADPH oxidase (Nox) family, in endothelial cells namely Nox2. The angiogenetic potential induced by HGF depends on Nox2. The ability of HGF to induce aortic ring outgrowth was significantly reduced in aortic rigs of Nox2 deficient (Nox2y/‐) mice when compared to wildtype mice. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow into peripheral blood has been suggested to be an essential step in the formation of new vessels. Indeed HGF induced mobilization of EPCs in wildtype mice. This effect of HGF was blocked in Nox2y/‐ mice. Accordingly in wildtype mice HGF induced colony forming unit formation which was absent in Nox2y/‐ mice. In human EPCs HGF acutely induced the production of hydrogen peroxide measured by Amplex Red. After depletion of Nox2‐expression by antisense‐oligonucleotides no HGF inducible ROS production was detectable. Further analyses revealed an HGF inducible phosphorylation of Jak2 and STAT3 which was absent in Nox2 depleted cells.We conclude that EPC mobilization might contribute to the angiogenetic effects of HGF. Nox2 derived ROS play an essential role in HGF inducible EPC‐mobilization and aortic ring outgrowth.
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