Journal
CIRCULATION RESEARCH
Volume 105, Issue 6, Pages 537-544Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.109.205138
Keywords
oxidative stress; superoxide; NADPH oxidase
Funding
- Deutsche Forschungsgemeinschaft [SFB815/TP1, BR1839/3-2]
- excellence cluster cardio-pulmonary system (ECCPS)
- Schauffler-Stiftung
- Goethe-University
- European Vascular Genomic Network
- European Community [LSHM-CT-2003-503254]
Ask authors/readers for more resources
Rationale: Endothelial progenitor cells (EPCs, defined as sca-1(+)flk-1(+)lin(-) mononuclear blood cells) contribute to vascular repair. The role of hypoxia and reactive oxygen species (ROS) in mobilization and function of these cells is incompletely understood. Objective: We studied the contribution of the NADPH oxidase Nox2, an important vascular source of ROS in this context. Methods and Results: Hypoxia (10% oxygen) induced the mobilization of EPCs in wild-type (WT) and Nox1 but not in Nox2 knockout (Nox2(y/-)) mice. As erythropoietin (EPO) is known to induce EPC mobilization, we focused on this hormone. EPO induced the mobilization of EPCs in WT and Nox1(y/-) but not Nox2(y/-) animals. Transplantation of bone marrow from Nox2(y/-) mice into WT-mice blocked mobilization in response to hypoxia and EPO, whereas transplantation of WT bone marrow into Nox2(y/-) mice restored mobilization. Reendothelialization of the injured mouse carotid artery was enhanced by hypoxia as well as by EPO, and this effect was not observed in Nox2(y/-) mice or after transplantation of Nox2(y/-) bone marrow. In cultured EPCs from WT but not Nox2(y/-) mice, EPO induced ROS production, migration, and proliferation. EPO signaling involves the STAT5 transcription factor. EPO-induced STAT5-dependent reporter gene expression was absent in Nox2-deficient cells. siRNA against the redox-sensitive phosphatase SHP-2 restored EPO-mediated STAT5 induction and inhibition of SHP-2 restored EPO-induced migration in Nox2-deficient cells Conclusions: We conclude that Nox2-derived ROS inactivate SHP-2 and thereby facilitate EPO signaling in EPCs to promote hypoxia-induced mobilization and vascular repair by these cells. ( Circ Res. 2009; 105: 537-544.)
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available