Nitric oxide differentially regulates proliferation and mobilization of endothelial progenitor cells but not of hematopoietic stem cells

Summary

To investigate the role of nitric oxide in controlling endothelial progenitor (EPC) and hematopoietic stem cell (HSC) mobilization, wild-type mice, L-NAME treated WT and eNOS-/- mice received either PBS or G-CSF for 5 days. Under unstimulated conditions bone marrow of either L-NAME treated WT and eNOS-/- mice, representing acute and chronic NO-deficiency, showed higher CD34⁺Flk-1⁺ EPC numbers compared to their WT littermates. Furthermore, CD34⁺Flk-1⁺ progenitors under NO-deficient conditions showed a higher cell turn over since the proliferation and apoptosis activity underin vivo as well as in vitro conditions were enhanced. In line with this finding bone marrow derived EPC differentiation towards endothelial cells was modulated in an NO-dependent manner. Administration of G-CSF resulted in an increase of EPC within the bone marrow of WT animals with a consecutive release of these cells into the peripheral circulation. Under NO-deficient conditions G-CSF failed to increase EPC numbers. In contrast, the HSC population c-kit⁺Lin⁻ was not influenced by nitric oxide. Thus, NO differentially supports the mobilization of the endothelial committed progenitor subpopulation in bone marrow but does not have an effect on HSCin vivo.

Keywords

Nitric oxide - vasculogenesis - cytokines

^* Both authors contributed equally

• References

• 1 Asahara T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-7.
• 2 Vasa M. et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89: E1-E7.
• 3 Heiss C. et al. Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol 2005; 45: 1441-8.
• 4 Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 2004; 95: 343-53.
• 5 Reya T. et al. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105-11.
• 6 Balsam LB. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004; 428: 668-73.
• 7 Kalka C. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 2000; 97: 3422-7.
• 8 Murohara T. et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest 1998; 101: 2567-78.
• 9 Aicher A. et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003; 9: 1370-6.
• 10 Laufs U. et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 2004; 109: 220-6.
• 11 Dai C. et al. Increased erythropoiesis in polycythemia vera is associated with increased erythroid progenitor proliferation and increased phosphorylation of Akt/PKB. Exp Hematol 2005; 33: 152-8.
• 12 Bruhl T. et al. p21Cip1 levels differentially regulate turnover of mature endothelial cells, endothelial progenitor cells, andin vivo neovascularization. Circ Res 2004; 94: 686-92.
• 13 Punjabi CJ. et al. Production of nitric oxide by murine bone marrow cells. Inverse correlation with cellular proliferation. J Immunol 1992; 149: 2179-84.
• 14 Michurina T. et al. Nitric oxide is a regulator of hematopoietic stem cell activity. Mol Ther 2004; 10: 241-8.