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Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells

Nature Medicine volume 9, pages 1370–1376 (2003)Cite this article

An Erratum to this article was published on 01 September 2004

Abstract

Endothelial nitric oxide synthase (eNOS) is essential for neovascularization. Here we show that the impaired neovascularization in mice lacking eNOS is related to a defect in progenitor cell mobilization. Mice deficient in eNOS (Nos3−/−) show reduced vascular endothelial growth factor (VEGF)-induced mobilization of endothelial progenitor cells (EPCs) and increased mortality after myelosuppression. Intravenous infusion of wild-type progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization of Nos3−/− mice in a model of hind-limb ischemia, suggesting that progenitor mobilization from the bone marrow is impaired in Nos3−/− mice. Mechanistically, matrix metalloproteinase-9 (MMP-9), which is required for stem cell mobilization, was reduced in the bone marrow of Nos3−/− mice. These findings indicate that eNOS expressed by bone marrow stromal cells influences recruitment of stem and progenitor cells. This may contribute to impaired regeneration processes in ischemic heart disease patients, who are characterized by a reduced systemic NO bioactivity.

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Figure 1: In vivo recruitment of hematopoietic stem cells and EPCs into the circulation.
Figure 2: Rescue of impaired angiogenic phenotype in eNOS-deficient mice by intravenous (i.v.) injection of wild-type cells.
Figure 3: Incorporation of infused CellTracker-labeled BMCs into the vascular structures of limb muscles of Nos3−/− mice on day 7 after induction of ischemia.
Figure 4: Bone marrow transplantation of wild-type cells does not rescue the impaired angiogenic phenotype of Nos3−/− mice.
Figure 5: In vitro characterization of hematopoietic stem cells from Nos3−/− and wild-type (WT) bone marrow.
Figure 6: Molecules involved in stem and progenitor cell mobilization.

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Acknowledgements

We thank M. Muhly-Reinholz, S. Rhiel, T. Röxe and A. Knau for their excellent technical assistance, and H.E. Schaefer (University of Freiburg) for helpful discussion. This work was supported by the Sonderforschungsbereich (SFB 553) and the Alfried Krupp-Stiftung to S.D.

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  1. Alexandra Aicher and Christopher Heeschen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine IV, Molecular Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany

    Alexandra Aicher, Christopher Heeschen, Christiane Mildner-Rihm, Carmen Urbich, Andreas M Zeiher & Stefanie Dimmeler

  2. Department of Pathology, University of Freiburg, Albertstrasse 19, Freiburg, 79104, Germany

    Christian Ihling & Katja Technau-Ihling

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  1. Alexandra Aicher
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Correspondence to Stefanie Dimmeler.

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Aicher, A., Heeschen, C., Mildner-Rihm, C. et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9, 1370–1376 (2003). https://doi.org/10.1038/nm948

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