Nature Medicine9, 1370 - 1376 (2003)
Published online: 12 October 2003; | doi:10.1038/nm948
There is an Erratum (September 2004) associated with this Article.
Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells
Alexandra Aicher1, 3, Christopher Heeschen1, 3, Christiane Mildner-Rihm1, Carmen Urbich1, Christian Ihling2, Katja Technau-Ihling2, Andreas M Zeiher1
& Stefanie Dimmeler1
1
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
2
Department of Pathology, University of Freiburg, Albertstrasse 19, 79104 Freiburg, Germany.
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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