Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells.
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.
Aicher
Alexandra
A
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Heeschen
Christopher
C
Mildner-Rihm
Christiane
C
Urbich
Carmen
C
Ihling
Christian
C
Technau-Ihling
Katja
K
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000818:Animals; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D007511:Ischemia / Q000628:therapy; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013234:Stem Cells / Q000502:physiology*
D004792:Enzyme Precursors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase