Aicher Alexandra, Heeschen Christopher, Mildner-Rihm Christiane, Urbich Carmen, Ihling Christian, Technau-Ihling Katja, Zeiher Andreas M, Dimmeler Stefanie
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Nat Med. 2003 Nov;9(11):1370-6. doi: 10.1038/nm948. Epub 2003 Oct 12.
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.
内皮型一氧化氮合酶（eNOS）对新血管形成至关重要。在此我们表明，缺乏eNOS的小鼠中血管生成受损与祖细胞动员缺陷有关。缺乏eNOS（Nos3(-/-)）的小鼠显示血管内皮生长因子（VEGF）诱导的内皮祖细胞（EPCs）动员减少，且骨髓抑制后死亡率增加。在一个后肢缺血模型中，静脉输注野生型祖细胞而非骨髓移植可挽救Nos3(-/-)小鼠的血管生成缺陷，这表明Nos3(-/-)小鼠中骨髓来源的祖细胞动员受损。从机制上讲，干细胞动员所需的基质金属蛋白酶-9（MMP-9）在Nos3(-/-)小鼠的骨髓中减少。这些发现表明，骨髓基质细胞表达的eNOS影响干细胞和祖细胞的募集。这可能导致缺血性心脏病患者再生过程受损，这类患者的特征是全身一氧化氮生物活性降低。
