Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils
Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils
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DOI：
10.1096/fj.04-3496fje
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发表时间：
2005-10-01
期刊：
影响因子：
4.8
通讯作者：
Ohsaka, A
中科院分区：
文献类型：
--
作者：
Ohki, Y;Heissig, B;Ohsaka, A
粒细胞集落刺激因子（G-CSF）促进血管生成。然而，确切的机制尚不清楚。我们证明血管内皮生长因子（VEGF）在体外和体内由GCSF预刺激的Gr-1(+) CD11b（-）中性粒细胞释放，而不是Gr-1(-)CD11b（+）单核细胞释放。同样，在体内，伴随着循环中中性粒细胞数量的增加，G-CSF增加了体内血浆VEGF水平。局部给予缺血组织G-CSF增加毛细血管密度，提供功能血管，促进缺血组织新生血管。阻断VEGF通路可消除g - csf诱导的血管生成。另一方面，正如我们之前所显示的，VEGF可以诱导内皮祖细胞（EPC）动员。在这里，我们发现与未治疗的对照组相比，G-CSF也增加了循环VEGF受体-2 (VEGFR2) EPCs的数量。阻断VEGF/VEGFR1通路，但在较小程度上，gcsf处理动物的VEGF/VEGFR2通路延迟了后肢模型的组织血运重建。这些数据清楚地表明，G-CSF通过增加骨髓单核细胞（VEGFR1（+）中性粒细胞）及其VEGF的释放来调节血管生成。我们的研究结果表明，在缺血组织中给予G-CSF提供了一种新的、安全的治疗策略来改善新生血管。
The granulocyte colony-stimulating factor (G-CSF) promotes angiogenesis. However, the exact mechanism is not known. We demonstrate that vascular endothelial growth factor ( VEGF) was released by Gr-1(+) CD11b(-) neutrophils but not Gr-1(-)CD11b(+) monocytes prestimulated with GCSF in vitro and in vivo. Similarly, in vivo, concomitant with an increase in neutrophil numbers in circulation, G-CSF augmented plasma VEGF level in vivo. Local G-CSF administration into ischemic tissue increased capillary density and provided a functional vasculature and contributed to neovascularization of ischemic tissue. Blockade of the VEGF pathway abrogated G-CSF-induced angiogenesis. On the other hand, as we had shown previously, VEGF can induce endothelial progenitor cell ( EPC) mobilization. Here, we show that G-CSF also augmented the number of circulating VEGF receptor-2 (VEGFR2) EPCs as compared with untreated controls. Blocking the VEGF/VEGFR1, but to a much lesser extent, the VEGF/VEGFR2 pathway in GCSF-treated animals delayed tissue revascularization in a hindlimb model. These data clearly show that G-CSF modulates angiogenesis by increasing myelomonocytic cells (VEGFR1(+) neutrophils) and their release of VEGF. Our results indicated that administration of G-CSF into ischemic tissue provides a novel and safe therapeutic strategy to improve neovascularization.