Heissig Beate, Rafii Shahin, Akiyama Haruyo, Ohki Yuichi, Sato Yayoi, Rafael Tejada, Zhu Zhenping, Hicklin Daniel J, Okumura Ko, Ogawa Hideoki, Werb Zena, Hattori Koichi
Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
J Exp Med. 2005 Sep 19;202(6):739-50. doi: 10.1084/jem.20050959. Epub 2005 Sep 12.
Mast cells accumulate in tissues undergoing angiogenesis during tumor growth, wound healing, and tissue repair. Mast cells can secrete angiogenic factors such as vascular endothelial growth factor (VEGF). Ionizing irradiation has also been shown to have angiogenic potential in malignant and nonmalignant diseases. We observed that low-dose irradiation fosters mast cell-dependent vascular regeneration in a limb ischemia model. Irradiation promoted VEGF production by mast cells in a matrix metalloproteinase-9 (MMP-9)-dependent manner. Irradiation, through MMP-9 up-regulated by VEGF in stromal and endothelial cells, induced the release of Kit-ligand (KitL). Irradiation-induced VEGF promoted migration of mast cells from the bone marrow to the ischemic site. Irradiation-mediated release of KitL and VEGF was impaired in MMP-9-deficient mice, resulting in a reduced number of tissue mast cells and delayed vessel formation in the ischemic limb. Irradiation-induced vasculogenesis was abrogated in mice deficient in mast cells (steel mutant, Sl/Sl(d) mice) and in mice in which the VEGF pathway was blocked. Irradiation did not induce progenitor mobilization in Sl/Sl(d) mice. We conclude that increased recruitment and activation of mast cells following irradiation alters the ischemic microenvironment and promotes vascular regeneration in an ischemia model. These data show a novel mechanism of neovascularization and suggest that low-dose irradiation may be used for therapeutic angiogenesis to augment vasculogenesis in ischemic tissues.
在肿瘤生长、伤口愈合和组织修复过程中，肥大细胞会在发生血管生成的组织中聚集。肥大细胞可分泌血管生成因子，如血管内皮生长因子（VEGF）。电离辐射在恶性和非恶性疾病中也已显示出具有血管生成潜力。我们观察到，在肢体缺血模型中，低剂量辐射可促进肥大细胞依赖性血管再生。辐射以基质金属蛋白酶-9（MMP-9）依赖的方式促进肥大细胞产生VEGF。辐射通过基质细胞和内皮细胞中由VEGF上调的MMP-9，诱导Kit配体（KitL）的释放。辐射诱导的VEGF促进肥大细胞从骨髓迁移至缺血部位。在MMP-9缺陷小鼠中，辐射介导的KitL和VEGF释放受损，导致缺血肢体中组织肥大细胞数量减少和血管形成延迟。在肥大细胞缺陷小鼠（钢突变体，Sl/Sl(d)小鼠）和VEGF途径被阻断的小鼠中，辐射诱导的血管生成被消除。辐射未在Sl/Sl(d)小鼠中诱导祖细胞动员。我们得出结论，辐射后肥大细胞募集和激活增加会改变缺血微环境，并在缺血模型中促进血管再生。这些数据显示了一种新的血管生成机制，并表明低剂量辐射可用于治疗性血管生成，以增强缺血组织中的血管生成。
