Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization.
Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization.
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低剂量辐照通过从肥大细胞和MMP-9介导的祖细胞细胞动员中释放VEGF来促进组织血运重建。
DOI：
10.1084/jem.20050959
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发表时间：
2005-09-19
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肥大细胞在肿瘤生长、伤口愈合和组织修复期间积累在经历血管生成的组织中。肥大细胞可以分泌血管生成因子，如血管内皮生长因子（VEGF）。电离辐射也被证明在恶性和非恶性疾病中具有血管生成潜力。我们观察到，低剂量辐射促进肥大细胞依赖性血管再生的肢体缺血模型。辐射促进肥大细胞以基质金属蛋白酶-9（MMP-9）依赖的方式产生VEGF。照射通过VEGF上调基质细胞和内皮细胞中MMP-9的表达，诱导Kit-ligand（KitL）的释放。辐射诱导的VEGF促进肥大细胞从骨髓迁移到缺血部位。照射介导的KitL和VEGF的释放在MMP-9缺陷小鼠中受损，导致组织肥大细胞数量减少和缺血肢体血管形成延迟。在肥大细胞缺乏的小鼠（钢突变体，Sl/Sld小鼠）和VEGF途径被阻断的小鼠中，辐照诱导的血管发生被废除。在S1/Sld小鼠中，辐射没有诱导祖细胞动员。我们的结论是，增加招聘和激活的肥大细胞照射后改变缺血微环境，促进血管再生缺血模型。这些数据显示了新血管形成的新机制，并表明低剂量照射可用于治疗性血管生成，以增强缺血组织中的血管生成。
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/Sld mice) and in mice in which the VEGF pathway was blocked. Irradiation did not induce progenitor mobilization in Sl/Sld 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.