Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization

被引:184
作者
Heissig, B
Rafii, S
Akiyama, H
Ohki, Y
Sato, Y
Rafael, T
Zhu, ZP
Hicklin, DJ
Okumura, K
Ogawa, H
Werb, Z
Hattori, K
机构
[1] Univ Tokyo, Inst Med Sci, Tokyo 1088639, Japan
[2] Juntendo Univ, Sch Med, Atopy Allergy Res Ctr, Tokyo 1138421, Japan
[3] Cornell Univ, Coll Med, Dept Hematol Oncol, New York, NY 10021 USA
[4] ImClone Syst, New York, NY 10014 USA
[5] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
关键词
D O I
10.1084/jem.20050959
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页码:739 / 750
页数:12
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