Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization.
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.
Heissig
Beate
B
Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
Rafii
Shahin
S
Akiyama
Haruyo
H
Ohki
Yuichi
Y
Sato
Yayoi
Y
Rafael
Tejada
T
Zhu
Zhenping
Z
Hicklin
Daniel J
DJ
Okumura
Ko
K
Ogawa
Hideoki
H
Werb
Zena
Z
Hattori
Koichi
K
D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D005121:Extremities / Q000098:blood supply; D005720:Gamma Rays; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000528:radiation effects*; D007511:Ischemia / Q000532:radiotherapy; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism* / Q000528:radiation effects*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D018919:Neovascularization, Physiologic / Q000528:radiation effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000528:radiation effects*
D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9