Mechanisms underlying the impairment of ischemia-induced neovascularization in matrix metalloproteinase 2-deficient mice.
Matrix metalloproteinases (MMPs) have been implicated in the process of neovascularization. However, the exact roles of individual MMPs in vessel formation are poorly understood. To study the putative role of MMP-2 in ischemia-induced neovascularization, a hindlimb ischemia model was applied to MMP-2(+/+) and MMP-2(-/-) mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in MMP-2(-/-) young and old mice remained impaired throughout the follow-up period. At day 35, microangiography and anti-l-lectin immunohistochemical staining revealed lesser developed collateral vessels and capillary formation in both old and young MMP-2(-/-) mice compared with the age-matched MMP-2(+/+) mice. An aortic-ring culture assay showed a markedly impaired angiogenic response in MMP-2(-/-) mice, which was partially recovered by supplementation of the culture medium with recombinant MMP-2. Aorta-derived endothelial cells or bone marrow-derived endothelial progenitor cell (EPC)-like c-Kit(+) cells from MMP-2(-/-) showed marked impairment of invasive or/and proliferative abilities. At day 7, plasma and ischemic tissues of vascular endothelial growth factor protein were reduced in MMP-2(-/-). Flow cytometry showed that the numbers of EPC-like CD31(+)c-Kit(+) cells in peripheral blood markedly decreased in MMP-2-deficient mice. Transplantation of bone marrow-derived mononuclear cells from MMP-2(+/+) mice restored neovascularization in MMP-2(-/-) young mice. These data suggest that MMP-2 deficiency impairs ischemia-induced neovascularization through a reduction of endothelial cell and EPC invasive and/or proliferative activities and EPC mobilization.
Cheng
Xian Wu
XW
Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. xianwu@med.nagoya-u.ac.jp
Kuzuya
Masafumi
M
Nakamura
Kae
K
Maeda
Keiko
K
Tsuzuki
Michitaka
M
Kim
Weon
W
Sasaki
Takeshi
T
Liu
Zexuan
Z
Inoue
Natsuo
N
Kondo
Takahisa
T
Jin
Hai
H
Numaguchi
Yasushi
Y
Okumura
Kenji
K
Yokota
Mitsuhiro
M
Iguchi
Akihisa
A
Murohara
Toyoaki
T
D000367:Age Factors; D000671:Amputation, Surgical; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005434:Flow Cytometry; D006614:Hindlimb / Q000098:blood supply / Q000503:physiopathology; D007511:Ischemia / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D009924:Organ Culture Techniques; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D042461:Vascular Endothelial Growth Factor A; D019009:Proto-Oncogene Proteins c-kit; D020778:Matrix Metalloproteinase 2