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(Circulation Research. 2007;100:904.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Matrix Metalloproteinase 2–Deficient Mice

Xian Wu Cheng^*, Masafumi Kuzuya^*, Kae Nakamura, Keiko Maeda, Michitaka Tsuzuki, Weon Kim, Takeshi Sasaki, Zexuan Liu, Natsuo Inoue, Takahisa Kondo, Hai Jin, Yasushi Numaguchi, Kenji Okumura, Mitsuhiro Yokota, Akihisa Iguchi, Toyoaki Murohara

From the Departments of Geriatrics (X.W.C., M.K., K.N., K.M., T.S., Z.L., A.I.) and Cardiology (M.T., W.K., N.I., T.K., Y.N., T.M.), Nagoya University Graduate School of Medicine, Japan; Department of Cardiovascular Research Medicine (X.W.C., K.O.), Nagoya University School of Medicine, Japan; Department of Genome Science (M.Y.), Aichigakuin University School of Dentistry, Nagoya, Japan; and Cardiovascular Department (X.W.C., H.J.), College of Medical Yanbian University, Juzijie, Yanji, Jilin Province, China.

Correspondence to Xian Wu Cheng, MD, PhD, Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail xianwu{at}med.nagoya-u.ac.jp

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.

Key Words: ischemia • angiogenesis • matrix metalloproteinase • endothelium • mobilization • migration

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