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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1465.)
© 2006 American Heart Association, Inc.

Vascular Biology

Combination of In Vivo Angiopoietin-1 Gene Transfer and Autologous Bone Marrow Cell Implantation for Functional Therapeutic Angiogenesis

Koichi Kobayashi; Takahisa Kondo; Natsuo Inoue; Mika Aoki; Masaaki Mizuno; Kimihiro Komori; Jun Yoshida; Toyoaki Murohara

From the Departments of Cardiology (K. Kobayashi, T.K., N.I., M.A., T. M.), Molecular Neurosurgery (M.M.), Vascular Surgery (K. Komori), and Neurosurgery (M.M., J.Y.), Nagoya University Graduate School of Medicine, Nagoya, Japan

Correspondence to Toyoaki Murohara, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. E-mail murohara{at}med.nagoya-u.ac.jp

Objective— Autologous bone marrow mononuclear cell (BM-MNC) implantation into ischemic tissues promotes angiogenesis, but a large amount of marrow aspiration is required, which is a major clinical limitation. Angiopoietin-1 (Ang-1) is requisite for vascular maturation during angiogenesis. We examined the impacts of combinatorial Ang-1 gene transfer and low-dose autologous BM-MNC implantation on therapeutic angiogenesis in a rabbit model of hind limb ischemia.

Methods and Results— Rabbits were divided into 4 groups: phosphate-buffered saline (control), 500 µg Ang-1 plasmid (Ang-1), 1x10⁶ autologous BM-MNCs (BMC), and Ang-1 plasmid plus BM-MNCs (combination). The Ang-1 group had a greater angiographic score and capillary density compared with the control (P<0.05), but the Ang-1 gene therapy alone did not improve transcutaneous oxygen pressure (TcO₂) and skin ulcer score. However, the combination group showed a significant improvement in not only angiographic score and capillary density (P<0.05) but also TcO₂ (P<0.05) and skin ulcer score. These efficacies were greater in the combination group compared with the BMC group.

Conclusions— This Ang-1 gene and BM-MNC combination therapy enhances not only quantitative but also qualitative angiogenesis in ischemic tissues. Moreover, the combination therapy will enable a reduction in the amount of BM aspiration required for significant therapeutic angiogenesis.

Ang-1 gene and BM-MNCs combination therapy significantly augmented the angiographic score and capillary density, accompanied by functional improvement of skin ulcer score and TcO₂ in the ischemic limb. This new Ang-1 gene and BM-MNC combination therapy enhances not only quantitative but also qualitative angiogenesis in ischemic tissues.

Key Words: angiogenesis • angiopoietin-1 • bone marrow cells • vasculogenesis

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