Combination of in vivo angiopoietin-1 gene transfer and autologous bone marrow cell implantation for functional therapeutic angiogenesis.
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.


RESULTS
Rabbits were divided into 4 groups: phosphate-buffered saline (control), 500 microg Ang-1 plasmid (Ang-1), 1 x 10(6) 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.
Kobayashi
Koichi
K
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan.
Kondo
Takahisa
T
Inoue
Natsuo
N
Aoki
Mika
M
Mizuno
Masaaki
M
Komori
Kimihiro
K
Yoshida
Jun
J
Murohara
Toyoaki
T
D000792:Angiography; D042683:Angiopoietin-1 / Q000235:genetics* / Q000494:pharmacology; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D002196:Capillaries / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003097:Collateral Circulation; D004423:Ear / Q000098:blood supply; D042783:Endothelial Cells / Q000502:physiology; D015870:Gene Expression; D015316:Genetic Therapy; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007083:Iliac Artery / Q000000981:diagnostic imaging; D007511:Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D009000:Monocytes / Q000637:transplantation*; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D018919:Neovascularization, Physiologic; D010101:Oxygen Consumption; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012883:Skin Ulcer / Q000473:pathology; D013234:Stem Cells / Q000502:physiology; D014182:Transplantation, Autologous; D016042:Transplantation, Heterotopic
D042683:Angiopoietin-1; D011994:Recombinant Proteins