Skeletal myoblast based delivery of angiogenic growth factors: a comparison between angiopoietin-1 and VEGF gene delivery for therapeutic angiogenesis in the heart

Objectives This study investigated the efficacy of human skeletal myoblasts (SkJVI) mediated either human vascular endothelial growth factor-! 65 (hVEGF1(5) or angiopoietin-1 (Ang-1) on vascular development and myocardial regional perfusion. Methods A porcine heart model of chronic infarction was created in 28 female swine by coronary artery ligation. The animals were randomized into: (1) group- 1, DMEM injected (n=6), (2) group-2, Ad-null transduced SkM transplanted (n=6), (3) group-3, Ad-hVEGF65 transduced SkM transplanted (n=8), and (4) group-4, Ad-Ang-1 transduced SkM (n=8). Three weeks later, 5 ml DMEM containing 3X 10s SkM carrying exogenous genes were intramyocardially injected into 20 sites in left ventricle in groups-2, -3 and -4. Animals in group- 1 were injected 5 ml DMEM without cells. Animals were kept on 5 mg/kg cyclosporine per day for 6 weeks. Regional blood flow was measured using fluorescent microspheres. The heart was explanted at 2, 6 and 1 2 weeks after transplantation for histological studies. Results Histological examination showed survival of lac-z expressing myoblasts in host tissue. Capillary density based on Von Willebrand factor-VHI (vWF-VIH) at low power field (x 100) was 57.1 3±1 1.85 in group-3 at 6 weeks and declined to 32. 1±5.21 at 12 weeks, while it was 39.9±10.26 at 6 weeks and increased to 45. 14±6.54 at 12 weeks in group-4. The mature blood vessel index was highest in group-4 at 6 and 1 2 weeks after transplantation. The regional blood flow in the center and peri-infarct area was significantly increased in animals of groups-3 and -4. Conclusions SkM carrying either hVEGF|65 or Ang-1 induced neovascularization with increased blood flow. Ang-1 overexpression resulted in mature and stable blood vessel formation and may be a more potent arteriogenic inducer for neovascularization.