Combination of VEGF(165)/Angiopoietin-1 gene and endothelial progenitor cells for therapeutic neovascularization.

Previous studies have established that vascular endothelial growth factor (VEGF), Angiopoietin-1 (Ang1) and endothelial progenitor cells (EPCs) play important roles in neovascularization, suggesting that combination of them would be a promising therapy for ischemic diseases. So we constructed the adeno-associated virus-2 (AAV-2) vectors simultaneously encoding human VEGF(165) and Ang1 (AAV-Ang1/VEGF), and investigated the combination therapeutic effect of AAV-Ang1/VEGF with EPCs in a rabbit ischemic hindlimb model. In the present study we found that AAV-Ang1/VEGF could successfully and efficiently transfer VEGF(165) and Ang1 gene into bone marrow derived EPCs for gene therapy. Combined administration of AAV-Ang1/VEGF with EPCs had higher blood flow recovery, cellularity, capillary density and smooth muscle alpha-actin positive vessel density than administration of either of them alone. Furthermore, the strategy of pre-intramuscular injection of AAV-Ang1/VEGF followed by EPCs transplantation had a higher therapeutic effect than the strategy of transplantation of AAV-Ang1/VEGF transduced EPCs. It seemed that the former strategy may be a promising therapy for ischemic diseases.