Pre‐administration of angiopoietin‐1 followed by VEGF induces functional and mature vascular formation in a rabbit ischemic model

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Abstract
Background Angiopoietin‐1 (Ang1) and vascular endothelial growth factor (VEGF) play important roles in vascular formation and maturation, suggesting that the combination of these two would be a promising therapy for ischemia. However, it remains unclear what the best schedule of administration of these cytokines might be. Methods Six experimental groups were used to prepare the rabbit ischemic hindlimb model following naked plasmid intramuscular administration as follows: empty vector (C), single gene (Ang1, A; VEGF, V), Ang‐1 followed by VEGF (A − V), co‐administration of Ang1 and VEGF (A + V), and VEGF followed by Ang1 (V − A). Results Thirty days after gene administration, A − V showed a significantly increased blood pressure and blood‐flow recovery in the ischemic limb compared with the control group. Histological findings by α‐smooth muscle‐actin (α‐SMA) staining revealed that the two combination groups had more mature vessels as compared with the control group. Significantly, A − V revealed the highest density of α‐SMA‐positive vessels compared with VEGF alone or Ang1 alone. Angiographic assessment revealed that A − V had a greater increased arterial diameter compared with VEGF alone. Edema, one of the major adverse effects induced by VEGF, was not found in A − V throughout the experiments, while VEGF alone and V − A showed severe edema induced by VEGF. Conclusions The pre‐administration of Ang1 followed by VEGF resulted in an improvement of hemodynamic status, an increased number of vessels covered with α‐actin‐positive mural cells, and prevention of VEGF‐mediated edema. Thus, priming by Ang1 gene administration would be beneficial for therapeutic angiogenesis in VEGF gene therapy. Copyright © 2003 John Wiley & Sons, Ltd.