{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T03:53:01Z","timestamp":1767844381086,"version":"3.49.0"},"reference-count":65,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2003,7,8]],"date-time":"2003-07-08T00:00:00Z","timestamp":1057622400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2003,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Angiopoietin\u20101 (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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u20101 followed by VEGF (A \u2212 V), co\u2010administration of Ang1 and VEGF (A + V), and VEGF followed by Ang1 (V \u2212 A).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty days after gene administration, A \u2212 V showed a significantly increased blood pressure and blood\u2010flow recovery in the ischemic limb compared with the control group. Histological findings by \u03b1\u2010smooth muscle\u2010actin (\u03b1\u2010SMA) staining revealed that the two combination groups had more mature vessels as compared with the control group. Significantly, A \u2212 V revealed the highest density of \u03b1\u2010SMA\u2010positive vessels compared with VEGF alone or Ang1 alone. Angiographic assessment revealed that A \u2212 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 \u2212 V throughout the experiments, while VEGF alone and V \u2212 A showed severe edema induced by VEGF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The pre\u2010administration of Ang1 followed by VEGF resulted in an improvement of hemodynamic status, an increased number of vessels covered with \u03b1\u2010actin\u2010positive mural cells, and prevention of VEGF\u2010mediated edema. Thus, priming by Ang1 gene administration would be beneficial for therapeutic angiogenesis in VEGF gene therapy. 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