Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1

Background & Aims. Angiogenesis, formation of new, capillary blood vessels, is crucial for gastroduodenal ulcer healing because it enables delivery of oxygen and nutrients to the healing site. Because angiogenesis is stimulat ed by vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang:1), we studied whether, local gene therapy with nonviral DNA encoding VEGF and /or Ang1 into the ulcer base could accelerate ulcer healing through enhance d angiogenesis. Methods. Gastric ulcers were induced in rats by acetic acid applied to the serosal surface of the stomach, and the site around the ulc er was injected with. nonviral plasmid-encoding full-length complementary D NA (cDNA) of human recombinant (rh) VEGF(165), rhAng1, or their combination . For some studies, neutralizing anti-VEGF antibody was administered. Resul ts. Single local injection of plasmids encoding VEGF(165) and Ang1 signific antly increased neovascularization and accelerated ulcer healing. A neutral izing anti-VEGF antibody significantly reduced the acceleration of ulcer he aling resulting from the treatment. Coinjection of both plasmids encoding r hVEGF(165) and rhAng1 resulted in formation of more mature vessels, and to more complete restoration of gastric glandular structures within the ulcer scar. However, this did not result in further reduction of ulcer size. Conc lusions: VEGF and Ang1 gene therapy, with limited duration of target gene e xpression, significantly accelerates gastric ulcer healing. Coinjection of both plasmids leads to more complete structural restoration. Inhibition of accelerated healing by a neutralizing anti-VEGF antibody indicates an essen tial role for VEGF and enhanced angiogenesis in ulcer healing.