Gene therapy with adenoviral plasmids or naked DNA of vascular endothelial growth factor and platelet-derived growth factor accelerates healing of duodenal ulcer in rats.

Abstract

After we demonstrated that daily intragastric administration of angiogenic growth factors like basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), or vascular endothelial growth factor (VEGF) accelerated the healing of chronic duodenal ulcers in rats, we hypothesized that a single dose of gene therapy related to these growth factors may be enough to accelerate the healing of duodenal ulcers through enhancement of synthesis of endogenous angiogenic growth factors. Thus, we compared the effects of intraduodenal or intravenous adenoviral vectors and naked DNA transducing the genes for either VEGF or PDGF in experimental duodenal ulcers induced by cysteamine in rats. Sprague-Dawley female rats with confirmed duodenal ulcers were randomly divided into control and treatment groups. The controls received either intraduodenal injection of buffer or the beta-galactosidase-transducing adenoviral vector. Rats treated with a single or double dose of adenoviral vector or naked DNA of VEGF or PDGF had significantly smaller ulcers than the controls. Histologic analysis demonstrated that reepithelized granulation tissue with prominent angiogenesis replaced the ulcers. Western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay of duodenal mucosa confirmed that the expression of VEGF or PDGF proteins was enhanced by the transgenes, whereas beta-galactosidase staining in multiple organs identified that the transgenes, especially after local administration were only localized in the duodenum, stomach, and jejunum. These results suggest that gene therapy with either VEGF or PDGF may be a rapid approach to achieve duodenal ulcer healing.