Gastroenterology

Gastroenterology

Volume 121, Issue 5, November 2001, Pages 1040-1047
Gastroenterology

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

https://doi.org/10.1053/gast.2001.29308Get rights and content

Abstract

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 stimulated by vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1), we studied whether local gene therapy with nonviral DNA encoding VEGF and/or Ang1 into the ulcer base could accelerate ulcer healing through enhanced angiogenesis. Methods: Gastric ulcers were induced in rats by acetic acid applied to the serosal surface of the stomach, and the site around the ulcer was injected with nonviral plasmid-encoding full-length complementary DNA (cDNA) of human recombinant (rh) VEGF165, rhAng1, or their combination. For some studies, neutralizing anti-VEGF antibody was administered. Results: Single local injection of plasmids encoding VEGF165 and Ang1 significantly increased neovascularization and accelerated ulcer healing. A neutralizing anti-VEGF antibody significantly reduced the acceleration of ulcer healing resulting from the treatment. Coinjection of both plasmids encoding rhVEGF165 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. Conclusions: VEGF and Ang1 gene therapy, with limited duration of target gene expression, 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 essential role for VEGF and enhanced angiogenesis in ulcer healing.

GASTROENTEROLOGY 2001;121:1040-1047

Section snippets

Experimental ulcer model

This study was approved by the subcommittee for animal studies of the Long Beach (California) Department of Veterans Affairs Medical Center. Male Sprague-Dawley rats (200-225 g in weight) were used. Rats fasted for 12 hours underwent laparotomy under nembutal anesthesia (50 mg/kg body weight). One hundred percent acetic acid (50 μL) was applied to the serosa of glandular stomach at the anterior wall through a polyethylene tube (4.0 mm inner diameter) for 90 seconds. The acetic acid was removed

Results

At 7 days, no significant difference was discernable in ulcer size or macroscopic appearance between rats injected with either plasmid-encoding rhVEGF165 or plasmid-encoding rhAng1 and rats injected with a nonexpressing control plasmid. This is not unexpected because the ulcer healing process follows the normal ulcer healing curve phases consisting of an early lag phase, a rapid healing phase, a late lag phase, and a remodeling phase.12 Therefore, at 7 days, differences cannot be detected. In

Discussion

Gene therapy has shown only limited efficacy for treatment of congenital diseases mainly caused by temporary gene expression and adverse host-immune responses. However, temporary gene expression locally in cells involved in the ulcer healing process is ideal for treatment of chronic ulcers where temporary gene activation is beneficial. The critical requirement for angiogenesis during the healing of chronic gastric injury appears to make VEGF, the most potent angiogenic factor, an ideal

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    Address requests for reprints to: Andrzej S. Tarnawski, M.D., D.Sc., Professor of Medicine, Chief, Division of Gastroenterology, University of California, Irvine and VA Medical Center, Long Beach (CA), 5901 East Seventh Street, Long Beach, California 90822. e-mail: [email protected]; fax: (562) 494-5675.

    ☆☆

    Supported by a VA Merit Review (AST) and Research Enhancement Award Programs.

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