Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1.
OBJECTIVE
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.
Jones
M K
MK
Department of Medicine, Veterans Administration Medical Center, Long Beach, California 90822, USA.
Kawanaka
H
H
Baatar
D
D
Szabó
I L
IL
Tsugawa
K
K
Pai
R
R
Koh
G Y
GY
Kim
I
I
Sarfeh
I J
IJ
Tarnawski
A S
AS
D042683:Angiopoietin-1; D000818:Animals; D018076:DNA, Complementary / Q000008:administration & dosage*; D016228:Endothelial Growth Factors / Q000235:genetics*; D015316:Genetic Therapy; D007267:Injections; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D010957:Plasmids; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics; D013276:Stomach Ulcer / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; C467629:Angpt1 protein, rat; D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors