VEGF gene therapy augments localized angiogenesis and promotes anastomotic wound healing: A pilot study in a clinically relevant animal model

C. Kristian Enestvedt, Luke Hosack, Shelley R. Winn, Brian S. Diggs, Barry Uchida, Robert W. O'Rourke, Blair A. Jobe

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Background: Anastomotic leak related to ischemia is a source of significant morbidity and mortality in gastrointestinal surgery. The aim of this study was to apply growth factor gene transfection for the purpose of up-regulating angiogenesis, increasing anastomotic strength, and ultimately preventing dehiscence. Methods: An opossum esophagogastrostomy model was employed. The human vascular endothelial growth factor (VEGF165) gene was incorporated into a recombinant plasmid. The VEGF plasmid vector was then complexed with a cationic synthetic carrier, polyethyleneimine. Control animals received plasmid devoid of VEGF165 (n=6). The experimental group received VEGF165 plasmid (n=5). After esophagogastrectomy and gastric tubularization, plasmid was injected into the submucosa of the neoesophagus at the anastomotic site. Conduit arteriography was performed before and 10 days after injection. Euthanasia occurred on post-injection day 10 and the anastomosis was removed en bloc. A second group of animals treated with VEGF165 were euthanized 30 and 37 days post injection. Blood flow was measured with laser-Doppler prior to euthanasia. Ex vivo anastomotic bursting pressure was performed. Tissue samples were procured for RNA extraction and von Willebrand Factor staining. Microvessel counts were obtained by two blinded observers. Tissue VEGF transcript levels were measured with reverse transcriptase polymerase chain reaction (RT-PCR). Results: There was one anastomotic leak in the control group. Experimental animals demonstrated significantly increased bursting pressure (104.25±6.2 vs 86.73±9.4 mmHg, p=0.021) and neovascularization (33.87±9.6 vs 20.33±8.1 vessels/hpf, p=0.032) compared to controls. In addition, there was a strongly positive correlation between the number of microvessels and bursting pressure (r=0.808, p=0.015, Pearson's). On angiographic examination, treated animals demonstrated more neovascularization compared to controls. RT-PCR demonstrated up to a 5.6-fold increase in VEGF mRNA in treated compared to controls. Discussion: This description of gene therapy in gastrointestinal surgery using VEGF165 transfection demonstrates increased angiogenesis with subsequently improved anastomotic healing in a clinically relevant model.

Original languageEnglish (US)
Pages (from-to)1762-1772
Number of pages11
JournalJournal of Gastrointestinal Surgery
Volume12
Issue number10
DOIs
StatePublished - Oct 2008

Keywords

  • Anastomosis
  • Angiogenesis
  • Healing
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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