Recombinant vascular endothelial growth factor165 gene therapy improves anastomotic healing in an animal model of ischemic esophagogastrostomy

Abstract

Proper anastomotic healing is dependent upon many factors including adequate blood flow to healing tissue. The aim of this study was to investigate the impact of vascular endothelial growth factor (VEGF(165)) transfection on anastomotic healing in an ischemic gastrointestinal anastomosis model. Utilizing an established opossum model of esophagogastrectomy followed by esophageal-gastric anastomosis, the gastric fundus was transfected with recombinant human vascular endothelial growth factor via direct injection of a plasmid-based nonviral delivery system. Twenty-nine animals were divided into three groups: two concentrations of VEGF and a control group. Outcomes included VEGF mRNA transcript levels, neovascularization, tissue blood flow, and anastomotic bursting pressure. To determine whether local injection resulted in a systemic effect, distant tissues were evaluated for VEGF transcript levels. Successful gene transfection was demonstrated by quantitative polymerase chain reaction analysis of anastomotic tissue, with significantly higher VEGF mRNA expression in treated animals compared to controls. At the gastric side of the anastomosis, there was significantly increased neovascularization, blood flow, and bursting pressure in experimental animals compared to controls. There were no differences in outcome measures between low- and high-dose VEGF groups; however, the high-dose group demonstrated increased VEGF mRNA expression across the anastomosis. VEGF production was not increased at distant sites in treated animals. In this animal model, VEGF gene therapy increased VEGF transcription at a healing gastrointestinal anastomosis without systemic VEGF upregulation. This treatment led to improved healing and strength of the acutely ischemic anastomosis. These findings suggest that VEGF gene therapy has the potential to reduce anastomotic morbidity and improve surgical outcomes in a wide array of patients.

A Rat Model of Esophagogastric Anastomotic Stricture

“…Ischemia is considered a great risk factor for anastomosis leakage and stricture [12]. To our knowledge, most animal models designed for studying the esophagogastric anastomosis wound healing were focused on the postoperative leakage and used anastomotic bursting pressure to test the strength of anastomosis [13, 14], while only a few were designed to explore the anastomotic stricture. In conventional esophagectomy, the ischemia area is usually found at the tip of the gastric tube [15].…”

Comparison of cervical anastomotic leak and stenosis after oesophagectomy for carcinoma according to the interval of the stomach ischaemic conditioning

“…17 Other studies have explored the possibilities of pharmaceutical support of neovascularisation and vasodilatation of stomach conduit during resection of oesophagus; so far with no clear impact on clinical practice. 18,19 Neither preoperative chemotherapy nor chemoradiotherapy has any effect on the incidence of postoperative complications. 20 In one group of patients in our cohort, chemotherapy was administered between conditioning and stomach resection, with the same results as in patients without chemotherapy.…”

Angiogenesis after plasmid VEGF165 gene transfer in an animal model

“…However, further stages, especially maturity of blood vessels, require collaboration of numerous cells and cytokines [16][17][18].…”

“…This gene may be represented in five different forms that differ in the number of amino acids per protein molecule: 121, 145, 165, 189 or 206 [9,14]. Vascular endothelial growth factor is synthesized by several cell types: endothelial, tumor, macrophages, T lymphocytes, smooth muscle, kidney, keratocytes, astrocytes and osteoblasts [15][16][17][18]. The main transcription factor that regulates VEGF cell synthesis is HIF-1, hypoxia inducible factor-1, which stimulates the protein expression in response to insufficient blood supply or cell damage.…”