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Vascular endothelial growth factor gene therapy induces early re-establishment of canine bronchial circulation

^a Lung and Airway Laboratory, Federal University of Rio Grande do Sul School of Medicine, Hospital de Clínicas de Porto Alegre, Brazil
^b Department of Anesthesiology, Federal University of Rio Grande do Sul School of Medicine, Hospital de Clínicas de Porto Alegre, Brazil
^c Department of Pathology, Federal University of Rio Grande do Sul School of Medicine, Hospital de Clínicas de Porto Alegre, Brazil
^d Gene Therapy Center, Federal University of Rio Grande do Sul School of Medicine, Hospital de Clínicas de Porto Alegre, Brazil

Received 19 August 2007; received in revised form 18 December 2007; accepted 19 December 2007.

^_* Corresponding author. Address: Hospital de Clínicas de Porto Alegre, Serviço de Cirurgia Torácica, Rua Ramiro Barcelos 2350, Sala 2050-M1, 90035-003 Porto Alegre, RS, Brazil. Tel.: +55 51 2101 8684; fax: +55 51 2101 8684. (Email: msaueressig{at}hcpa.ufrgs.br).

Objective: To evaluate the usefulness of gene therapy with human vascular endothelial growth factor 165 (phVEGF₁₆₅) to promote the early re-establishment of systemic arterial perfusion in canine bronchi deprived of bronchial circulation. Methods: To disrupt bronchial circulation, dogs were submitted to transversal bronchotomy dividing the left mainstem bronchus into a proximal and a distal portion. phVEGF₁₆₅ (VEGF group, n = 8) or physiologic saline solution (control group, n = 8) were then delivered to the left distal bronchus. After that, the airway was reconstituted with interrupted suture. On day 3, nine dogs (four VEGF and five controls) were euthanized and their left distal bronchi were harvested to evaluate VEGF₁₆₅ gene expression by reverse transcription-polymerase chain reaction. In the other dogs (four VEGF and three controls), a microvascular dye was injected through the canine aorta to verify the re-establishment of arterial blood supply to the distal bronchus. Additionally, VEGF immunohistochemistry was performed in distal airway specimens. Results: Microvascular dye was observed in 100% of specimens transfected with phVEGF₁₆₅ compared to none in controls. VEGF gene expression (p < 0.01) and VEGF protein expression (p < 0.05) were higher in VEGF₁₆₅-treated bronchi. Conclusions: Local transfection with phVEGF₁₆₅ promoted the early re-establishment of systemic arterial perfusion to bronchi previously deprived of bronchial circulation. Gene therapy with phVEGF₁₆₅ may be a useful tool to restore bronchial circulation by promoting early airway angiogenesis.

Abbreviations: VEGF = vascular endothelial growth factor • DNA = deoxyribonucleic acid • phVEGF₁₆₅ = naked plasmid enclosed human VEGF₁₆₅ • cDNA = complementary DNA • bp = base pairs • mRNA = messenger ribonucleic acid • RT-PCR = reverse transcription-polymerase chain reaction • GAPDH = glyceraldehydes-3-phosphate dehydrogenase • RU = relative optical density unit • PBS = phosphate-buffered saline

Key Words: Gene therapy • Angiogenesis-inducing agents • Pulmonary surgical procedures • Models • Animal • Vascular endothelial growth factor