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(American Journal of Pathology. 2005;167:981-991.)
© 2005 American Society for Investigative Pathology

Improved Survival of Ischemic Cutaneous and Musculocutaneous Flaps after Vascular Endothelial Growth Factor Gene Transfer Using Adeno-Associated Virus Vectors

Serena Zacchigna^*, Giovanni Papa, Andrea Antonini, Federico Novati, Silvia Moimas^*, Alessandro Carrer^*, Nikola Arsic^*, Lorena Zentilin^*, Valentina Visintini, Michele Pascone and Mauro Giacca^*

From the Molecular Medicine Laboratory,^* International Centre for Genetic Engineering and Biotechnology, Trieste; and the Plastic Surgery Unit, Faculty of Medicine, University of Trieste, Trieste, Italy

A major challenge in reconstructive surgery is flap ischemia, which might benefit from induction of therapeutic angiogenesis. Here we demonstrate the effect of an adeno-associated virus (AAV) vector delivering vascular endothelial growth factor (VEGF)165 in two widely recognized in vivo flap models. For the epigastric flap model, animals were injected subcutaneously with 1.5 x 10¹¹ particles of AAV-VEGF at day 0, 7, or 14 before flap dissection. In the transverse rectus abdominis musculocutaneous flap model, AAV-VEGF was injected intramuscularly. The delivery of AAV-VEGF significantly improved flap survival in both models, reducing necrosis in all treatment groups compared to controls. The most notable results were obtained by administering the vector 14 days before flap dissection. In the transverse rectus abdominis musculocutaneous flap model, AAV-VEGF reduced the necrotic area by >50% at 1 week after surgery, with a highly significant improvement in the healing process throughout the following 2 weeks. The therapeutic effect of AAV-VEGF on flap survival was confirmed by histological evidence of neoangiogenesis in the formation of large numbers of CD31-positive capillaries and -smooth muscle actin-positive arteriolae, particularly evident at the border between viable and necrotic tissue. These results underscore the efficacy of VEGF-induced neovascularization for the prevention of tissue ischemia and the improvement of flap survival in reconstructive surgery.

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