Vascular endothelial growth factor-C gene therapy restores lymphatic flow across incision wounds

Edema and insufficient blood perfusion are common problems in reconstructive surgery. The blood vasculature is reconstructed in microvascular flaps, whereas lymphatic vessel function is lost after surgical incision. Here, we demonstrate that vascular endothelial growth factor C (VEGF-C) gene transfer can be used to reconstruct a lymphatic vessel network severed by incision of skin flaps. We used adenoviral VEGF-C gene transfer at the edges of epigastric skin flaps in mice. Our results show that VEGF-C gene expression results in the formation of anastomoses between the lymphatic vessels of the skin flap and the surrounding lymphatic vasculature. Some spontaneous lymphangiogenesis also took place in the control mice, but the lymphatic vessels generated remained nonfunctional even 2 months postoperatively. In contrast, the VEGF-C treated mice demonstrated persistent lymphatic vessel function during the 2 month follow-up despite the transient nature of the adenoviral VEGF-C gene expression. The restoration of lymphatic function by VEGF-C in skin flaps provides new tools to promote vascular perfusion and to reduce tissue edema in skin and muscle flaps. These results have important implications for the prevention and treatment of surgically induced secondary lymphedema.