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

Abstract

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.

In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis

“…A strong correlation between macrophage recruitment and wound healing has been reported previously (36). Moreover, during skin wound healing, angiogenesis and lymphangiogenesis take place at the periphery of the wound, contributing to optimal healing (37,38). We have used the Vegfr3 EGFPLuc reporter to image lymphangiogenesis during skin wound healing and to further explore its dependence on inflammation.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Among them, VEGF-C has been best characterized and is considered to be the most promising therapeutic agent to treat human lymphedema (Norrmen et al 2011). Administration of a VEGF-C-expressing adenovirus enhanced generation of functional lymphatic vessels in Chy mutant mice (Karkkainen et al 2001), and adenoviral delivery of VEGF-C in normal skin or at the edge of epigastric skin flaps in mice strongly induced lymphangiogenesis (Enholm et al 2001;Saaristo et al 2004). In addition, recombinant VEGF-C was shown to be sufficient to activate in vivo lymphangiogenesis and reversed the symptoms of lymphedema in rabbit ears (Szuba et al 2002); VEGF-C gene therapy stimulated postnatal lymphangiogenesis and thus ameliorated secondary lymphedema in animal models (Yoon et al 2003).…”

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

“…39 However, efforts to reconstitute the lymphatic vessels and cure lymphedema are rarely successful. 40 VEGF-C gene transfer via adenoviruses, adenoassociated viruses, or naked plasmids, as well as the application of recombinant VEGF-C protein, has been shown to stimulate the formation of new lymphatic capillaries and alleviate edema in preclinical animal models of lymphedema, [41][42][43] suggesting the potential to restore lymphatic vessels in lymphedema patients. Furthermore, as seen in Figure 2d, the temporal changes in the interstitial pressure was significantly higher in the group treated with celecoxib.…”