Extracorporal Shock Wave Therapy Enhances Receptor for Advanced Glycated End-Product-Dependent Flap Survival and Angiogenesis

BACKGROUND/OBJECTIVES: Loss of skin flaps due to deteriorated wound healing is a crucial clinical issue. Extracorporal shock wave therapy (ESWT) promotes flap healing by inducing angiogenesis and suppressing inflammation. The receptor for advanced glycation end-products (RAGEs) was identified to play a pivotal role in wound healing. However, to date, the role of RAGE in skin flaps and its interference with ESWT are unknown.

METHODS: Caudally pedicled musculocutanous skin flaps in RAGE and wt mice were treated with low-dose extracorporal shock waves (s-RAGE, s-wt) and analyzed for flap survival, histomorphologic studies, and immunohistochemistry during a 10-day period. Animals without ESWT served in each genotype as a control group (c-RAGE, c-wt). Statistical analysis was carried out by repeated-measures analysis of variance.

RESULTS: Flap necrosis was significantly reduced after ESWT in wt animals but increased in RAGE-deficient animals. Morphometric differences between the 4 groups were identified and showed a delayed wound healing with dysregulated inflammatory cells and deteriorated angiogenesis in RAGE animals. Furthermore, spatial and temporal differences were observed.

CONCLUSIONS: The RAGE controls inflammation and angiogenesis in flap healing. The protective effects of ESWT are dependent on intact RAGE signaling, which enables temporary targeted infiltration of immune cells and neoangiogenesis.