Identification of the Fra-1 transcription factor in healing skin flaps transplants: A potential role as a negative regulator of VEGF release from keratinocytes

The molecular mechanisms underlying successful myocutaneous skin flap integration, as well as the ischemic loss of transplanted tissue on surgery, remain largely unknown. In this study we used a mouse model of caudally based skin flaps to determine molecular patterns of acute transplant re-integration. Gene chip-based transcriptional analysis revealed an up-regulation of the transcription factor Fra-1 in murine skin flap tissue. Epidermal keratinocytes at the wound margins represented a dominant cellular source of Fra-1 in mice. Moreover, Fra-1 protein showed a clear nuclear localization. In addition, Fra-1 protein was also present in nuclei of wound margin keratinocytes located near the suture line in human skin flaps. In vitro studies using the human keratinocyte cell line HaCaT showed that epidermal growth factor (EGF) was a potent inducer of Fra-1 expression in keratinocytes. Ablation of Fral-1 protein using a specific Fra-1 small interfering (si)RNA markedly increased the EGF-induced vascular endothelial growth factor (VEGF) expression from keratinocytes. These data suggest the involvement of an injury-induced Fra-1 transcription factor as a regulator of keratinocyte gene expression, which might act as an antagonistic player to restrict epithelial-driven angiogenic responses during normal skin flap integration.