Understanding the role of VEGF in scar formation

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PROJECT SUMMARY: Complications in the wound repair process, including the formation of excessive or abnormal scar formation, affect millions of patients and result in substantial health care costs. Scar tissue impedes normal skin function and can have severe psychosocial consequences. The ability to limit the amount of scar tissue that forms following injury or surgical procedures would be a major clinical advance that would have a tremendous impact on patients. In order to develop novel therapies to combat scarring, a more precise understanding of the mechanisms that regulate scar formation is needed. A growing body of evidence is emerging suggesting that the pro-angiogenic growth factor vascular endothelial growth factor-A (VEGF) promotes scar formation. However, little has been done to dissect the mechanisms by which VEGF contributes to scarring. Our preliminary data suggest that fibroblasts, the cell type responsible for scar formation, express VEGF receptors and that cultured fibroblasts respond directly to VEGF. Therefore, it is possible that in addition to regulating wound angiogenesis, VEGF may also directly stimulate to scar formation by signaling through VEGFR-1 and/or VEGFR-2 in dermal fibroblasts. Based on the evidence suggesting that VEGF promotes scar formation as well as preliminary data suggesting that VEGF receptors are present on dermal fibroblasts and that these cells can respond to VEGF, the central hypothesis of the proposed studies is that VEGF promotes scar tissue deposition through direct stimulation of dermal fibroblasts. The following specific aims will be carried out to test this hypothesis: Aim 1 – Assess the effects of VEGF on fibroblast function in vitro; Aim 2 – Determine the effects of VEGF on fibroblast function in vivo. Despite the mounting evidence that VEGF regulates scar formation, no detailed mechanistic studies have been performed. Here, novel mouse models will be used to address this gap in knowledge by characterizing direct effects of VEGF on fibroblasts and dissecting the mechanisms by which VEGF promotes scar formation. The mechanisms identified as a result of these studies could extend beyond wound-induced scar formation, and have the potential to also play a role in the regulation of fibrosis in the skin as well as other organs.