Understanding the role of VEGF in scar formation

项目总结： 伤口修复过程中的并发症，包括形成过多或异常的疤痕 形成，影响数以百万计的患者，并导致大量的医疗费用。疤痕组织阻碍正常 皮肤功能，并可能产生严重的心理社会后果。限制疤痕组织数量的能力 在损伤或外科手术后形成的这种形式将是一项重大的临床进步，它将具有 对患者的巨大影响。为了开发对抗疤痕的新疗法，一种更精确的 需要了解调控疤痕形成的机制。 越来越多的证据表明，促血管生成生长因子血管 内皮生长因子-A(VEGF)促进瘢痕形成。然而，几乎没有采取什么行动来剖析 血管内皮生长因子促进瘢痕形成的机制。我们的初步数据表明，成纤维细胞是一种 负责瘢痕形成，表达血管内皮生长因子受体，培养的成纤维细胞直接对血管内皮生长因子作出反应。 因此，有可能血管内皮生长因子除了调节创面血管生成外，还可能直接刺激 真皮成纤维细胞通过VEGFR-1和/或VEGFR-2信号转导形成瘢痕。 基于表明血管内皮生长因子促进疤痕形成的证据以及初步数据 这表明真皮成纤维细胞上存在血管内皮生长因子受体，这些细胞可以对血管内皮生长因子做出反应。 拟议研究的中心假设是，血管内皮生长因子通过直接促进瘢痕组织沉积 刺激真皮成纤维细胞。将执行以下具体目标来检验这一假设：目标1-- 评价血管内皮生长因子对成纤维细胞功能的影响；目的2-确定血管内皮生长因子对成纤维细胞的影响 在体内发挥作用。 尽管越来越多的证据表明血管内皮生长因子调节疤痕的形成，但还没有详细的机制研究。 已经完成了。在这里，将使用新的老鼠模型来解决这一知识差距，方法是 血管内皮生长因子对成纤维细胞的直接作用及促进瘢痕形成的机制剖析。 这些研究确定的机制可能超越了创伤诱导的疤痕形成， 并有可能在调节皮肤和其他器官的纤维化方面发挥作用。

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.