Role of VEGF and PlGF signaling in sepsis

我们已经证明，循环中的血管内皮生长因子(VEGF)和 胎盘生长因子(PlGF)在脓毒症小鼠和人类模型中升高， 血管内皮生长因子在脓毒症中起致病作用，而PlGF的上调代表着一种 适应性宿主反应，防止败血症的发病率和死亡率。致我们的 据了解，这些数据首次证明了PlGF的任何生理作用。在……里面 尽管PlGF在脓毒症中具有保护作用，但携带酪氨酸激酶缺陷的小鼠 VEGFR1/Flt-1受体可降低内毒素介导的死亡率。基于这些 我们假设，血管内皮生长因子和平台生长因子信号之间的微调平衡 是宿主反应的中心，失衡会导致病理生理学。这个 总体目标是了解血管内皮生长因子和PlGF信号是如何在 宿主先天免疫反应。目的1描述血管内皮生长因子在宿主反应中的作用 与感染有关。在修订后的申请(为期两年的ARRA奖励)中，我们有 我们在目标1中的研究重新聚焦于在动物模型中测量VEGFA异构体的表达 脓毒症的发生，确定血管内皮生长因子-B在脓毒症动物模型中的作用 HPRT靶向可诱导的血管内皮生长因子、血管内皮生长因子受体1、血管内皮生长因子R2和 血管内皮生长因子受体1。目的2描述PlGF在宿主对感染的反应中的作用。在 修订的应用，Aim 2特别关注VEGFR1和PlGF-VEGF的作用 异二聚体在脓毒症中的作用。

We have shown that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are elevated in mouse and human models of sepsis, that VEGF plays a pathogenic role in sepsis, and that the upregulation of PlGF represents an adaptive host response that protects against sepsis morbidity and mortality. To our knowledge, these data are the first to demonstrate any physiological role for PlGF. In spite of the protective role of PlGF in sepsis, mice carrying a tyrosine kinase-deficient VEGFR1/Flt-1 receptor displayed reduced endotoxin-mediated mortality. Based on these findings we hypothesize that a finely tuned balance between VEGF and PlGF signaling is central to the host response and that an imbalance leads to pathophysiology. The overall goal is to understand how VEGF and PlGF signaling is coordinated during the host innate immune response. Aim 1 is delineate the role of VEGF in the host response to infection. In the revised application (for the two-year ARRA award), we have refocused our studies in Aim 1 to measure VEGFA isoform expression in animal models of sepsis, determine the role of VEGF-B in animal models of sepsis and to generate Hprt-targeted mice with inducible over-expression of VEGF, VEGFR1, VEGFR2 and sVEGFR1. Aim 2 is to delineate the role of PlGF in the host response to infection. In the revised application, Aim 2 focuses specifically on the role of VEGFR1 and PlGF-VEGF heterodimers in sepsis.