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.
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