Preeclamptic (PE) women have elevated circulating cytokines, Natural killer cells, T cells and blood pressure, however, the pathway linking placental ischemia and immune activation with the hypertension and IUGR during pregnancy is unknown. One possible mechanism is that chronic inflammation from CD4+THelper 1 cells results in the release of cytokines activating cytolytic NK cells which promotes oxidative stress leading to IUGR and endothelial dysfunction leading to altered renal hemodynamics and hypertension. We have shown that reduced uterine perfusion pressure (RUPP) in pregnant rats, a rat model of PE, is an important stimulus for hypertension and chronic inflammation which is associated with reductions in renal plasma flow, GFR, and renal excretory function. Our preliminary data indicate the RUPP is associated with an imbalance among the T regulatory (?TReg) and T helper 17 cells (? THelper 17) and increased activated NK cells and that adoptive transfer of RUPP THelper 17 cells into normal pregnant rats causes hypertension and IUGR. Our preliminary data demonstrates that adoptive transfer of TReg from normal pregnant rats into RUPP rats decreased hypertension and inflammatory cytokines. Importantly we demonstrate that adoptive transfer of CD4+ T cells from PE women increase blood pressure in NP Nude/Athymic pregnant rats. These studies demonstrate the importance of these T cell subtypes in pathological pregnancies. We believe the decrease in the TReg cells and increased TH17 causes prolonged activation of NK cells that attack the placenta leading to IUGR and for prolong activation of cytokines leading to the production of vasoactive substances, ET-1 and ROS. The central hypothesis to be tested that placental ischemia induced increases in CD4+THelper 1 cells lead to increases in TH17 and decreases in TRegs that in turn results in increases in IL-2, IL-17, and IL-15. These cytokines then stimulate NK cytolytic activity, thereby increasing placental and renal oxidative stress and contributing to hypertension and IUGR during pregnancy. To test this hypothesis an integrative physiological approach complemented with molecular, pharmacological immunological, in vitro cell culture and in vivo techniques will be used to address the following 3 specific aims:
Specific Aim 1. To test the hypothesis that increases in CD4+THelper 1 cells from PE women or in response to placental ischemia results in NK cell activation leading to placental and renal oxidative stress via perforin- granzyme mediated cytotoxicity and hypertension during pregnancy Specific Aim 2. To test the hypothesis that Thelper17 from PE women or in response to placental ischemia cause NK cell activation via IL-17.
Specific Aim 3. To test the hypothesis that increased IL-2 as a result of decreased CD4+T regulatory cells increases blood pressure and stimulates NK cells in response to placental ischemia.
Preeclamptic women, women with newly developed hypertension during pregnancy, have elevated inflammatory markers and cells programmed to kill virus infected cells or tumor cells and cells that secrete an autoantibody to the angiotensin II type I receptor (AT1-AA), one of the most important receptors controlling blood pressure. However, the exact pathway linking the pregnancy and the activation of these specialized cells or the production of this autoantibody with the increase in blood pressure and intrauterine growth restriction associated with preeclampsia has yet to be clearly defined. This proposal focuses on determining specific cellular interactions that lead to the activation of these killer cells and production of this autoantibody and examine the ways in they lead to increases blood pressure and decreased fetal growth during pregnancy.
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