Chronic activation of immune mechanisms contribute to the pathophysiology of preeclampsia, hypertension during pregnancy. Preeclamptic women have elevated circulating cytokines, neutrophils and lymphocytes producing an agonistic autoantibody to the angiotensin II type I receptor (AT1-AA). However, the exact pathway linking placental ischemia and immune activation with the development of hypertension during pregnancy has yet to be clearly defined. One possible mechanism is that chronic inflammation resulting in the AT1-AA promotes oxidative stress and endothelial dysfunction leading to altered renal hemodynamics and reduced renal pressure natriuresis by enhanced interactions with Angiotensin II and the Angiotensin II type 1 receptor. We have shown that reduced uterine perfusion pressure (RUPP) in pregnant rats, a rat model of preeclampsia, is an important stimulus for the production of the AT1-AA. Moreover, hypertension produced by RUPP is associated with enhanced inflammatory cytokines, endothelin-1 (ET-1) and reactive oxygen species (ROS) and reductions in renal plasma flow, GFR, and renal excretory function. Our preliminary data indicate the RUPP is associated with elevated lymphocytes adoptive transfer of these T lymphocytes into normal pregnant rats causes hypertension and AT1-AA production. The central hypothesis to be tested in this proposal is hypertension in response to placental ischemia in pregnant rats is associated with T helper cell activation which in turn mediate the production of AT1-AA via B lymphocytes. In addition, we propose that the AT1-AA via the AT1 receptor stimulates the production of ET-1 and ROS leading to increases in blood pressure during pregnancy. To test this hypothesis an integrative physiological approach complemented with molecular, immunological, in vitro cell culture and in vivo techniques will be used to address the following specific aims:1. To test the hypothesis that T lymphocyte mediated AT1-AA production increases blood pressure in response to placental ischemia in pregnant rats 2.To test the hypothesis that Endothelin-1 and ROS facilitate T lymphocyte mediated AT1-AA induced increases blood pressure response to placental ischemia in pregnant rats .
Preeclamptic women, women with newly developed hypertension during pregnancy, have elevated inflammatory markers and immune cells producing 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 production of this autoantibody with the increase in blood pressure has yet to be clearly defined. This proposal focuses on determining specific cellular interactions that lead to the production of this autoantibody and examine the ways in which these cells cause this autoantibody to increase blood pressure during pregnancy.
