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 .

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL108558-02
Application #
8435008
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2012-02-16
Project End
2014-02-15
Budget Start
2013-02-16
Budget End
2014-02-15
Support Year
2
Fiscal Year
2013
Total Cost
$31,659
Indirect Cost
Name
University of Mississippi Medical Center
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Wallace, Kedra; Cornelius, Denise C; Scott, Jeremy et al. (2014) CD4+ T cells are important mediators of oxidative stress that cause hypertension in response to placental ischemia. Hypertension 64:1151-8
Wallace, Kedra; Morris, Rachael; Kyle, Patrick B et al. (2014) Hypertension, inflammation and T lymphocytes are increased in a rat model of HELLP syndrome. Hypertens Pregnancy 33:41-54
Wallace, Kedra; Novotny, Sarah; Heath, Judith et al. (2012) Hypertension in response to CD4(+) T cells from reduced uterine perfusion pregnant rats is associated with activation of the endothelin-1 system. Am J Physiol Regul Integr Comp Physiol 303:R144-9
LaMarca, Babbette; Parrish, Marc R; Wallace, Kedra (2012) Agonistic autoantibodies to the angiotensin II type I receptor cause pathophysiologic characteristics of preeclampsia. Gend Med 9:139-46
Dhillion, Pushpinder; Wallace, Kedra; Herse, Florian et al. (2012) IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy. Am J Physiol Regul Integr Comp Physiol 303:R353-8
Novotny, Sarah Richards; Wallace, Kedra; Heath, Judith et al. (2012) Activating autoantibodies to the angiotensin II type I receptor play an important role in mediating hypertension in response to adoptive transfer of CD4+ T lymphocytes from placental ischemic rats. Am J Physiol Regul Integr Comp Physiol 302:R1197-201