Chronic activation of immune mechanisms contributes 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 and that depletion of these lymphocytes blunts production of the AT1-AA, ET-1 and hypertension in RUPP rats. Furthermore, our preliminary data supports the hypothesis that interactions between AT1-AA with the AT1 receptor, enhances renal microcirculatory and vascular sensitivity to ANGII. 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 and ANGII interact via the AT1 receptor to enhance the production of ET-1 and ROS leading to decreases in renal hemodynamics and 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 3 specific aims: 1) Does inhibited CD4+T lymphocyte regulatory mechanism in response to placental ischemia lead to endogenous AT1-AA mediated hypertension during pregnancy?2) To test the hypothesis that effector CD4+Thelper/TH17 mediated AT1-AA production increases blood pressure and decreases renal hemodynamics in response to placental ischemia in pregnant rats 3) To test the hypothesis that AT1-AA enhances renal and blood pressure sensitivity to ANG II in pregnant rats.

Public Health Relevance

Preeclamptic women, women with newly developed hypertension during pregnancy, have elevated inflammatory markers and 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 this autoantibody increases blood pressure during pregnancy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD067541-04
Application #
8681487
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Reddy, Uma M
Project Start
2011-09-15
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Jackson
State
MS
Country
United States
Zip Code
39216
Cunningham Jr, Mark W; Williams, Jan M; Amaral, Lorena et al. (2016) Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II-Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy. Hypertension 68:1308-1313
Harmon, Ashlyn C; Cornelius, Denise C; Amaral, Lorena M et al. (2016) The role of inflammation in the pathology of preeclampsia. Clin Sci (Lond) 130:409-19
LaMarca, Babbette; Amaral, Lorena M; Harmon, Ashlyn C et al. (2016) Placental Ischemia and Resultant Phenotype in Animal Models of Preeclampsia. Curr Hypertens Rep 18:38
Amaral, Lorena M; Cornelius, Denise C; Harmon, Ashlyn et al. (2015) 17-hydroxyprogesterone caproate significantly improves clinical characteristics of preeclampsia in the reduced uterine perfusion pressure rat model. Hypertension 65:225-31
Amaral, Lorena M; Cunningham Jr, Mark W; Cornelius, Denise C et al. (2015) Preeclampsia: long-term consequences for vascular health. Vasc Health Risk Manag 11:403-15
Przybyl, Lukasz; Ibrahim, Tarek; Haase, Nadine et al. (2015) Regulatory T cells ameliorate intrauterine growth retardation in a transgenic rat model for preeclampsia. Hypertension 65:1298-306
Cornelius, Denise C; Castillo, Javier; Porter, Justin et al. (2015) Blockade of CD40 ligand for intercellular communication reduces hypertension, placental oxidative stress, and AT1-AA in response to adoptive transfer of CD4+ T lymphocytes from RUPP rats. Am J Physiol Regul Integr Comp Physiol 309:R1243-50
Cornelius, Denise C; Amaral, Lorena M; Harmon, Ashlyn et al. (2015) An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia. Am J Physiol Regul Integr Comp Physiol 309:R884-91
Harmon, Ashlyn; Cornelius, Denise; Amaral, Lorena et al. (2015) IL-10 supplementation increases Tregs and decreases hypertension in the RUPP rat model of preeclampsia. Hypertens Pregnancy 34:291-306
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

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