Preeclampsia is a disease that affects 5% of all pregnant women and accounts for almost 15 % of maternal mortality. Thus its prevention would have a significant impact on maternal and perinatal outcome worldwide. It is believed that preeclampsia originates in defective trophoblast invasion, resulting in activation of the vascular endothelium triggered by placental ischemia. A disturbed renin-angiotensin system (RAS) and prostanoid balance are implicated in preclampsia. Despite extensive research, the pathophysiology of preeclampsia remains poorly understood. Two obstacles hindered a better understanding. First, research has been limited to mid and late gestation, probably long after the disease-causing initiating events occur. Second, models of preeclampsia have deficiencies, especially regarding early events of pregnancy. The studies will examine early and late events of pregnancy in the uteroplacental unit, using a new transgenic rat (TGR) model of the RAS [the female human (/?) angiotensinogen (AGT) TGR mated with the male ftrenin (REN) TGR] with characteristic features of preeclampsia. Our hypothesis is: Ang-(1-7) acts as a local autocrine/paracrine hormone in the uteroplacental unit regulating prostanoids during early and late pregnancy, comprising a crucial feature of cardiovascular regulation during uncomplicated pregnancy. In early gestation, we hypothesize that a reduced Ang-(1-7) allows for an increase in prostanglandin E2 (PGE2) required for normal implantation. In late pregnancy increased Ang-(1-7) opposes the actions of Ang II on PGE2 release, while facilitating the release of prostacylin (PGI2). Preeclampsia disrupts this regulation by activation of RAS in early pregnancy and a further unbridled activation of RAS resulting in increased TXA2 formation in late gestation. The following Specific Aims will be addressed:
Specific Aim 1 will assess the early stages of pregnancy (implantation and decidualization) and the expression of Ang-(1-7). We will use biochemical, immunocytochemical and molecular tools to assess the regulation of RAS peptides and enzymes during early normal and pre-hypertensive pregnancy.
Specific Aim 2 will determine the contribution of endogenous and exogenous Ang-(1-7) to prostanoid production during implantation in normal and pre-hypertensive pregnancy. Biochemical and physiological tools will be used to demonstrate how Ang-(1-7) influences the early events of pregnancy (implantation, decidualization and angiogenesis) in normal and pre-hypertensive pregnancy and how prostanoids are involved in its mediation.
Specific Aim 3 will assess the late effects of pregnancy on the expression of Ang-(1-7) and Ang II in normal and hypertensive TGR models. Their contribution to global and uteroplacental blood flow will be studied.
Specific Aim 4 will determine the contribution of endogenous and exogenous Ang-(1-7) to prostanoid content during late gestation during normal and hypertensive pregnancy. The autocrine and paracrine effects of Ang- (1-7) on prostanoid production from placenta and fetal membrane explants from normal pregnant and TGR at late gestation will be assessed. Since prostanoids regulate the angiogenic growth factor, VEGF, the release of VEGF and its soluble receptor, sfltl, from placenta explants will also be determined. The novel aspects of this project are elucidating the role of Ang-(1-7) in regulating prostanoid production during implantation and parturition, both as a circulating hormone and as a local autocrine/paracrine regulator of prostanoids in the utereoplacental unit in normal pregnancy and preeclampsia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL051952-20
Application #
8450149
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
20
Fiscal Year
2013
Total Cost
$257,204
Indirect Cost
$83,417
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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