Project 003 - Lorena Amaral

Preeclampsia (PE) affects 5-7% of all pregnancies in the U.S and 30% of hypertensive disorders in pregnancy
are caused by chronic hypertension (HTN) prior to pregnancy which increases the risk of superimposed PE
(SIPE). Despite being a leading cause of maternal death and perinatal morbidity, the mechanisms responsible
for PE and SIPE are unclear. Healthy normal pregnancy (NP) is associated with elevations in progesterone
and T helper 2 (TH2)/uterine natural killer cells (NK cells), favoring immunotolerance of the fetus. Activated
lymphocytes during NP express progesterone receptors, which stimulate a protein called Progesterone Induced
Blocking Factor (PIBF). PIBF increases during NP and stimulates interleukin-4 and TH2 cells (IL- 4/TH2) cells,
both of which are reduced during PE. PIBF also decreases the deleterious effects of cytolytic NK cells in
murine pregnancy. Importantly, we showed that PE is a progesterone deficient state that is associated with an
imbalance between TH1/TH2 cells, NK cells, and inflammatory cytokines that lead to endothelial dysfunction,
intrauterine growth restriction (IUGR) and HTN. We also reported that the increase in TH1 cells contributes to
production of agonistic angiotensin 1 receptor autoantibody (AT1-AA) by B cells, increases in endothelin (ET1) and soluble fms-like tyrosine kinase-1 (sFlt-1), all of which are associated with PE and SIPE. Even though
PIBF is essential for maintenance of NP, a role for PIBF to stimulate IL-4/TH2 as a mechanism to improve the
pathophysiology associated with PE or SIPE has not been studied. My recent published data indicate that PIBF
attenuates HTN and improves fetal IUGR in response to placental ischemia in the reduced uterine perfusion
pressure rat model of PE. In addition, my exciting clinical data show that PE patients have reduced PIBF, and
supplementation with progesterone (as 17-hydroxyprogesterone caproate (17-OHPC)) improves TH1/TH2 ratio.
Although PIBF stimulates TH2 lymphocytes secreting IL-4, whether 17-OHPC stimulates PIBF to protect
against PE or SIPE is unknown. Thus my hypothesis is that an increase in uterine artery resistance index leads
to a decrease in PIBF and IL-4 leading to increased TH1, NK and AT1-AA, causing changes in vasoactive
factors (increased sFlt-1, ET-1; decreased nitric oxide), thus contributing to SIPE with exacerbation of HTN in
the mother and IUGR in the offspring. This hypothesis will be tested using the pregnant Dahl salt-sensitive (DS)
rat, a model of superimposed PE, and will utilize a combination of in vitro and in vivo approaches to examine
the following specific aims: Aim 1: To test the hypothesis that 17-OHPC supplementation in the pregnant DS
rat, a model of SIPE, reduces BP and stimulates PIBF, reduces inflammation, AT1-AA, sFlt-1, ET-1, improves
endothelial-dependent relaxation, and prevents development of IUGR in offspring. Aim 2: To test the
hypothesis that PIBF supplementation in pregnant DS rat, a model of SIPE, reduces BP, stimulates IL-4/TH2,
reduces cytolytic NK cells, inflammation, AT1-AA, and reduces sFlt-1, ET-1, improves endothelial dependent
relaxation, and prevents the development of IUGR in offspring

Grant Number: 5P20GM121334-09
NIH Institute/Center: NIH
Principal Investigator: Lorena Amaral