Progesterone as a treatment option for superimposed PE
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. Even though PIBF is essential for maintenance of healthy pregnancy, 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 mimic 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 in this current project 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 I 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.