Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension in mid-late gestation and can include multi-organ dysfunction with or without proteinuria. It affects 5%-7% of all pregnancies in the U.S., making PE a major contributor to maternal and fetal morbidity and mortality. Currently, there is no cure for this pregnancy complication except for early delivery of the placenta and fetus. Moreover, the therapeutic options to treat PE are very limited. One potential trigger for the development of PE is progesterone deficiency-induced imbalance between T Helper 1(Th1)/Th2 cells, an increase in cytolytic natural killer (NK) cells and inflammatory cytokines that in turn leads to endothelial dysfunction, intrauterine growth restriction (IUGR) and hypertension. Importantly, progesterone signals the synthesis of progesterone-induced blocking factor (PIBF) which has anti-inflammatory effects and could promote the regulation of inflammation balance during pregnancy. However, the role of progesterone and PIBF in the pathophysiology of PE is still not fully understood. Thus, this current study was designed to test the hypothesis that inhibition of PIBF causes signs of PE in pregnant Sprague Dawley rats. In order to address our hypothesis, rabbit anti-PIBF IgG (0.25, low dose-LD or 0.50 mg/mL, high dose-HD) was administered intraperitoneally on gestation day (GD) 15 to normal pregnant Sprague Dawley (NP) rats. On GD 18, carotid catheters were inserted and on GD 19 mean blood pressure (MAP) and samples were collected for further analysis. MAP in normal pregnant rats (NP) rats (n = 7) was 99 ± 3 mmHg, which increased to 116 ± 2 mmHg in NP+ anti-PIBF LD (n = 10) and 113 ± 4 mmHg in NP+ anti-PIBF HD (n = 4), p <0 .05. Plasma TNF-alpha levels were 35 ± 8 pg/mL in NP rats and increased to 84 ± 21 pg/mL in NP+ Anti-PIBF HD (n = 4), p <0 .05. Plasma IL-4 and IL-10 levels were 22 ± 5 and 25+6 pg/mL in NP (n = 5), which decreased to 6 ± 1 and 8 ± 1 pg/mL in NP+ Anti-PIBF LD (n = 6, p < 0.05) and 16 ± 4 and 15 ± 5 pg/mL in NP+ Anti-PIBF HD (n = 4). Circulating total NK cells were 67 ± 11 % gate in NP rats (n = 3), which decreased to 28 ± 7% gate in NP+ Anti-PIBF LD and 45 ± 6% gate in NP+ Anti-PIBF HD. Cytolytic NK cells were increased in NP+ Anti-PIBF HD, p <0 .05. Moreover, circulating NO levels were significantly decreased while renal cortex PPET-1 levels increased NP+ Anti-PIBF HD. Our study demonstrates that PIBF blockade causes hypertension, inflammation and signs of endothelial dysfunction, all of which are associated with PE, thus indicating the importance of progesterone signalling pathways during a healthy pregnancy.

Abstract Preeclampsia (PE) is characterized by de novo hypertension (HTN) and is often associated with intrauterine growth restriction (IUGR). Hallmarks of PE are placental ischemia, decreased nitric oxide (NO) bioavailability, oxidative stress (OS), and organ damage in the kidneys and brain. This study aims to characterize a new model of PE using pregnant IUGR rats from hypertensive placental ischemic dams. It is hypothesized that pregnant IUGR rats from hypertensive placental ischemic dams will have elevated blood pressure (BP), OS, and organ damage. In this study, pregnant rats are divided into two groups: normal pregnant (NP) and hypertensive placental ischemic dams (RUPP). Offspring from NP and RUPP dams were mated at 10 weeks of age to generate pregnant IUGR (IUGR Preg) and pregnant control (CON Preg) rats. BP and other markers of PE were evaluated during late gestation. Pregnant IUGR rats had elevated BP and systemic OS. The maternal body weight of pregnant IUGR rats and their pups' weights were decreased, while the brains were enlarged with elevated OS. In summary, pregnant IUGR rats, born from hypertensive placental ischemic dams, have HTN and increased systemic and brain OS, with larger brain sizes and smaller pups. Furthermore, this study shows that pregnant IUGR rats exhibit a preeclamptic‐like phenotype, suggesting a new epigenetic model of PE.

Male IUGR offspring have mt-Dys and elevated IL-17, which may contribute to hypertension and a greater impairment in CBF autoregulation. Female IUGR offspring may be protected due to an increase in mitochondrial antioxidants. In summary, studying the dimorphic sex differences in the mechanisms of hypertension and cerebrovascular dysfunction in offspring of preeclamptic women, may improve the offspring's risk of hypertension, cardiovascular disease, stroke, and cognitive dysfunction later in life.

Introduction: Preeclampsia, syndrome with hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, affects 5% of pregnancies. It is a major cause of fetal and matern...