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Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity in the U.S. While the pathogenesis remains unclear, PE is characterized by new onset hypertension associated with progesterone deficiency, elevated cytolytic natural killer cells (cNK), inflammation, and endothelial dysfunction. Progesterone is essential in the initiation and maintenance of pregnancy. We have shown that progesterone supplementation regulates endothelial function and suppresses endothelin-1 (ET-1) and stimulates nitric oxide (NO) in response to placental ischemia during pregnancy. In addition, progesterone signals the synthesis and release of progesterone induced blocking factor (PIBF) from lymphocytes in order to regulate the proinflammatory balance of early pregnancy. However the role of PIBF in PE pathology is not well examined. This study was designed to test the hypothesis that inhibition of PIBF causes inflammation and increases markers of endothelial dysfunction and hypertension during pregnancy. Rabbit anti-PIBF IgG (0.25, low dose-LD or 0.50 mg/mL, high dose-HD) was administered intraperitoneal on gestation day (GD) 15 to normal pregnant Sprague Dawley (NP) rats, on GD 18 carotid catheters were inserted and on GD 19 blood pressure (MAP) and samples were collected. MAP in NP rats (n=7) was 99 + 3 mmHg, which increased to 116 + 2 in NP+ anti-PIBF LD (n =10) and 113 + 4 mmHg in NP+ anti-PIBF HD (n=6), p+ 8 pg/mL in NP rats and increased to 84 + 21 pg/mL in NP+ Anti-PIBF HD (n=4), p+ 11 in NP rats (n=4), which decreased to 36 + 4 in NP+ Anti-PIBF HD however, cytolytic NK cells were 0.6 + 0.2 in NP which were increased to 3.0 + 1 in NP+ Anti-PIBF HD, p+ 11 μM in NP rats (n=5), which significantly decreased to 21 + 1 μM in NP+ Anti-PIBF (n=6) HD, p

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Infusion of sFlt-1 causes hypertension and other characteristics of PE in pregnant rodents. However a role for sFlt-1 in causing mt dysfunction and ROS is unknown. Progesterone induced blocking factor (PIBF), is a product of progesterone signaling which lowers inflammatory processes. We have shown that PIBF lowers blood pressure in a rat models of PE. This study was designed not only examine the role of mt ROS in sFlt-1 induced hypertension during pregnancy but to also examine the effect of PIBF to improve mt function and hypertension in response to elevated sFlt-1 during pregnancy. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg –1 ·day –1 for 6 days, gestation days (GD) 13-19 ) in the presence or absence of PIBF (2.0 μg/mL) administered intraperitoneal on GD 15 to sFlt-1 induced hypertensive pregnant rats. Mean arterial blood pressure (MAP), placental and endothelial mt ROS and function were measured on GD 19. Infusion of sFlt-1 into NP rats increased MAP to 112 + 2 (n=11) compared with control NP rats 98 + 2 mmHg (n=15, p+ 1 mmHg in the presence of sFlt-1(n=5, p+ 6 in NP (n=4), 429 + 32 in NP+ sFlt-1(n=3) and reduced to 234 + 15 in NP+ sFlt-1+ PIBF (n=3). State 3 respiration, which is indicative of ATP production, was reduced in placentas of sFlt-1 infused rats versus NP, but was improved with PIBF. Moreover, sera from NP+sFlt-1 treated with PIBF attenuated endothelial cell mtROS ( 29 + 8 % gate) compared with sera from NP+sFlt-1 (54 + 15 % gate (n=4)). Our study indicates a role of sFlt-1 induced hypertension during pregnancy to reduce placental and endothelial cell mt function. Importantly, supplementation of PIBF improved mt function and ROS which was associated with improved blood pressure in sFlt-1 induced hypertensive pregnant rats indicating the efficacy of improved progesterone signaling as a potential therapeutic for PE.

Preeclampsia (PE) affects 5-7% of all pregnancies in the U.S and it is characterized by new onset hypertension in association with progesterone deficiency, elevated natural killer (NK) cells and inflammatory cytokines. Despite being a leading cause of maternal death and perinatal morbidity, the mechanisms responsible for the pathogenesis of PE are unclear. Progesterone is crucial for establishing and maintaining pregnancy and it exerts immune modulatory effects by the lymphocyte-derived protein progesterone induced blocking factor (PIBF). Its immunological effects include inhibition of natural killer (NK) cell activity and can regulate the proinflammatory balance. PIBF has been shown to act through IL-4/TH2, which are reduced during PE and increased during normal pregnancy, however the role of PIBF deficiency in PE pathology is not well examined. Thus, this study was designed to test the hypothesis that PIBF blockade stimulates cytolytic NK cells to cause the symptoms of PE during pregnancy. Rabbit anti-PIBF IgG (0.25, low dose-LD or 0.50 mg/mL, high dose-HD) was administered intraperitoneal on gestation day 15 to normal pregnant Sprague Dawley (NP) rats and on day 18 carotid catheters were inserted and on GD 19 blood pressure and samples were collected. MAP in NP rats (n=7) was 99± 3 mmHg, which increased to 116± 2 in NP+ anti-PIBF LD (n =10) and 113±4 in NP+ anti-PIBF HD (n=4), p

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines which are likely culprits for decreased fetal weight during PE pregnancies. Progesterone induced blocking factor (PIBF) increases during normal pregnancy and has been shown to decrease inflammation and cytolytic NK cells, both of which are increased during PE. Currently, there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE the leading cause for premature births worldwide. We have previously shown that progesterone supplementation with 17-OHPC improves inflammation, fetal weight and blood pressure in the preclinical RUPP rat model of PE. However the mechanism where by progesterone improves the pathophysiology of PE has never been determined. This study was designed to test the hypothesis that PIBF reduces inflammation while improving hypertension in response to placental ischemia. To test this hypothesis, PIBF (2.0 μg/mL) was administered intraperitoneally on gestation day 15 to RUPP or normal pregnant (NP) rats and on day 18 carotid catheters were inserted and on GD 19 blood pressure and samples were collected. MAP in NP rats (n=9) was 101 + 3 and 110 + 3 in NP+PIBF (n=5), 122 + 2 in RUPP rats (n=7), which improved to 110 + 3 mmHg in RUPP+PIBF (n=9), p+ 0.1 g in NP, 2.5 + 0.1 in NP+PIBF, 1.9 + 0.1 in RUPP and improved to 2.2 + 0.1 in RUPP+PIBF. Neither placental weight nor litter size was affected by PIBF. Fetal reabsorption was lower in RUPP+PIBF compared to RUPP rats. Total placental NK cells were 31 + 9 in NP (n=4), 31 + 5 in NP+PIBF (n=4), 42 + 8 in RUPP rats (n=4) and reduced to 26 + 2 in RUPP+PIBF (n=6). Placental cytolytic NK cells were 0.8 + 0.1 in NP, 0.2 + 0.1 in NP+PIBF, and 1.4 + 0.1 in RUPP rats, which decreased to 0.4+0.1 in RUPP+PIBF. CD4 + T cells were decreased from 21 + 6 in RUPP rats (n=4) to 8 + 2 gate in RUPP+PIBF (n=7). Collectively, our findings demonstrate that PIBF, a produce to progesterone receptor stimulation by progesterone, could be a mechanism to improve fetal growth restriction, inflammation as indicated by CD4+ T cells and cytolytic NK cells while normalizing blood pressure in response to placental ischemia during pregnancy.