Fas ligand neutralization attenuates hypertension, endothelin-1, and placental inflammation in an animal model of HELLP syndrome.

Neutralization of FasL is linked to suppression of hypertension, placental inflammation, and endothelin system activation in an animal model of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. During HELLP syndrome the placenta has been reported to serve as the primary source of Fas ligand (FasL), which has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP syndrome decreases inflammation and placental apoptosis, improves endothelial damage, and improves hypertension. On gestational day (GD) 12, rats were chronically infused with placental antiangiogenic factors sFlt-1 and sEng to induce HELLP syndrome. To neutralize FasL, MFL4 or FasL antibody was infused into a subset of HELLP or normal pregnant rats on GD13. IgG infusion into another group of NP and HELLP rats on GD13 was used as a control for FasL antibody, and all rats were euthanized on GD19 after blood pressure measurement. Plasma and placentas were collected to assess inflammation, apoptosis, and the degree of placental debris activation of endothelial cells. Administration of MFL4 to HELLP rats significantly decreased blood pressure compared with untreated HELLP rats and HELLP rats infused with IgG and improved the biochemistry of HELLP syndrome. Both circulating and placental FasL were significantly attenuated in response to MFL4 infusion, as were levels of placental and circulating TNFα when compared with untreated HELLP rats and HELLP rats infused with IgG. Endothelial cells exposed to placental debris and media from HP + MFL4 rats secreted significantly less endothelin-1 compared with stimulated endothelial cells from HELLP placentas. Neutralization of FasL is associated with decreased MAP and improvement in placental inflammation and endothelial damage in an animal model of HELLP syndrome.

Maternal immune suppression during pregnancy does not prevent abnormal behavior in offspring.

BACKGROUND: Offspring of hypertensive disorders of pregnancy are at an increased risk of developing neurodevelopmental and neurobehavioral disorders compared to offspring from non-affected pregnancies. Using rodent models of Preeclampsia (PreE; new onset of hypertension after 20 weeks gestation) and HELLP (hemolysis, elevated liver enzymes, and low platelets), we studied the behavioral outcome of their offspring in adolescence. METHODS: A subset of dams received Orencia, a T-cell activation inhibitor, as T cells have been associated with the induction of hypertension and inflammation during pregnancy. We hypothesized that offspring from hypertensive dams would experience adverse behavioral outcomes in social, cognitive, locomotor, and anxiety tests, and offspring from dams treated with Orencia would demonstrate less adverse behaviors. RESULTS: Male offspring of PreE + Orencia dams (p < 0.05) and female offspring from HELLP + Orencia dams (p < 0.05) spent more time playing compared to normal pregnant offspring. All offspring from hypertensive and Orencia-treated dams performed worse on the Barnes Maze test compared to normal pregnant. We also measured adult (postnatal day > 60) myelin basic protein (MBP) and NeuN expression in both the prefrontal cortex and hippocampus. In the hippocampus and prefrontal cortex, there was no difference in expression of either MBP or NeuN in all groups regardless of sex. CONCLUSION: The results from this study suggest that offspring of hypertensive disorders of pregnancy have behavioral changes, specifically cognitive differences. This study has shown that there is a sex dependent difference in offspring neurobehavioral development, influenced in part by the type of hypertensive disorder of pregnancy, and alterations in the maternal immune system.

Children of pregnancies that are complicated by hypertensive disorders of pregnancy (HDP) such as Preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome have an increased risk of having behavioral deficits and changes in brain development. Both Preeclampsia and HELLP have been shown to activate the immune and inflammation systems in the body of the mother. In this study, we used offspring of rat models of Preeclampsia and HELLP to study their behavior including anxiety-like behaviors and memory deficits. We also compared offspring of rat models of Preeclampsia and HELLP that were given Orencia, which minimizes immune responses by blocking the activation of T cells. We also studied two regions of the brain (prefrontal cortex and hippocampus) to measure two proteins (myelin basic protein (MBP) and NeuN) involved in brain function. Our study found that offspring from dams that were treated with Orencia during pregnancy with HDP had sex differences in time playing. All offspring, regardless of the HDP dam being treated with or without Orencia, had evidence of spatial learning deficits. When sexes and groups were compared there was no difference in MBP or NeuN expression in the prefrontal cortex or hippocampus.

Evidence of Anxiety, Depression and Learning Impairments following Prenatal Hypertension.

BACKGROUND: Hypertensive disorders of pregnancy, such as Preeclampsia (PreE) and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome, affects approximately 5-10% of pregnancies and increases the risk of women developing disorders, such as anxiety or depression, in the postpartum period. Using preclinical rodent models, we set out to determine whether rats with a history of PreE or HELLP had evidence of anxiety, depression or cognitive impairment and whether immune suppression during pregnancy prevented these changes in mood and/or cognition. METHODS: Timed-pregnant rats were infused with sFlt-1 and/or sEng to induce PreE or HELLP beginning on gestational day 12. After delivery, a battery of validated behavioral assays was used to assess post-partum depression, anxiety and learning. RESULTS: There was no negative effect on maternal pup interaction due to PreE or HELLP; however, hypertensive dams spent more time immobile in the forced swim test (p < 0.0001). Hypertensive dams also spent less time in the open area of the open field (p = 0.001). There were no significant changes in recognition memory (p = 0.08); however, spatial learning was impaired in hypertensive dams (p = 0.003). Immobility time in the forced swim test was positively correlated with increased circulating S100B (p = 0.04), while increased time spent in the outer zones of the open field was negatively correlated with BDNF levels (p < 0.0001). CONCLUSION: The results from this study suggest that hypertensive pregnancy disorders are associated with depression, anxiety and learning impairments in the post-partum period.

Male HELLP pups experience sensorimotor delays and reduced body weight.

Offspring of Preeclampsia (PreE) and HELLP Syndrome are at an increased risk of developing neurodevelopmental disorders. In the current study we sought to determine if offspring from experimental models of PreE and HELLP had evidence of early onset neurodevelopmental delay. Offspring from PreE, HELLP and normal pregnant dams were assessed in a battery of sensorimotor tests beginning on postnatal day (PND) 3. Male HELLP offspring showed altered behavior in the surface righting reflex on PND 3 and cliff avoidance task from PND 3-6 relative to other groups. Results suggest that there are sex differences in offspring born to dams with PreE and HELLP.