Women with hypertensive forms of pregnancy such as hemolysis-elevated liver enzymes-low platelet syndrome have increased circulating endothelin 1; however, the relationship between hypertension and endothelin 1 has not been studied. Using an animal model, we sought to determine whether there was an increased activation/dysfunction of endothelin 1, the effect of endothelin 1 receptor-A blockade on hypertension and other manifestations of hemolysis, elevated liver enzymes, and low platelets syndrome. On gestational day 12, timed-pregnant rats were infused with soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEndoglin; 4.7 and 7 µg/kg) via mini-osmotic pumps for 8 days. A subset of rats were treated with receptor-A antagonist (ABT-627, 5mg/kg) for 8 days. Rats with hemolysis-elevated liver enzymes-low platelet syndrome had significantly increased hypertension (P = .0001), circulating endothelin 1 (P = .03), and a significant 3.3- and 7.2-fold increase in preproendothelin messenger RNA (mRNA) expression in the placenta and liver (P = .01 and .04). Urinary protein:creatinine ratio was significantly increased in these animals (P = .0007), and circulating factors from these rats stimulated a significant increase in endothelial cell secretion of endothelin 1 (P = .001) in an in vitro assay. Blockade of the endothelin 1 receptor A significantly decreased hypertension (P = .001), circulating endothelin 1, and interleukin 17 (P = .004 and .003), placental preproendothelin mRNA expression (P = .016), and urinary protein:creatinine ratio (P = .007) in rats with hemolysis-elevated liver enzymes-low platelet syndrome. Blockade of the endothelin 1 receptor A significantly decreased hemolysis (P = .009), liver enzymes (P = .011), and significantly increased platelet levels (P = .03) and decreased circulating CD4+ and CD8+ T lymphocytes (P = .0004 and .0001) in rats infused with sFlt-1 and sEndoglin. These data support the hypothesis that endothelin 1 activation has a critical role in pathophysiology of as hemolysis-elevated liver enzymes-low platelet syndrome.

Problem Angiogenic imbalance during pregnancy is associated with immune activation, hypertension, increased T cell infiltration, and neurological insults. Method of Study On gestational day (GD) 12 timed-pregnant rats were infused with anti-angiogenic factors sFlt-1 and sEndoglin (4.7 and 7μg/kg) to create HELLP syndrome via mini-osmotic pumps for 8 days, with a subset of these rats having Orencia (2mg/kg) infused on GD13. On GD19, blood brain barrier (BBB) permeability was evaluated via Evan’s Blue infusion, blood was collected for T cell measurements, inflammatory cytokine secretion. Brain tissues were also collected to examine inflammatory cytokine infiltration. Results T cell attenuation with Orencia decreased circulating CD4+ and CD8+ T cells, circulating TNFα and IL-17, BBB permeability and significantly decreased biochemical evidence of HELLP compared to untreated HELLP rats. Conclusions These data support the hypothesis that T cells have a critical role in contributing to the pathophysiology that is seen in angiogenic imbalance during pregnancy.

Anxiety during pregnancy is associated with adverse outcomes in mothers and infants. Unfortunately, as anxiety is often synonymously mentioned with depression, the studies focusing solely on anxiety during pregnancy are not as robust as those in the field of depression are. In this work, we provide an overview of what is currently known about general anxiety during pregnancy, pregnancy-related anxiety and the potential impacts anxiety could have on post-partum care. An overview of potential risk factors, post-partum maternal outcomes, infant outcome along with pharmacological and nonpharmacological treatments are covered with a specific focus on high-risk pregnancies. Although anxiety during pregnancy is normative; anxiety can become problematic and negatively impact upon behavior, resulting in potential harm to the mother, as well as her developing fetus or child (ren) at home. The clinical diagnosis for anxiety and conditions associated with anxiety often require lengths of time that are not applicable for the pregnant patient, which has led to diagnosis and terms such as pregnancy-related anxiety. Importantly, increasing awareness about the increased potential risk to mothers who may be affected by anxiety during pregnancy or the post-partum period has the potential to improve maternal mental health screening and access to care.

Hypertension and inflammation during pregnancy are suggested to contribute to the development of post-partum depression and anxiety. Using a rat model of severe preeclampsia and Hemolysis Elevated Liver enzymes Low Platelet syndrome which displays both hypertension and inflammation during pregnancy we evaluated whether rats were prone to develop depression or anxiety in the post-partum period. On gestational day 12, mini-osmotic pumps infusing sFlt-1 and sEng were placed into rats, a subset of these rats were infused with 2mg/kg of Orencia (Abatacept) the following day to determine if immune suppression via T cell depletion prevented any changes in maternal depression and/or anxiety-like behavior. All rats including normal pregnant controls delivered between gestational days 21–22. Post-partum severe preeclamptic rats buried significantly more marbles compared to normal pregnant rats (p=0.002) and Orencia treated rats (p=0.05). Severe preeclamptic rats spent significantly more time in closed arms of the elevated plus maze compared to normal pregnant rats (p=0.009) and Orencia treated rats (p=0.05). Severe preeclamptic rats were hypertensive compared to normal pregnant (p=0.03) and Orencia treated rats (p=0.01). Finally, severe preeclamptic rats had increased blood brain barrier permeability compared to normal pregnant rats (p=0.03), which was reversed in Orencia treated rats (p=0.008). These results suggest that severe preeclampsia/Hemolysis Elevated Liver enzymes Low Platelet syndrome during pregnancy contributes to an increase in anxiety-like behavior, blood brain barrier permeability and hypertension in the post-partum. The current results suggest that T cell suppression during pregnancy can also help prevent chronic hypertension and increased anxiety in the post-partum period.

Introduction Placental FasL is up-regulated in women with HELLP (hemolysis elevated liver enzyme and low platelet) syndrome and has been proposed to contribute to the liver damage seen in these patients. Objective This study aimed to determine if an experimental rodent model of HELLP also had dysregulation of Fas/FasL compared to normal pregnant (NP) rats. We also set out to determine if blockade of the endothelin system regulated Fas/FasL expression in HELLP rats. Study Design On gestational day (GD) 12, sEng (7ug/kg) and sFlt-1 (4.7ug/kg) infusion began via mini-osmotic pump into NP rats. On GD19 plasma and tissue were collected and FasL and Fas were measured via enzyme linked immunosorbent assay and gene expression via real-time PCR. Results HELLP rats had significantly more circulating and placental FasL compared to NP rats, whereas hepatic FasL was decreased and placental Fas was increased compared to NP rats. Administration of an endothelin A receptor antagonist (ETA) beginning on GD12 significantly decreased placental expression of Fas in HELLP rats. Liver mRNA transcript of Fas was significantly increased in HELLP rats compared to NP rats). Conclusion These data suggest that rats in this experimental model of HELLP syndrome have abnormal expression of the Fas/FasL system. Future studies will examine the sources of Fas/FasL dysregulation in this model and if blockade could reduce some of the inflammation and hypertension associated with HELLP syndrome.