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.

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.

INTRODUCTION: 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. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP decreases inflammation, placental apoptosis, improves endothelial damage and improves hypertension. METHODS: On gestational day (GD) 12 rats were chronically infused with placental anti-angiogenic factors sFlt-1 and sEng to induce HELLP. To neutralize FasL, MFL4 or FasL antibody was infused into a subset of HELLP or normal pregnant rats on GD13. IgG infusion into another groups 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. RESULTS: Administration of MFL4 to HELLP rats significantly decreased blood pressure compared to HELLP rats and HELLP+IgG rats and improved the biochemistry of HELLP syndrome. Both circulating and placental FasL were attenuated in response to MFL4 as were levels of placental and circulating TNF-alpha when compared to HELLP rats and HELLP+IgG rats. Endothelial cells exposed to placental debris and media from HP+MFL4 rats secreted significantly less endothelin-1 compared to stimulated endothelial cells from HELLP placentas. CONCLUSIONS: Neutralization of FasL is associated with decreased MAP, improvement in placental inflammation and endothelial damage in a model of HELLP syndrome.

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isolated proteinuria (n¼13, GA: 28AE6 wks). Misfoldome proteins were enriched by Congo Red precipitation and subjected to UPLC/MS/MS. Deep RNA sequencing (RNA-seq) was performed on decidua basalis (n¼5) and villous trophoblast (n¼5) of women with preterm severe PE (GA: 32AE1 wks). These reads, together with RNA-Seq data from the Illumina Human BodyMap 2.0 database (n¼16, adult tissues including kidney), were used to intersect specific transcripts that may contribute to aberrant proteinuria in PE. RESULTS: 646 unique proteins IDs comprised the urinary misfoldome of PE women. Our intersection analysis showed a potential contribution of villous trophoblast, decidua and kidney to the misfoldome (Figure). Villous trophoblast was a larger contributor than either kidney or decidua (Table). Kidney-specific transcripts such as solute carrier family 22 (SLC22A12, a urate transporter), SMIM24 (an uncharacterized small integral membrane protein), MMP7 (matrilysin), and CALB1 (calbindin 1, a protein linked to Huntington disease) mapped to distinct PE subphenotypes. CONCLUSION: The urinary misfoldome harbors a considerable number of peptides of placental and kidney origin which may interact to play key pathogenic roles in various PE subphenotypes. 183 Interleukin 1 beta is increased in the hippocampus and posterior cortex of rats with hypertension and systemic inflammation during pregnancy