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.
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
OBJECTIVE: The Fas ligand (FasL) system has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We have recently reported that endothelin antagonism impacted the Fas/FasL system, therefore in the current study we tested the hypothesis that neutralization of FasL in an animal model of HELLP syndrome decreases inflammation, improves endothelial damage and in turn improves hypertension. STUDY DESIGN: Mini-osmotic pumps infusing anti-angiogenic factors sFlt-1 and sEng were placed into normal pregnant (NP) rats on gestational day (GD) 12 to induce HELLP syndrome (n¼15). On GD13, 7 of these HELLP rats were infused with 500ng/kg of MFL4 via the jugular vein to inhibit FasL. Untreated NP rats (n¼5) served as controls. On GD19 mean arterial pressure (MAP) was measured and all rats were euthanized. Maternal tissues were collected, placentas were cultured under normal culture conditions and media collected (conditioned media -CM) and placed over human umbilical vein endothelial cells (HUVECs) for 24hrs. RESULTS: Administration of FasL to HP rats significant decreased MAP (p¼0.03) compared to untreated HP rats. However there was not a significant change in LDH (p¼0.164), AST (p¼0.52) or platelets (p¼0.746) due to attenuation of FasL in HELLP rats compared to untreated HELLP rats. Circulating FasL was significantly increased in HELLP rats compared to NP rats (p¼0.0006) but was attenuated with infusion of MFL4 (p¼0.0005). Placental protein expression of TNF-alpha, measured via ELISA, was significantly reduced due to MFL4 infusion in HELLP rats (p¼0.0009). Finally, HUVECs exposed to CM from HP+MFL4 rats secreted significantly less endothelin-1 compared to HUVECs exposed to CM from HP placentas (p¼0.004) and CM from NP placentas (p¼0.02). CONCLUSION: These data suggest that neutralization of FasL decreases MAP and improves placental inflammation and endothelial damage in an animal model of HELLP syndrome. However FasL neutralization does not improve the symptomology of HELLP syndrome, suggesting that FasL may only contribute to the inflammatory pathway.
In this case control study, human maternal plasma < 20 weeks from control (n¼40) and preeclamptic (n¼21) pregnancies and nonpregnant women (n¼113) and clinical data were obtained from the Iowa Women's Health Tissue Repository (IRB# 200910784, 201010769). CP was measured using a commercially available ELISA. Posm was measured using the freezing point depression method. RESULTS: Compared to non-pregnant women (288AE2 mOsm/kg) and consistent with previous studies, pregnant women exhibited a suppressed Posm (p<0.001). Posm was even more suppressed in PreE pregnancies than in control pregnancies in both first (276AE6 vs 288AE2 mOsm/kg, p<0.02) and second (275AE7 vs 288AE2, p¼0.13) trimesters. After controlling for age, chronic hypertension, diabetes, and BMI, first trimester Posm is significantly associated with PreE (aOR¼0.902, p<0.013). As previously published, first (1031AE87 vs 618AE72 pg/mL, p<0.003) and second (1070AE89 vs 501AE75, p<0.001) trimester plasma CP was elevated in PreE pregnancies. ROC curve analyses indicated that first trimester maternal plasma CP is predictive of PreE (AUC¼0.88, p<0.001), but the CP/Posm ratio did not add to the predictive strength of CP alone (AUC¼0.88, p<0.001). CONCLUSION: Consistent with an elevated secretion and action of AVP during PreE, Posm suppression is exaggerated in PreE pregnancies. While combining CP and Posm values did not improve the predictive power of CP alone, the data support the concept that excess AVP during PreE drives water retention, while the renal response to AVP is maintained. These data support an over-sensitization of the AVP-Posm relationship in very early gestation in pregnancies which develop PreE. The future identification of factors which amplify AVP secretion in very early gestation may lead to earlier and more accurate diagnostic tests and novel preventative therapeutic targets for PreE.
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