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  • br Materials and methods All studies were performed


    Materials and methods All studies were performed in 230–250g timed-pregnant Sprague Dawley rats (Harlan, Indianapolis, Indiana). Animals were housed in a temperature controlled room with a 12:12 light:dark cycle. All experimental procedures in this study were in accordance with the National Institute of Health guidelines for use and care of animals and were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center.
    Statistical analysis All of the data are reported as mean±standard error mean. Data was analyzed via two-way analysis of variance (ANOVA). Interactions that equaled p<0.05 were analyzed via Tukey’s multiple comparison test or Student’s T. Graphpad Prism version 5.0 was used as the statistical software program. P<0.05 was considered statistically significant.
    Discussion Studies have reported that trophoblast debris from ischemic placentas, such as in HELLP syndrome and preeclampsia can lead to the stimulation and activation of the vascular endothelium which results in endothelial dysfunction, inflammation and hypertension [24], [25], [26]. The Fas/FasL system has been implicated in contributing to some of the dysfunction present in HELLP syndrome [27] as the increase in MPC 6827 hydrochloride FasL-induced apoptosis of trophoblast MPC 6827 hydrochloride is suggested to be one cause for the excessive release of trophoblast debris from the placenta into the maternal circulation [11], [28], [29] . In the current study we investigated whether an experimental rat model of HELLP syndrome also exhibited alterations in Fas or FasL. We found that circulating and placental levels of FasL are increased in HELLP rats compared to NP rats and hepatic FasL was significantly decreased. These results correlate with data from human studies which have reported that circulating and placental FasL expression is increased in women with HELLP syndrome [10], [11]. Additionally placental derived FasL has been reported to not only be the primary source of FasL in women with HELLP syndrome but to also induce liver apoptosis and cytotoxicity in these women [10]. As the decrease in hepatic FasL in HELLP rats was statistically significant from NP rats, this suggests that indeed the placenta may serve as the primary source of FasL in the circulation. The lack of significant changes in circulating Fas is in contrast to what has been previously reported in the clinical literature, in which studies found that women with HELLP syndrome had increased circulating soluble Fas levels [30], [31]. It could be that as these other studies measured the soluble form of Fas and we did not assay the soluble only portion of Fas, but rather total Fas, we did not have any statistically significant changes in circulating Fas. Placental Fas expression was significantly increased in response to HELLP syndrome. Despite the lack of significant difference in protein levels of hepatic Fas, mRNA transcript of Fas was significantly increased in this model of HELLP syndrome. One might expect to see an increase in Fas levels as there was a statistically significant decrease in FasL protein levels. It’s possible that due to the short nature of disease development (GD12–GD19) in this experimental animal model there was not enough experimental time to allow for statistically significant changes in protein levels of Fas to be expressed. Future experiments will address the protein:mRNA levels of Fas and FasL in rats that have a full gestation. We have previously reported that attenuation of the endothelin system in this model of HELLP syndrome decreases hypertension, significantly decreases all of the symptoms of HELLP syndrome that were found to be significantly increased in untreated rats infused with sFlt-1 and sEng to mimic HELLP syndrome (i.e. a significant increase in hemolysis, a significant elevation in liver enzymes and a significant decrease in platelets), endothelial activation and cytokine secreting T cells [16]. Indeed, HELLP rats were found to have an average mean arterial pressure (MAP) of 121.5±2.44mmHg compared to 99.5±2.2mmHg in NP rats which was reduced to 100.7±4.8mmHg in HELLP+ETA treated rats [16]. In the current study we used previously collected samples from these same animals to determine if blockade of the endothelin system via the ETA receptor reversed any changes in Fas/FasL expression due to HELLP syndrome. Circulating FasL tended to decrease in response to ETA antagonism in HELLP rats but neither placental nor liver FasL were significantly affected by ETA antagonism. However, ETA blockade in HELLP rats tended to drive both liver FasL and placental Fas levels in the direction of a normal pregnant response. As NP rats treated with the ETA antagonist didn’t exhibit any statistically significant changes in Fas or FasL production compared to the untreated NP rats, we believe that the changes in Fas and FasL are due directly to HELLP syndrome induced by angiogenic imbalance.