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

Abstract

<jats:p> 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. </jats:p>

The BPH/5 Mouse Model of Superimposed Preeclampsia Is Not a Model of HELLP Syndrome

“…The etiologies of PE and HELLP syndrome are both thought to include abnormal placental development leading to a placental antiangiogenic factor released into the maternal circulation [8]. Yet, differences in cytokine expression and angiogenic profiles are reported [33][34][35]. For example, HELLP patients without PE have significantly lower sFlt-1/PlGF ratios (soluble fms-like tyrosine kinase-1/placental growth factor) than gestational age-matched patients with PE or PE and HELLP [36].…”