Abstract
IntroductionPreeclampsia (PE) is a life-threatening pregnancy disorder characterized by wide-spread endothelial dysfunction. Placental factors circulating in the maternal blood are believed to cause endothelial dysfunction. Our previous study identified HtrA4 as a placenta-specific serine protease that is released into the maternal circulation and significantly increased in early-onset PE. In this study, we examined the impact of HtrA4 on expression of endothelial genes related to vessel biology, using human umbilical vein endothelial cells (HUVECs) as a model. MethodsHUVECs were treated with 0 or 3 μg/ml HtrA4 (highest concentration seen in PE circulation) for 24 h and analysed by an endothelial cell biology PCR array containing 84 genes. HtrA4-induced changes were then validated by real-time RT-PCR and ELISA for time and dose dependency. ResultsHigh levels of HtrA4 significantly altered the expression of a range of genes related to inflammation, vaso-activity, angiogenesis, cell adhesion, platelet activation and coagulation. In particular, pro-inflammatory genes IL6, PTGS2 (COX2) and IL1B were significantly increased by HtrA4. IL6 protein in HUVEC media was also drastically increased. THBD, an anticoagulant factor reported to be increased in PE, was significantly up-regulated by HtrA4. In contrast, THBS1, which is involved in many regulatory processes of endothelial cell biology, was severely down-regulated by HtrA4. DiscussionHtrA4 significantly increased the inflammatory responses of HUVECs, and altered their expression of a number of genes important for vessel biology. These data suggest that placenta-derived HtrA4 that is increased in PE circulation is a potential causal factor of endothelial dysfunction.
Highlights
Preeclampsia (PE) is a life-threatening pregnancy disorder characterized by wide-spread endothelial dysfunction
We further demonstrated that high temperature requirement A4 (HtrA4) at high concentrations seen in early-onset PE disrupted the tube formation of human umbilical vein endothelial cell (HUVEC), disturbed cellular integrity and increased cellular permeability [23]
We used HUVECs as a model and examined the effect of HtrA4 on the expression of 84 genes that are involved in endothelial cell biology (Supplementary Table 2)
Summary
Preeclampsia (PE) is a life-threatening pregnancy disorder characterized by wide-spread endothelial dysfunction. Placental factors circulating in the maternal blood are believed to cause endothelial dysfunction. Our previous study identified HtrA4 as a placenta-specific serine protease that is released into the maternal circulation and significantly increased in early-onset PE. We examined the impact of HtrA4 on expression of endothelial genes related to vessel biology, using human umbilical vein endothelial cells (HUVECs) as a model. Preeclampsia (PE) is a life-threatening disorder of human pregnancy affecting 2e8% of pregnancies worldwide [1,2]. Elevated circulating factors in PE include cytokines, antiangiogenic factors, syncytiotrophoblast microparticles and activated leukocytes [5e8]. Changes in many of these factors are believed to reflect an exacerbated maternal response to pregnancy, which itself is considered as a low grade systemic inflammation [9]. One study has shown that serum from preeclamptic women is cytotoxic to endothelial cells in vitro, and that clinical condition improves drastically after 24e48 h postpartum when the cytotoxic activity is dramatically reduced [10]
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