Introduction: Preeclampsia (PE) is a life-threatening pregnancy disorder that is characterized by wide-spread endothelial dysfunction. Placental factors released into the maternal circulation are believed to cause endothelial dysfunction and contribute to PE development. We have previously demonstrated that: HtrA4 (a serine protease) is expressed only by the placenta, it is released into the maternal circulation, and its levels are significantly increased in PE. We hypothesized that high levels of circulating HtrA4 may disrupt endothelial cell function and contribute to PE development. Aims: We aimed to examine the impact of HtrA4 on expression of endothelial genes involved in vessel biology and on release of pro-inflammatory factors, using human umbilical vein endothelial cells (HUVECs) as a model. Methods: HUVECs were treated with 0 or 3μg/ml HtrA4 (highest concentration seen in PE circulation) for 24h, and an endothelial cell biology PCR array containing 84 genes was screened. The results were validated by real-time RT-PCR and ELISA on cells treated with 0, 1.5 and 3μg/ml HtrA4 for 24 and 48h. Results: High 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, expressions of pro-inflammatory factors IL6, PTGS2 (COX2) and IL1B were significantly increased by HtrA4, suggesting that HtrA4 induces endothelial inflammation. IL6 protein in HUVEC media was also drastically increased by HtrA4. IL6 is known to be considerably elevated in PE circulation and heightened inflammation is a hallmark of PE. Furthermore, THBD, an anticoagulant factor that is 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. Conclusions: High levels of placenta-derived HtrA4 that is seen in PE circulation is a potential causal factor of endothelial dysfunction.