[262-POS]: Alterations in placental eicosanoid production contribute to impaired vascular remodeling in preeclampsia

Objectives Preeclampsia (PreE) is thought to originate from an impaired vascular remodeling of the placental spiral arteries. Recent data suggests a possible role of cytochromeP450 (CYP450) vasoactive eicosanoids in the etiology of the disease. We tested the hypothesis that alterations in the profile of arachidonic acid (AA) metabolites of the CYP450 pathway may contribute to the impaired vascular remodeling in preeclampsia. Methods Proliferation of BeWo cells, an in vivo model of trophoblast syncytialisation, was measured in the presence of 20-HETE, the major CYP450 metabolite, and 17-ODYA, a mechanism-based suicide substrate CYP450 inhibitor, in order to determine the proliferative actions of 20-HETE. In addition, microsomes were isolated from placental vessels of normal pregnant (NP) and PreE women and CYP450 enzyme activity was determined by HPLC/mass spectrometry. Results Incubation of BeWo cells with 10 nM, 100 nM, and 1  μ M of 20-HETE displayed a dose-dependent increase in cell proliferation with an approximate 40% increase at 1  μ M, while inhibition of 20-HETE with 17-ODYA (10  μ M) displayed a 40% decrease in BeWo cell proliferation. Placental vascular microsomes isolated from PreE women displayed a significant increase in 20-HETE production relative to NP women. 15-HETE, 12-HETE, and total HETE production were also increased in PreE compared to NP. Conclusions Increases in 20-HETE production promote, while inhibition of 20-HETE reduces proliferation of trophoblasts in vitro . Increases in the production of an endogenous inhibitor of 20-HETE, such as15-HETE, may contribute to the reduced trophoblast invasion and impaired vascular remodeling seen in PreE. Disclosures N. Lee: None. S. Spencer: None. B.B. LaMarca: None. S. Murphy: None.