Alterations in Cytochrome P450 Expression and Circulating 20‐HETE Levels Contribute to Maternal Hypertension and Decreased Trophoblast Migration

Abstract

Preeclampsia (PreE) results from an impaired vascular remodeling of the placental spiral arteries. Recent data suggests cytochromeP450 (CYP450) vasoactive eicosanoids in the etiology of the disease. Therefore, we investigated whether CYP450 expression and 20‐HETE production are elevated in preeclamptic populations and if 20‐HETE plays a role in hypertension and trophoblast migration. CYP450 enzymatic activity and circulating eicosanoids were measured in normal pregnant (NP) and PreE patients by LC/MS. In addition, the proliferative actions of 20‐HETE, a major CYP450 metabolite were investigated in an in vivo model of trophoblast syncytialisation. PreE women displayed a significant increase in CYP450 enzyme expression and 20‐HETE production relative to NP women (0.192±0.04 vs 0.119±0.06 pg/min/mg, p<0.05). Circulating 20‐HETE:EETs were statistically increased in women with PreE (1.4±0.5 vs 0.1± 0.04 mg/ml, p<0.05). BeWo cell cultures displayed an increase (45%, p<0.05) in proliferation in response to exogenous 20‐HETE (1μM), while inhibition of endogenous 20‐HETE with 17‐ODYA (10uM) and HET0016 (1nM) displayed a 10% (ns) and 75% (p<0.05) inhibition. Moreover, trophoblast migration and invasion were decreased in the presence of exogenous 20‐HETE (1μM, p<0.05). Therefore, alterations in CYP450 enzyme activity and 20‐HETE may contribute to the altered vascular remodeling seen in women PreE.Support or Funding InformationAmerican Heart Association 14SDG20160020