Abnormalities in intracellular Ca2+ regulation in fetal vascular smooth muscle in pre-eclampsia: enhanced sensitivity to arachidonic acid.
Pre-eclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity. As free fatty acid metabolism is abnormally regulated in PE, we investigated the intracellular Ca2+([Ca2+]i) response to arachidonic acid (AA) in primary cultures of human umbilical artery smooth muscle cells (HUASMC). AA (50 microM) caused a significantly greater [Ca2+]i elevation in PE than in normal HUASMC, with many cells displaying a delayed secondary increase. The nonmetabolizable AA analog ETYA did not induce a response, suggesting that the augmented PE response depends on an AA metabolite. Inhibition of the AA metabolizing cyclooxygenase or lipoxygenase pathways did not affect the AA response of PE HUASMC but induced in normal cells the secondary rise of [Ca2+]i observed in PE cells. This potentiated response and the response in PE cells were blocked by inhibitors of the monooxygenase pathway, a third AA metabolizing pathway. We conclude that the [Ca2+]i response of HUASMC is elevated in PE because of an increased level of a monooxygenase metabolite that stimulates Ca2+ influx and that this can be mimicked in normal cells by blocking cyclooxygenase or lipoxygenase to divert AA to the monooxygenase. This and our work with fetal endothelial cells (FASEB J. 10.1096/fj.01-0916fje) demonstrate phenotypic changes in the fetal vasculature in PE.
Steinert
Joern R
JR
Centre for Cardiovascular Biology and Medicine, GKT Schools of Biomedical Sciences and Medicine, King's College London, Guy's Campus, London SE1 1UL, UK.
Poston
Lucilla
L
Mann
Giovanni E
GE
Jacob
Ron
R
D016718:Arachidonic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D009637:Masoprocol; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium; D007213:Indomethacin