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Abnormalities in intracellular Ca 2+ regulation in fetal vascular smooth muscle in pre‐eclampsia: enhanced sensitivity to arachidonic acid
Author(s) -
Steinert Joern R.,
Poston Lucilla,
Mann Giovanni E.,
Jacob Ron
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0507fje
Subject(s) - arachidonic acid , cyclooxygenase , metabolite , intracellular , lipoxygenase , monooxygenase , medicine , endocrinology , vascular smooth muscle , chemistry , biology , biochemistry , cytochrome p450 , metabolism , enzyme , smooth muscle
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 Ca 2+ ([Ca 2+ ] i ) response to arachidonic acid (AA) in primary cultures of human umbilical artery smooth muscle cells (HUASMC). AA (50 μM) caused a significantly greater [Ca 2+ ] 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 [Ca 2+ ] 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 [Ca 2+ ] i response of HUASMC is elevated in PE because of an increased level of a monooxygenase metabolite that stimulates Ca 2+ 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.