l -Tryptophan–Induced Vasodilation Is Enhanced in Preeclampsia

Abstract

l -tryptophan induces IDO (indoleamine 2,3-dioxygenase) 1–dependent vasodilation. IDO1 is expressed in placental endothelial cells and downregulated in preeclampsia. Hypothesizing that this may contribute to diminished placental perfusion, we studied l -tryptophan–induced vasodilation in healthy and early-onset preeclampsia placental arteries, focusing on placental kynurenine pathway alterations. Despite IDO1 downregulation, kynurenine pathway metabolite concentrations (measured with ultra-performance liquid chromatography-tandem mass spectrometry) were unaltered in preeclamptic versus healthy placentas. Most likely, this is due to enhanced l -tryptophan uptake, evidenced by increased l -tryptophan levels in preeclamptic placentas. Ex vivo perfused cotyledons from healthy and preeclamptic placentas released similar amounts of l -tryptophan and kynurenine pathway metabolites into the circulations. This release was not altered by adding l -tryptophan in the maternal circulation, suggesting that l -tryptophan metabolites act intracellularly. Maternally applied l -tryptophan did appear in the fetal circulation, confirming placental passage of this essential amino acid. After in vitro incubation of placental arteries with IDO1-upregulating cytokines interferon-γ and tumor necrosis factor-α, l -tryptophan induced vasodilation. This vasodilation was attenuated by both IDO1 and nitric oxide (NO) synthase inhibitors. Despite IDO1 downregulation, l -tryptophan–induced relaxation was enhanced in preeclamptic versus healthy placental arteries. However, cytokine stimulation additionally upregulated the LAT ( l -type amino acid transporter) 1 in preeclamptic placental arteries only. Vasodilation to the lipophilic, transporter independent ethyl ester of l -tryptophan was reduced in preeclamptic versus healthy placental arteries, in agreement with reduced IDO1 expression. In conclusion, l -tryptophan induces IDO1- and NO-dependent relaxation in placental arteries, which is determined by l -tryptophan uptake rather than IDO1 expression. Increased l -tryptophan uptake might compensate for reduced IDO1 expression in preeclamptic placentas.