l-Tryptophan-Induced Vasodilation Is Enhanced in Preeclampsia Studies on Its Uptake and Metabolism in the Human Placenta

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 studiedl-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 enhancedl-tryptophan uptake, evidenced by increasedl-tryptophan levels in preeclamptic placentas. Ex vivo perfused cotyledons from healthy and preeclamptic placentas released similar amounts ofl-tryptophan and kynurenine pathway metabolites into the circulations. This release was not altered by addingl-tryptophan in the maternal circulation, suggesting thatl-tryptophan metabolites act intracellularly. Maternally appliedl-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-gamma and tumor necrosis factor-alpha,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 ofl-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 byl-tryptophan uptake rather than IDO1 expression. Increasedl-tryptophan uptake might compensate for reduced IDO1 expression in preeclamptic placentas.