Syncytiotrophoblast extracellular vesicles contain functional kynurenine metabolising enzymes: potential implications for preeclampsia

Abstract

Background: Placentae of women with preeclampsia (PE) exhibit reduced levels of kynurenine (Kyn), a biological compound derived from tryptophan metabolism with antioxidant, vasorelaxant, and hypotensive properties. Little is known regarding functional levels of the Kyn metabolizing enzymes (KYNME) in women with preeclampsia. Since high circulating levels of syncytiotrophoblast extracellular vesicles (STB-EVs) have been associated with preeclampsia onset, we aimed to study whether Kyn reduction in preeclampsia may be attributed to increased degradation by KYNME present in STB-EVs. Methods: We conducted a study that included women with normal (n=9) and early-onset preeclamptic (EOPE) pregnancies (n=9). From them, STB-EVs were isolated by dual-lobe placental perfusions from normal (n=3) and EOPE (n=3). KYNME were identified using placental immunohistochemistry and western blot in placental and STB-EV extractions. Serum Kyn levels were measured using gas chromatography mass spectrometry. Results: Cargo of STB-EVs consist of functional KYNME, which break down Kyn in a dose and time-dependent manner. No significant differences in the content of Kyn metabolizing enzymes were found in STB-EVs between normal and EOPE pregnancies. However, decreased serum levels of Kyn were found in women with EOPE relative to normal pregnancies. Conclusion: STB-EVs carry functional KYNME and may regulate the levels of circulating Kyn during normal pregnancy and preeclampsia. Due to the dose effect of increased STB-EVs in EOPE, the functional KYNME content of said vesicles may contribute to reduced levels of Kyn. This finding opens a new avenue for investigating the potential benefits of KYNME inhibitors in conjunction with kynurenine replacement for managing preeclampsia. Key words: Extracellular vesicles; preeclampsia; Kynurenine; Tryptophan; Kynurenine metabolising enzymes