Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Zardoya Laguardia, P.
ENDOTHELIAL INDOLEAMINE 2,3-DIOXYGENASE-1 IN THE REGULATION OF PLACENTAL VASCULAR TONE AND ITS POTENTIAL ROLE IN INTRAUTERINE GROWTH RESTRICTION AND PREECLAMPSIA
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp.
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- Autor*innen der Med Uni Graz:
- Zardoya Laguardia Pablo
- Betreuer*innen:
- Frank Sasa
- Sedlmayr Peter
- Wadsack Christian
- Altmetrics:
- Abstract:
- A successful pregnancy requires the establishment and maintenance of an adequate feto-placental circulation. Indoleamine 2,3-dioxygenase-1 (IDO1), a L-tryptophan catabolising enzyme constitutively expressed in the endothelium of human placental chorionic vessels, has been demonstrated to modulate the vascular tone and blood pressure under systemic inflammation in mice. We asked the questions whether IDO1 may contribute to the regulation of placental vascular tone, which we supposed to have an impact on placental and fetal growth, and asked whether this mechanism is impaired in intrauterine growth restriction (IUGR) and preeclampsia (PE). Vasorelaxation to freshly-made and stored L-Trp-solutions of U46619-pre-constricted chorionic plate arteries stimulated with IFN¿ and TNF¿ as a strategy to upregulate IDO1 was assayed by myography. The back pressure of placental cotyledons in the presence and absence of U46619 was monitored in the fetal part of the placenta by ex-vivo perfusion during administration of Trp. IUGR, pre-eclampsia, term and gestational age matched pre-term controls (from placenta praevia) samples were assessed by Western blotting, immunohistochemistry (IHC), RT-qPCR in order to determine IDO1 mRNA and protein expression and its localization, whilst IDO1 activity was measured by LC/MS. IDO1 mRNA and protein expression in placental arterial endothelial cells (PLAECs) isolated from normal term placentas were also examined by Western blotting and qPCR. Trp produced vasorelaxation of U46619-pre-constricted and cytokine-stimulated placental arteries, an effect that was still observed in arteries lacking the endothelium. Trp-induced relaxation was partially blocked, in the presence and absence of endothelium, by using different IDO1 competitive inhibitors. Additionally, Trp induced vasorelaxation of perfused U46619-pre-constricted and non-pre-constricted placental cotyledons without prior induction of IDO1. PLAECs from normal term placentas showed a consistently upregulated IDO1 mRNA and protein expression following stimulation with IFN¿/TNF¿ but also exhibited a constitutive expression (without cytokine stimulation) on the mRNA level of IDO1, whereas on the protein level this was the case only in part of the samples. IUGR and PE samples showed no differences regarding IDO1 mRNA levels when compared with pre-term controls, however, IDO1 protein expression and activity were reduced. These data suggest that IDO1-mediated metabolism of Trp plays a role in the regulation of the placental vascular tone, and they are consistent with our hypothesis that a deficiency in chorionic IDO1 is linked to the pathogenesis of pregnancy complications such as IUGR and PE.