Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Nonn, O.
Maternal angiotensin increases placental leptin in early gestation via an alternative RAS-pathway – suggesting a link to preeclampsia
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2021. pp.
- Autor*innen der Med Uni Graz:
- Nonn Olivia
- Betreuer*innen:
- Gauster Martin
- Huppertz Berthold
- Wadsack Christian
- Altmetrics:
- Abstract:
- A role for placental Renin-Angiotensin-System (RAS) components was shown in preeclampsia. Investigating single cell RNA-sequencing (scRNA-seq) data showed differently expressed components than previously suggested. We hypothesised that an alternative maternal RAS pathway may explain pregnancy hypertensive disorders. We investigated placental RAS localisation via scRNA-seq and in situ padlock-probes and the influence of maternal and foetal factors on expression. Placental tissue was collected from early electively terminated gravidities of healthy patients, from healthy term controls (n=252), from early-onset preeclamptic and early control pregnancies (n=49), as well as first trimester placentae from women with a high uterine artery resistance index (high-risk) and controls (n=16). Serum levels of angiotensins from patients undergoing assisted reproductive technology before and after conception were measured via LC-MS/MS. Placental explants were cultured in 2.5% oxygen with AngII, AGTR1-blocker Candesartan and leptin. Seahorse XF96 MitoStress assays assessed trophoblast metabolism. AngIII and AngIV serum levels increased when pregnant, but not AngI and AngII. AGTR1 was located around foetal vessels, LNPEP was located in syncytiotrophoblast, both concordant with scRNA-seq data. In vitro studies with placental explants showed upregulation of leptin expression by AngII not inhibited by Candesartan. AngIV showed alteration of trophoblast mitochondrial metabolism in vitro. LNPEP expression decreased in explants treated with leptin, and was significantly downregulated in preeclamptic and early high-risk placentae. Maternal AngII may act as AngIV on placental LNPEP, encoding for angiotensin IV receptor AT4R and known as placental leucine aminopeptidase, seemingly involved in regulating trophoblast metabolism. Leptin may be upregulated following decreased metabolism, in turn downregulating LNPEP expression. This AngIV/LNPEP/Leptin pathway may explain early gestational contributions toward a preeclamptic phenotype.