Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Atallah, R.
The role of succinate-SUCNR1 axis in human placental endothelial cells
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 102
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- Autor*innen der Med Uni Graz:
- ATALLAH Reham
- Betreuer*innen:
- Heinemann Akos
- Luschnig Petra
- Wadsack Christian
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- Abstract:
- Abstract Placental insufficiency is a hallmark of pregnancy complications such as gestational diabetes mellitus (GDM). Placentas from GDM pregnancies are commonly reported to be hypervascularized. This phenomenon has been addressed in contexts of hypoxia and angiogenic imbalance. However, a possible contribution of placental/fetal metabolites to this anomaly has been overlooked to-date. Within this thesis, I investigated an axis comprised of succinate and its cognate receptor, SUCNR1, in human placenta as possible regulators of placental angiogenesis, which might be aggravated in GDM. I measured significantly higher succinate levels in placental tissue lysates from women with GDM relative to matched controls in parallel to an increase in vascular endothelial growth factor (VEGF). A positive correlation of SUCNR1 and VEGF protein levels in tissue lysates indicated a potential link between succinate-SUCNR1 axis and placental angiogenesis. At the cellular level, our data showed expression of SUCNR1 in human placental endothelial cells. SUCNR1 protein expression was upregulated in diabetic fetoplacental arterial endothelial cells (FpECAds) in comparison to normal cells (FpECAs). In our in vitro experiments, succinate prompted hallmarks of angiogenesis in human umbilical vein endothelial cells (HUVECs) such as cell proliferation, migration and spheroid sprouting in addition to barrier disruption. These results were further validated in FpECAs, where succinate induced endothelial tube formation. VEGF gene expression was increased in response to succinate in both HUVECs and FpECAs. Yet, knockdown of SUCNR1 in HUVECs led to suppression of VEGF gene expression and abrogated cell migratory ability, wound healing and barrier response upon treatment with succinate. To study the signaling machinery downstream of SUCNR1, we used endothelial cell line EA.hy926 and we demonstrated that extracellular signal-regulated kinase (ERK1/2) pathway was regulated upon treatment with succinate. In conclusion, this thesis highlighted succinate-SUCNR1 as an important signaling axis in human FpECs. The role of this axis in regulating angiogenesis was demonstrated. Our findings proposed a mechanism to the increased angiogenesis in GDM placentas.