Abstract Body (Do not enter title and authors here):
Introduction/Background: Gestational diabetes mellitus (GDM) is the most common metabolic complication during pregnancy. It increases the risk for endothelial dysfunction, hypertension and cardiovascular diseases in the mother and the child in later life. Endothelin-1 (ET-1) is a potent vasoconstrictor that promotes endothelial dysfunction and contributes to cardiovascular diseases.
Research Question/Hypothesis: We hypothesise that ET-1 is a key mediator of fetal endothelial dysfunction in GDM.
Methods/Approach: We obtained maternal and fetal vessels from human placentas of patients with insulin-treated GDM (iGDM) (n=10), diet-treated GDM (dGDM) (n=8) and normoglycemic controls (n=30). Groups were defined by oral glucose tolerance test and clinical data of mothers and newborns. Vascular function of fetal arteries was analyzed in a Mulvany Myograph. Fetal placental arteries from patients of all groups were incubated with the selective endothelin receptor A antagonist BQ123 and the selective endothelin receptor B antagonist BQ788. The impact of ET-1 on vascular function was studied in a concentration-dependent manner. Gene expression was quantified by real-time PCR in fetal vessels of the cotyledon base and maternal spiral arteries. ET-1 peptide levels in the venous fetal placental serum were quantified with a human ET-1 ELISA.
Results/Data: ET-1-mediated vasoconstriction was shown in fetal placental arteries from the chorionic base in all study groups. At higher concentrations, ET-1-mediated vasoconstriction was significantly lower in patients with iGDM compared to normoglycemic controls. No differences in mRNA expression of pre-pro ET-1 gene (EDN1), endothelin-converting enzyme 1 (ECE1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) were found between study groups. Notably, mRNA expression of EDNRB was higher compared to EDNRA expression in fetal placental vessels of all groups. Significantly increased levels of ET-1 were detected in venous fetal placental serum in dGDM patients compared to control. The ET-1-mediated vasoconstriction was blocked by BQ123 and BQ788 in GDM patients and controls. The relative contribution of EDNRB to ET-1-mediated vasoconstriction is significantly higher in GDM patients, compared to normoglycemic controls.
Conclusions: In conclusion, we could demonstrate that GDM impairs ET-1-mediated vasoconstriction in fetal placental vessels. This may contribute to the endothelial dysfunction in patients with GDM.