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 the 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 observed in fetal placental arteries from the chorionic base in all study groups. At higher concentrations, however, ET-1-mediated vasoconstriction was significantly lower in patients with iGDM than in normoglycaemic controls. There were no differences in the mRNA expression of the pre-pro ET-1 gene (EDN1), endothelin-converting enzyme 1 (ECE1), endothelin receptor A (EDNRA), or endothelin receptor B (EDNRB) between the study groups. Notably, EDNRB mRNA expression was higher than EDNRA expression in the fetal placental vessels of all groups. Significantly higher levels of ET-1 were found in the venous fetal placental serum of dGDM patients compared to the control group. After blocking EDNRA with BQ123, no ET-1-mediated vasoconstriction was observable in fetal placental arteries from both GDM patients and normoglycaemic controls. The application of BQ788 on EDNRB resulted in a significantly reduced ET-1-mediated vasoconstriction in GDM patients only. EDNRB may have a stronger contribution to ET-1-mediated vasoconstriction in GDM patients than in the normoglycemic control group.
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.
