Characterization of human placental fetal vessels in gestational diabetes mellitus

Abstract

Gestational diabetes mellitus is one of the most common complications during pregnancy. Its prevalence is rapidly increasing worldwide. Gestational diabetes mellitus is leading to an elevated risk for the development of endothelial dysfunction and cardiovascular diseases both in the mother and the child in later life. The underlying pathophysiological mechanisms are not well-understood. Therefore, we aimed to characterize the endothelial function in fetal placental vessels from mothers with gestational diabetes mellitus. In this study, we distinguished between insulin-treated and diet-controlled gestational diabetes mothers and compared them to a normoglycemic control group. The clinical data confirmed pre-conceptional overweight as a risk factor in women with insulin-treated gestational diabetes mellitus. The insulin-treated gestational diabetes group was also characterized by a recent family history of diabetes compared to mothers of the control or diet-controlled gestational diabetes group. Analyses of blood serum from umbilical cords suggested a reduced fetal insulin metabolism in the insulin-treated gestational diabetes group. Vascular function analysis in fetal placental vessels revealed an altered substance P-induced vasorelaxation in vessels from patients with insulin-dependent gestational diabetes. Inhibition of nitric oxide synthase affected only fetal vessel segments from the control group or diet-controlled gestational diabetes group, but not from insulin-dependent gestational diabetes. Finally, we found a significantly decreased substance P receptor (TACR1) mRNA expression in fetal vessel segments from patients with insulin-treated gestational diabetes. In conclusion, we provide evidence that different pathophysiological mechanisms might be responsible for the development of insulin-treated versus diet-controlled gestational diabetes. Only in fetal vessels from patients with insulin-treated gestational diabetes were we able to detect an endothelial dysfunction and a reduced fetal insulin conversion. This provides novel insights into the pathophysiology of the subtypes of gestational diabetes.

Keywords: Endothelial function; Fetal placental vessels; Gestational diabetes; Substance P.

Fig. 1

Differences in clinical data and family anamnesis of insulin-dependent gestational diabetes mellitus (iGDM). A Fasting blood glucose levels in pregnancy of study participants. Statistics: one-way ANOVA; p < 0.05; n = 8–17. B Weight and (C) BMI before pregnancy of women in the control group (CG), patients diagnosed with insulin-treated gestational diabetes mellitus (iGDM), and diet-controlled GDM (dGDM). Statistics: one-way ANOVA; p < 0.05; n = 9–49. D Percentages of reported cases with a family history of diabetes mellitus. The control group was compared with the insulin-dependent (iGDM) as well as the diet-controlled women with gestational diabetes (dGDM)

Fig. 2

Glucose levels and insulin concentrations in venous and arterial fetal blood. Arterial and venous level of glucose in (A) serum of umbilical cord blood in control group (CG), B serum of umbilical cord blood in insulin-treated (iGDM), and (C) diet-controlled (dGDM) gestational diabetes mellitus patients. Statistics: t-test; p < 0.05; n = 8–25. Arterial and venous level of insulin in (D) serum of umbilical cord blood in control group (CG), E serum of umbilical cord blood in insulin-treated (iGDM), and (F) diet-controlled (dGDM) gestational diabetes mellitus patients. Statistics: t-test; p < 0.05; n = 8–25

Fig. 3

Substance P–induced vasorelaxation in fetal placental vessels. A Representative histological image of a mature fetal villus with its blood vessels: 1 indicates a fetal vein and 2 indicates a fetal artery. B Dose–response curves of cumulative application of substance P in precontracted fetal placental vessels from control (CG) mothers with insulin-treated gestational diabetes (iGDM) and diet-controlled gestational diabetes (dGDM); n = 8–43. C Area under the curve of dose–response curves of substance P in fetal vessels from CG, iGDM, and dGDM. Statistics: one-way ANOVA; p < 0.05; n = 8–43. D Dose–response curves of substance P after application of L-NAME in fetal vessels from CG, iGDM, and dGDM; n = 8–40. E Relative eNOS mRNA expression in fetal placental vessels from the normoglycemic control group (CG) and insulin-treated gestational diabetes group. Statistics: unpaired t-test; p < 0.05; n = 7–10. F Relative TACR1 mRNA expression in fetal placental vessels from the normoglycemic control group (CG) and insulin-treated gestational diabetes group. Statistics: unpaired t-test; p < 0.05; n = 4–8

Fig. 4

Vascular analysis of fetal placental vessels. A Potassium chloride (KCl)–induced contraction in fetal vessels of normoglycemic controls (CG), insulin-treated gestational diabetic mothers (iGDM), and diet-controlled gestational diabetic mothers (dGDM); n = 10–47. B Concentration–response curves of serotonin-induced vasoconstriction in fetal placental vessels of CG, iGDM, and dGDM; n ≥ 10. C Concentration–response curves of insulin in fetal placental vessels of CG, iGDM, and dGDM; n ≥ 10. D Relative mRNA expression of insulin receptor INSR in fetal vessels of CG, iGDM, and dGDM; n = 5–10. E Concentration–response curve of sodium nitroprusside (SNP) in fetal vessels from CG, iGDM, and dGDM; n ≥ 3