Abstract 4146419: Maternal Gestational Diabetes Leads to Disturbed Fetal Vascular Function and Increased LOX-1 Expression

Introduction/Background: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and a major risk factor for endothelial dysfunction and cardiovascular diseases in later life. The underlying pathophysiology is not well-understood. An important mediator of endothelial dysfunction and atherosclerosis is the lectin-like receptor for oxidized low-density lipoprotein, LOX-1. Research Question/Hypothesis: We hypothesize that maternal GDM leads to impaired fetal vascular function and increased endothelial LOX-1 expression. Goals/Aim: Our aim is a better understanding of the impact of maternal GDM on fetal vascular function and LOX-1 as potential mediator of endothelial dysfunction. Methods/Approach: We obtained maternal and fetal vessels of mature human placentas from normoglycemic mothers (n=32) and patients with insulin-treated GDM (iGDM) (n=8) or diet-treated GDM (dGDM) (n=8). Groups were defined by oral glucose tolerance test and clinical data of mothers and newborns. Vascular function of fetal vessels from mothers with iGDM, dGDM, or normoglycemic controls was analyzed by Mulvany Myograph. Gene expression was quantified by real-time PCR in RNA from fetal vessels of cotyledone base and maternal spiral arteries of patients. Results/Data: Birth weight to placenta weight-ratio showed a significantly reduced placenta efficiency in the iGDM group ( P <0.0016), but not in the dGDM group, compared to control. We observed a significant reduction of insulin-mediated vasodilatation in fetal arterial vessels of the chorionic plate from iGDM ( P <0.0003) and dGDM patients ( P <0.0421), compared to control. NO synthase inhibition significantly reduced insulin-dependent vasorelaxation in the control, but not GDM groups. This was independent of eNOS mRNA expression. We could show a significant LOX-1 overexpression in fetal placental vessels of iGDM patients, compared to normoglycemic mothers. In addition, the mitochondrial uncoupling protein 2 (UCP2) was elevated in fetal vessels of iGDM mothers compared to control. This supports a fetal compensatory mechanism in response to impaired vascular function in spiral arteries of the mother. Conclusions: In conclusion, the endothelial function of the fetus is more severely affected by maternal iGDM, compared to dGDM. Furthermore, iGDM might have an adverse effect on placenta efficiency. The LOX-1 receptor could be a promising therapeutic target in the treatment of vascular dysfunction in GDM.