Metformin affects vascular function in fetal placental vessels with gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy. It is a major risk factor for endothelial dysfunction, hypertension, and future cardiovascular diseases in both mother and child. In Germany, treatment is limited to dietary management and insulin. Metformin is widely used as first-line therapy for type 2 diabetes, but not approved for GDM monotherapy in Germany due to limited data on fetal safety. Because it improves insulin sensitivity and endothelial function and reduces oxidative stress in type 2 diabetes, metformin may have protective effects in fetal vessels with GDM. We hypothesize that metformin has an impact on fetal endothelial function and mitigates GDM-associated endothelial dysfunction.

Maternal and fetal placental vessels were collected from normoglycemic pregnancies (NG, n=25), insulin-treated GDM (iGDM, n=13), and diet-controlled GDM (dGDM, n=10). Clinical parameters were recorded. Vessels were incubated for 24 hours in a normoglycemic medium with or without metformin. Endothelial function was assessed using a Mulvany myograph. Human umbilical vein endothelial cells (HUVECs) were isolated and treated with metformin (± VEGF), followed by RNA extraction and qPCR analysis.

iGDM patients had a significantly higher body mass index than NG and dGDM groups. Vessels from iGDM patients displayed impaired insulin-induced vasorelaxation, suggesting early endothelial dysfunction. Metformin-treated NG and iGDM vessels showed reduced contractile responses to serotonin and potassium. Insulin-mediated relaxation was significantly diminished in metformin-treated NG and iGDM vessels (p<0.0001). Notably, nitric oxide synthase (NOS) inhibition with L-NAME had a stronger effect in metformin-treated NG vessels (p=0.0022), suggesting increased eNOS activity. This effect was absent in GDM vessels. In HUVECs, VEGF induced KLF2 and PGC1α expression, while co-treatment with metformin attenuated the KLF2 response.

Metformin significantly alters vascular responses in fetal placental vessels from normoglycemic and GDM pregnancies. It did not enhance insulin-mediated vasorelaxation, but increased sensitivity to NOS inhibition suggesting higher eNOS activity in normoglycemic tissue. These findings suggest an impact of metformin on vascular function in fetal placental vessels with gestational diabetes mellitus.