Therapeutic doses of metformin do not have impact on angiogenesis in presence of sera from pre-eclamptic, IUGR and healthy pregnancies

Recent evidence suggests that metformin may prevent pre-eclampsia by reverting the angiogenic imbalance in maternal sera. In this study, we investigated effect of metformin on angiogenesis by quantifying tubule formation in a human-based in vitro test with co-culture of human adipose stromal cell (hASC) and human umbilical vein endothelial cell (HUVEC). A total of 20 pregnant women were recruited in the study. Serum samples were obtained from women with early- and late-onset pre-eclampsia and from women with pregnancies complicated by intrauterine growth restriction (IUGR) without pre-eclampsia (N = 5 in each of the three groups). Serum samples from women with healthy pregnancies served as controls (N = 5). The direct effect of metformin on angiogenesis was first assessed without maternal sera. Secondly, we investigated the impact of metformin on angiogenesis in the present of maternal sera. Metformin was used at 5, 50 and 600 µg/ml concentrations. Angiogenic and inflammatory biomarkers in maternal sera were analyzed by immunoassays. When the direct effect of metformin was studied, the two lowest concentrations of metformin did not affect tubule formation (angiogenesis), but the highest concentration inhibited angiogenesis. When metformin was supplemented at therapeutic concentrations of 5 and 50 µg/ml along with serum samples, there was no change in tubule formation in comparison to maternal sera alone. However, strong inhibitory effect on tubule formation was observed in all groups with the highest, non-therapeutic (600 µg/ml), concentration of metformin.