Combining metformin and esomeprazole additively decreases sFlt-1 secretion and expression, and increases VEGF expression in placental and endothelial cells.

<p>Isolated primary cytotrophoblast were treated with either metformin alone (Met), esomeprazole alone (Eso) or Met + Eso in combination and the effect on sFlt-1 secretion assessed (A). Neither Met or Eso alone reduced sFlt-1 secretion, however a significant reduction was observed when the two were added in combination (A). Similarly, neither Met nor Eso alone altered sFlt-1 secretion from placental explants, but sFlt-1 secretion was significantly reduced with combination Met and Eso treatment (B). In primary HUVECs, secretion of sFlt-1 was significantly reduced with all treatments compared to control (C). In primary cytotrophoblast both Met and Eso alone significantly reduced sFlt-1 i13 (D) and sFlt-1 e15a mRNA expression (E). A significant increase was observed in VEGF mRNA expression with Eso and Met treatment (F). Met treatment of placental explants caused a significant increase in the expression of sFlt-1-i13 (G) whilst combination Met + Eso caused a significant reduction in the expression of sFlt-1-e15a (H). No change was observed in placental VEGF mRNA expression with any treatment (I). In primary HUVECs, significant reductions in sFlt-1 i13 (J) and sFlt-1 e15a (K) compared to control were observed when Met or Eso were added alone. Combination Met + Eso also significantly reduced expression of both variants compared to control (J-K). VEGF mRNA was significantly increased with either Met alone, and with combination of Met + Eso treatment (L). The following treatment doses were used: <i>Cytotrophoblasts</i>: Met; 125 μM, Eso; 25 μM or same doses in combination. <i>Placental explant tissue</i>: Met; 500 μM, Eso; 25 μM or same doses in combination. <i>HUVECs</i>: Met; 1000 μM, Eso; 25 μM or same doses in combination. All treatments were carried out over 48 h. Data are mean fold change from control ± SEM (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 compared to control). (n ≥3).