Soluble Guanylate Cyclase Stimulators and Activators Attenuate Placental Production of sFlt‐1

Abstract

Preeclampsia (PE) is a pregnancy specific disorder associated with maternal hypertension due to widespread endothelial dysfunction. Placental ischemia leads to increases in the circulating anti‐angiogenic factor, sFlt‐1 and a PE‐like phenotype. PE and chronic sFlt‐1 excess is also associated with depletion of nitric oxide (NO), which, during normal pregnancy, binds to soluble guanylate cyclase (sGC), and synthesizes cGMP, to facilitate vasodilation.. In fact, studies in reduced uterine perfusion pressure (RUPP) model of placental ischemia demonstrate that restoring the angiogenic imbalance, administration of placental growth factor or VEGF abolishes hypertension. A novel drug, sGC stimulators and activators, which increase sGC activity independently of NO, are currently in clinical trials for the treatment of hypertension, however, whether this drug could be beneficial during PE is not known. We tested the hypothesis that sGC stimulators (Riociguat, Sigma‐Aldrich) and activators (Cinaciguat, Sigma‐Aldrich) attenuate sFlt‐1 production by the placenta. Placentas were isolated from normal pregnant rats on gestational day 19. Villous bundles were excised and plated in 24‐well plate coated with Matrix Matrigel Basement Membrane. Increasing concentrations of each the sGC stimulator and activator (0.1 μM, 1 μM, 10 μM, 30 μM) were added to the media for treatments. The explants were then exposed to a hypoxic environment (1% oxygen) to determine whether sFlt‐1 production, directly by the placenta, is attenuated by sGC stimulators and activators in a dose‐dependent manner. Interestingly, each of the doses administered significantly reduced sFlt‐1 production in response to hypoxia compared to the untreated group. However, the 30 μM sGC activator treatment produced the most profound effect (Untreated, n=6, 4699±942 pg/mL; 30 μM sGC stimulator‐treated, n=6, 3647±1385 pg/mL, 30 μM sGC activator‐treated, n=6, 3247±1402 pg/mL; P<0.01). The results of this study demonstrate that increasing sGC activity attenuates sFlt‐1 production from the placenta and could improve the angiogenic imbalance seen in this condition. In conclusion, these findings suggest there is a therapeutic potential for treating preeclampsia with sGC activatorsSupport or Funding InformationFunding source: NIH HL51971This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.