Abstract P3047: Soluble Guanylyl Cyclase Stimulators And Activators Inhibit Hypoxia-induced Placental Sflt-1 Levels

Abstract

Preeclampsia (PE) is a pregnancy-specific disease characterized by placental ischemia, maternal endothelial dysfunction, and hypertension. The ischemic placenta releases anti-angiogenic factors, such as sFlt-1, which antagonizes the angiogenic factors, Placental Growth Factor (PlGF) and Vascular Endothelial Growth Factor (VEGF), causing endothelial dysfunction and impaired nitric oxide (NO) signaling. During normal pregnancy, NO would bind soluble guanylyl cyclase (sGC) increasing cGMP levels leading to vasodilation. However, in PE this signaling is reduced. sGC stimulators and activators are a novel class of drug that directly stimulate sGC despite low levels of NO. Our preliminary data suggest that sGC modulators reduce hypertension in an animal model of PE, but the mechanisms are not known. Therefore, this study tested the hypothesis that sGC stimulators (Riociguat) and activators (Cinaciguat) attenuate sFlt-1 production and increase PlGF levels in the placenta. Placentas were obtained from normal pregnant rats on gestational day 19. Isolated placental villi were plated (1 per well) and coated with Matrix Matrigel Basement Membrane. The villi were treated with various doses of sGC modulators (0.2μM, 1μM, 10μM, 30μM) and then exposed to a hypoxic environment (1% oxygen) for 48 hours. Levels of sFlt-1, PlGF, and VEGF were determined using an Enzyme-Linked Immunosorbent Assay kit.sFlt-1 concentration was significantly reduced in both groups treated with the stimulator or activator compared to the untreated group. The greatest attenuation was observed with the 30μM sGC activator treatment (Untreated, 5117±1313 pg/mL; 30μM sGC stimulator, 3975±621pg/mL, 30μM sGC activator, 3811±712 pg/mL, P<0.05). PlGF was not significantly different between groups, however, VEGF concentrations were significantly increased at higher doses (Untreated, 3099±100 pg/mL; 30μM sGC stimulator, 3871±449 pg/mL 30μM sGC activator, 3952±252 pg/mL; p<0.05). These data suggest that sGC modulators significantly attenuate sFlt-1 and thus, improve the sFlt-1/PlGF and sFlt-1/VEGF ratios. Therefore, a potential mechanism whereby sGC modulators reduce blood pressure in PE is by inhibiting hypoxia-induced placental sFlt-1 levels.