Abstract P639: Sildenafil Treatment Improves Placental Levels of Placental Growth Factor in the Dahl Salt-Sensitive Pregnant Rat Model of Superimposed Preeclampsia

Abstract

Although the etiology of preeclampsia (PE) remains unclear, evidence indicates that impaired trophoblast invasion followed by placental ischemia promotes the release of placental anti-angiogenic factors into the maternal circulation. These factors then elicit maternal endothelial dysfunction and hypertension by blocking the action of molecules such as the placental growth factor (PlGF). Inhibition of phosphodiesterase (PDE)-5 with sildenafil or other has been proposed as a potential therapy for PE; however, the mechanisms whereby PDE-5 inhibitors reduce blood pressure (BP) and improve uteroplacental perfusion during pregnancy are not clear. While previous studies have shown that PDE-5 inhibition induces PlGF production from human umbilical vein endothelial cells; it is unknown whether PDE-5 inhibitors also increase PlGF from placenta. Thus, the aim of this study was to evaluate whether sildenafil enhance placental secretion/production of PlGF in vitro and in vivo. In our in vitro protocol, we incubated placental villous explants from Sprague Dawley (SD) pregnant rats (n=4, 2-3 placentas per rat) at gestational day (GD)19 with different doses of sildenafil for 48h at 37°C under normoxia (8% O 2 ). PlGF-2 was measured in media of cultured explants by ELISA. We observed that sildenafil had no effect on PlGF-2 secretion from rat placental villi (vehicle: 562.7±46.6, 10nM: 559.3±39.5, 100nM: 556.4±35.9, 10uM: 546.2±37.5, and 100uM: 558.7±48.2pg/mg; P>0.05). In our in vivo protocol, we treated Dahl Salt-Sensitive (DS) pregnant rats (n=6-8 per group), which we had previously characterized as a model of superimposed PE, with sildenafil (50mg/kg per day, via food) from GD10 to 20. PlGF-2 was measured in placental homogenates by ELISA. While untreated DS dams exhibited an increase in BP and uterine artery resistance index (UARI) from baseline to late pregnancy, sildenafil-treated DS dams exhibited a significant decrease in BP and UARI. In addition, we found that placental levels of PlGF-2 were elevated in sildenafil-treated DS dams compared with untreated counterparts (1019±107.3 and 646.8±125.1pg/mg; P=0.0407). In conclusion, our findings suggest that the BP and UARI reduction in response to sildenafil may involve the indirect production of PlGF.