877: Sildenafil treatment of non-severe hypertension during pregnancy alters placental protein expression involved in angiogenesis

Abstract

Multiple proteins are involved in signaling pathways that regulate placental angiogenesis. We have previously described a murine model of non-severe hypertension (eNOS+/-) in which treatment with sildenafil (SIL) during pregnancy lowered maternal blood pressure without reducing fetal growth. Our aim was to investigate a potential mechanism for these findings. A murine model of non-severe hypertension (eNOS+/-) was obtained by breeding females with severe hypertension (eNOS-/-) with wild-type (WT) males. On gestational day 1 (GD 1), pregnant dams were randomly assigned either to SIL or water for 3 weeks. Four groups were generated: WT, WT-SIL, eNOS+/- and eNOS+/-SIL. On GD 18, dams were sacrificed, placentas were weighed and expression of placental proteins involved in angiogenesis were studied, including nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF), hypoia inducible factor-1 (HIF-1), angiotensin-2, heme oxygenase-1 (HO-1), platelet derived growth factor receptor (PDGF-R) and placental growth factor (PLGF). Placental weights were similar among all groups (P=0.71). Placental protein expression of VEGF was higher in the eNOS+/- (hypertension) group compared to the WT group. Treatment with SIL decreased VEGF expression to a level similar to WT placentas (P=0.04, Figure 1). iNOS expression was lower in the eNOS+/- group compared to WT controls; however, SIL treatment increased iNOS expression, similar to the WT group (eNOS+/-SIL 0.35±0.02 vs eNOS+/-0.47±0.04, P=0.04). PLGF was higher in the eNOS+/- group compared to WT controls and SIL decreased PLGF expression, similar to the WT placentas (P=0.01, Figure 2). HIF-1 was decreased in the eNOS+/- group compared to WT controls (eNOS+/- 0.01±0.01 vs WT 0.02±0.01, P=0.02), but no difference was observed after treatment with SIL. Angiotensisn-2 was also increased in the eNOS+/- group compared to WT controls (eNOS+/-0.52±0.11 vs WT 0.41±0.01, P=0.01), SIL did not alter its expression. HO-1 and PDGF-R were similar among groups. In a murine model of non-severe hypertension, alterations in iNOS, VEGF and PLGF expression were improved with SIL. These findings may explain how SIL treatment of non-severe hypertension during pregnancy improves maternal blood pressure without reducing fetal growthView Large Image Figure ViewerDownload Hi-res image Download (PPT)