323: Pravastatin improves pregnancy outcome and placental development in heme oxygenase-1 deficient mice

Abstract

Pravastatin is currently being studied clinically for prevention of preeclampsia. Low expression of heme oxygenase-1 (HO-1) due to polymorphisms in the human HO-1 promoter region may cause impaired placental development resulting in intrauterine growth restriction (IUGR), preeclampsia, and recurrent miscarriages. We have shown that pregnant HO-1 heterozygous (HO-1+/-, Het) mice have abnormal placental development, with thinner spongiotrophoblast layers and increased Sflt-1 levels (Zhao H. et al., 2009). We have also found that statins can induce HO-1 expression. Therefore, our aim was to evaluate the effect of pravastatin on pregnancy outcome and placental development in HO-1-deficient mice. We compared untreated Het mice (control, n=5) with Het mice treated with pravastatin (10 mg/g/d; n=9) added to their drinking water 1 wk prior to timed-pregnancy breeding for a total of 3.5 wks. At E14.5, dams were sacrificed, litter sizes recorded, and livers and placentas (fetal side) harvested for total HO activity (expressed as percent of Het controls). A subset of whole placentas (control n=3, pravastatin n=4) was stained for H&E to assess placental development. At E14.5, litter sizes of the pravastatin-treated dams were significantly larger (8.0±2.5 vs 5.0±2.0 p<0.05), with increases in HO activity in livers (154%, p=0.012) and in placentas (119%, p=0.059). Histologically, placentas of pravastatin-treated mice had less apoptosis, more glycogen-laden cells, and larger vessel diameters in the spongiotrophoblast (SP) layer, reflecting improved placental development (Figs. 1 and 2). Pravastatin induces liver and placental HO activity and appears to improve pregnancy outcome and placental development in HO-1-deficient mice. We conclude that pravastatin has potential for use in the treatment of not only preeclampsia, but also of IUGR due to its effects on placental development. We speculate that among women at risk, those with low HO-1 expression may specifically benefit from pravastatin.View Large Image Figure ViewerDownload Hi-res image Download (PPT)