Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia

Abstract

Abstract-Preeclampsia is a major pregnancy complication where excess placental release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin causes maternal endothelial and multisystem organ injury. Clinical trials have commenced examining whether pravastatin can be used to treat preeclampsia. However, the preclinical evidence supporting pravastatin as a treatment is limited to animal models, with almost no studies in human tissues. Therefore, we examined whether pravastatin reduced sFlt-1 and soluble endoglin secretion and decreased endothelial dysfunction in primary human tissues. Pravastatin reduced sFlt-1 secretion from primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm preeclampsia. It increased soluble endoglin secretion from endothelial cells but did not change secretion from placental explants. The regulation of sFlt-1 by pravastatin seemed to be mediated via the 3-hydroxy-3-methylglutaryl-coenzyme A reductase cholesterol synthesis pathway. Pravastatin also reduced markers of endothelial dysfunction, including vascular cell adhesion molecule-1 expression and leukocyte adhesion on endothelial cells and increased endothelial cell migration and invasion. We also treated 4 patients with preterm preeclampsia presenting at <30 weeks of gestation with daily pravastatin. Pravastatin seemed to stabilize blood pressure, proteinuria, and serum uric acid levels. Furthermore, serum sFlt-1 levels decreased. We collected the placentas at delivery and found that pravastatin reduced sFlt-1 secretion. These results indicate that pravastatin reduced sFlt-1 and soluble endoglin production and decreased endothelial dysfunction in primary human tissues. We also present pilot data, suggesting that pravastatin can stabilize clinical and biochemical features of preterm preeclampsia. Our data obtained in human tissues support the concept that pravastatin is a candidate therapeutic for preeclampsia. Clinical Trial Registration-URL: http://www.anzctr.org.au. Unique identifier: ACTRN12613000268741.

The role of anti-phospholipid antibodies in autoimmune reproductive failure

“…These studies were systematically reviewed recently by Tong et al (2015). That systematic review showed that there is strong in vitro evidence that aPL detrimentally affect trophoblast syncytialization, viability and invasion, and this in vitro data support the lesions seen in the placentae of aPL-affected pregnancies (Viall & Chamley 2015).…”

“…ii) Proliferating cytotrophoblasts are also progenitors for extravillous trophoblasts, and thus, reduced trophoblast proliferation would lead to a limited pool of extravillous trophoblasts, resulting in inadequate invasion of the spiral arteries, underperfusion, oxidative stress and ischaemia-reperfusion injury in the placenta. These, in turn, could contribute to the early pregnancy loss, pre-eclampsia and IUGR that are often seen in women with aPL (Tong et al 2015). The same consequences would result from an aPL-induced reduction in invasiveness of extravillous trophoblasts.…”

“…The deciduae of women with APS show signs of inflammation (Tong et al 2015). In vitro studies suggest that aPL may alter the cytokine and hormonal milieu produced by trophoblasts, leading to a pro-inflammatory environment at the maternal-placental interface and altered trophoblast function (Abrahams 2009).…”

“…However, the disruption of the annexin A5 shield is not a universal feature of placentae from pregnancies complicated by aPL (Lakasing et al 1999). Furthermore, enhanced coagulation at the placental surface is not a common histopathologic feature of pregnancies affected by aPL (Tong et al 2015), and thus, it is unclear how important disruption of the annexin A5 anticoagulant shield is in the pathogenesis of obstetric APS.…”

“…However, as most placentae of women with aPL do not show signs of thrombosis, heparin likely acts via another mechanism to prevent fetal loss (Tong et al 2015). In vitro studies suggest that heparin prevents the binding of polyclonal and monoclonal aPL to trophoblasts and may inhibit the binding of β 2 GPI to anionic phospholipids.…”