The potential role of pregnancy-associated plasma protein-A2 in angiogenesis and development of preeclampsia

Compromised placentation strongly predisposes to preeclampsia (PE) which is a severe complication of pregnancy. Pregnancy-associated plasma protein-A2 (PAPP-A2) has higher expression in the placenta than in any other tissues. However, the possible role of PAPP-A2 in placental development and in the pathogenesis of PE remains unclear. In this study, we aimed at exploring placental expression of PAPP-A2 in early- and late-onset of severe PE and its role in the mechanism inducing the development of PE. We found that expression of PAPP-A2 mRNA and protein was elevated in placentas from women with severe PE compared to control placentas and was localized to differentiated trophoblasts; higher in early-onset PE than that in late-onset PE. PAPP-A2 was expressed in the cytoplasm of both primary trophoblasts and HTR-8/SVneo cells. Elevated PAPP-A2 attenuated migration, invasion, explant outgrowth and network formation of trophoblast cells in vitro without affecting cell proliferation and apoptosis. PAPP-A2 attenuated trophoblast invasion and migration by restraining epithelial-mesenchymal translations via downregulation of the Hedgehog signaling pathway. Overall, the increased expression of placental PAPP-A2 is specific to different period of PE onset and PAPP-A2 may contribute to poor placentation and inadequate angiogenesis thereby leading to the development of preeclampsia.