Molecular Basis of Pregnancy Complications in the Antiphospholipid Syndrome

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The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the production of antiphospholipid antibodies (aPL) that promote adverse pregnancy outcomes including fetal loss, premature birth, intrauterine growth restriction (IUGR), and maternal hypertension during pregnancy. Whereas treatment with heparin has improved the rate of live births in APS patients with recurrent pregnancy loss, the incidence of pregnancy complications remains high. As such, more effective mechanism-based therapies are urgently needed. Previously we showed that pregnant mice globally lacking apolipoprotein E receptor 2 (apoER2) are protected from the fetal loss and IUGR induced by the administration of aPL isolated from APS patients. We also revealed in cultured trophoblasts that via recognition of the cell surface protein β2GPI and its interaction with apoER2, aPL inhibit stimulatory Akt phosphorylation, leading to decreased cell proliferation and migration. More recently, we discovered that aPL potently activate the serine/threonine protein phosphatase 2A (PP2A) in cultured human trophoblasts, in mouse placenta in vivo, and in human placental explants ex vivo. We further found that the PP2A inhibitor Cantharidin prevents aPL inhibition of cultured trophoblast cell growth and migration. Based upon these novel findings, the overall goal of the proposed project are to determine how aPL cause fetal loss, IUGR and maternal hypertension through impairment of trophoblast function, and to test whether pregnancy outcomes are improved by novel interventions directed at these mechanisms. Aim 1 will determine whether and how trophoblast apoER2 and its adaptor molecules contribute to aPL-induced fetal loss and IUGR using trophoblast-specific loss-of-function mouse models in vivo and human trophoblasts in culture. Aim 2 will investigate the role of trophoblast PP2A in aPL-induced fetal loss and IUGR in vivo using genetic and pharmacological loss-of-function approaches in mice. We will also identify the trophoblast genes impacted by aPL treatment through PP2A activation in vivo, using our recently-established method to selectively isolate ribosome-associated RNA in mice. Aim 3 will elucidate how aPL induce maternal hypertension. Recently we determined that aPL administration promotes hypertension in pregnant mice, and that aPL stimulate the secretion of soluble Flt-1 (sFlt-1) and soluble Endoglin (sEng) from cultured trophoblasts in an apoER2- and PP2A-dependent manner. We will determine whether stimulation of sFlt-1/sEng secretion caused by aPL activation of apoER2-PP2A in trophoblasts underlies the blood pressure elevation, using the mice with trophoblast specific deletion of apoER2, PP2A or sFlt-1/sEng. We will also test if aPL-induced maternal hypertension can be prevented by the administration of a unique monoclonal anti-β2GPI blocking antibody that we identified prevents aPL-induced fetal loss, or a PP2A inhibitor. Accomplishing these aims will lead to better understanding of the pathogenesis of obstetric APS and the development of mechanism-based therapies to protect the fetus, as well as the mother, from this potentially life-threatening disorder.