Women with antiphospholipid syndrome (APS) have circulating antiphospholipid antibodies (aPL) and are at high risk for recurrent pregnancy loss (RPL) and late pregnancy complications, such as preeclampsia. While treatment with heparin may increase the live birth rate in APS patients, the incidence of late term complications, such as preeclampsia, remains high. Although the hypertension caused by preeclampsia is resolved after delivery of the baby and the placenta, women with a history of preeclampsia are at risk for hypertension and cardiovascular disease later in life. Since women with APS are already at risk for cardiovascular issues, having preeclampsia could exacerbate their APS-related thrombotic complications.aPL bind the placental trophoblast since the cell's constitutively express beta2 glycoprotein I (b2GPI). Our published studies have demonstrated that aPL against b2GPI: trigger human first trimester trophoblast to produce elevated levels of pro-inflammatory cytokines/chemokines via activation of Toll-like receptor 4 (TLR4); inhibit trophoblast migration; and modulate trophoblast angiogenic factor secretion. aPL can also affect the maternal side of the interface by binding directly to human endometrial endothelial cells (HEECs), however little is known about their responses to aPL or the mechanisms involved. One way in which TLR function can be regulated is through activation of the TAM tyrosine kinase receptors, a novel family of negative regulators. Thus, our central hypothesis is that aPL prevent constitutive trophoblast and HEEC TAM receptor activity, thus allowing TLR4-mediated inflammation, altered trophoblast/HEEC function and interactions, leading to adverse pregnancy outcome. Our specific aims are to: Aim 1. Determine the mechanism by which aPL regulates trophoblast Gas6 expression and TAM receptor function. Aim 2. Determine whether rGas6 can prevent aPL-modulation of trophoblast function. Aim 3. Determine the role of TAM receptors in regulating HEEC responses to aPL and reduced vascular remodeling in the setting of aPL. Our long-term goal is to use our mechanistic findings to develop and establish a new therapeutic strategy for pregnant women with aPL. By reducing the incidence of aPL-associated pregnancy complications, we might help to reduce the prevalence of hypertension and cardiovascular disease in these patients, thus improving the long-term health of the mother and baby.
|Effective start/end date||07/01/2015 → 06/30/2018|