Women with antiphospholipid syndrome have circulating antiphospholipid antibodies (aPL), such as anti-b2GPI antibodies, and are at high risk for thrombosis, recurrent pregnancy loss, and late pregnancy complications, such as preeclampsia. While the incidence of recurrent pregnancy loss can be reduced by treatment with heparin, the risk of a woman developing preeclampsia still remains high, and this significantly increases her risk of hypertension and cardiovascular disease later in life. Although aPL are strongly associated with thrombosis, intravascular or intervillous blood clots are rarely found upon histological examination. Instead, there appears to be insufficient placentation, evidenced by reduced trophoblast invasion and limited uterine spiral artery transformation. This suggests that aPL may directly impact trophoblast function, resulting in altered angiogenesis. However, the precise mechanisms by which this might occur are poorly understood. Our central hypothesis is that aPL directly affect first trimester trophoblast cell function, and this negatively impacts placentation and subsequent vascular remodeling, resulting in early pregnancy loss. The failure of heparin to reverse all effects of the aPL may explain why these women are still at risk for late pregnancy complications, such as preeclampsia. Our objectives are: 1) to further characterize the mechanisms by which aPL affect trophoblast function; 2) to determine how this may impact trophoblast remodeling of the maternal vasculature; and iii) to investigate the impact statins have on the aPL-induced trophoblast responses. Our specific aims are:Aim 1. To determine the mechanism by which aPL induce trophoblast inflammationAim 2. To evaluate the effects of aPL on trophoblast invasion and endothelial interactions.While women with APS are at high risk for pregnancy loss and pregnancy complications, it is currently impossible to predict which APS patients will develop an adverse pregnancy event. Our overall goal is to establish better diagnostic mechanisms and to find new therapeutic targets. By reducing the incidence of aPL-associated pregnancy complications, we might help to reduce the prevalence of cardiovascular disease in these patients, thus improving the long-term health of the mother.
|Effective start/end date||07/01/2010 → 06/30/2013|