Preeclampsia (PreE) is a prevalent hypertensive disorder in pregnancy and is a leading cause of worldwide obstetric mortality with 76,000 maternal and 500,000 neonatal deaths yearly. Due to the unclear early pregnancy etiology of PreE, prevention of PreE is limited to daily baby aspirin which may only modestly prevent PreE. A polymorphism in the gene encoding Regulator of G-Protein Signaling (RGS)-2 is associated with an increased risk for preeclampsia. RGS2 is a member of the B/R4 family of RGS proteins which acts as an endogenous inhibitor of G?q-calcium second-messenger signaling, a common pathogenic pathway for many PreE related hormones such as arginine vasopressin (AVP). Betamethasone (BTMZ) is commonly given to women at risk of preterm delivery to prevent neonatal morbidities. Our preliminary data and the literature suggest that steroids like BMTZ can induce RGS2, thereby turning off the excessive pathogenic G?q-calcium signaling seen in PreE. Together these data lead us to the overall hypothesis that BMTZ prevents PreE by restoring placental RGS2 signaling and decreasing the excessive G?q-calcium signaling that has been associated with PreE related placental dysfunction. The overall objectives of the current proposal are (i) to evaluate the impact excessive G?q signaling upon placental trophoblast function and preeclampsia phenotypes, and (ii) demonstrate that BMTZ increases RGS2 activity leading to decreased G?q-calcium signaling thereby preventing PreE.
Aim 1 will examine the role of excess placental G?q signaling on placental dysfunction and PreE in a placental specific hm3Dq (G?q-activating) DREDD receptor mouse model. Consistent with this, we will test that reduced RGS2 results in PreE through the excessive G?q signaling in a feto-placental RGS2 reduction mouse model (WT dams X RGS2-KO males). In isolated total trophoblasts from these mouse models and in primary human preeclamptic placental tissues, we will study if increased calcium release leads to the poor trophoblast migration consistent with PreE.
Aim 2 will test our hypothesis that the observed reduction in RGS2 in PreE is due to reduced trophoblast cAMP-CREB signaling as will be tested in (AVP)-induced HTR-8/svNeo cells and primary human trophoblasts from PreE pregnancies. We will examine if this reduction in cAMP-CREB-RGS2 signaling will be reversed by treatment with BMTZ in i) AVP-induced HTR-8/svNeo cells, ii) primary human trophoblasts clinically exposed to BMTZ and iii) in our chronic infusion of vasopressin (CIV) mouse model of PreE. Together these studies will greatly clarify a potential causal role of RGS2 in the pathogenesis of preeclampsia, physiological mechanisms controlling RGS2 expression in placental trophoblasts and the possible novel use of BMTZ in the prevention of preeclampsia.
We have demonstrated the AVP pathway is a novel, robust, and early predictor of the development of human preeclampsia and that AVP replicates human preeclampsia in mice. AVP and other preeclampsia/ cardiovascular hormones can work through excessive G?q signaling to cause calcium overload potentially leading to trophoblast dysfunction. The current project aims to 1.) mechanistically link excessive G?q-calcium signaling due the loss of RGS2 to trophoblast dysfunction [a key feature of preeclampsia] and 2.) demonstrate betamethasone as an inducer of RGS2 signaling prevents preeclampsia.