Vasopressin and Preeclampsia: Early Mechanisms for Prevention

子痫前期(Preeclampsia，Pree)是一种常见的妊娠期高血压疾病，是世界范围内导致子痫的主要原因。 产科死亡率，每年76,000名产妇和500,000名新生儿死亡。由于很早就不清楚 Pree的妊娠病因，预防Pree仅限于每天服用婴儿阿司匹林，可能仅适量 阻止普里。编码G蛋白信号转导调节因子(RGS)-2的基因多态性与此相关 增加了患先兆子痫的风险。RGS2是RGS蛋白B/R4家族中的一员，其作用是 G-Q-钙第二信使信号的内源性抑制物，一种常见的致病途径 许多与Pre相关的激素，如精氨酸加压素(AVP)。倍他米松(BTMZ)是常用的 对于有早产风险的妇女，以预防新生儿发病率。我们的初步数据和文献 提示BMTZ等类固醇可以诱导RGS2，从而关闭过度致病的GQ-钙 在普里看到的信号。综合这些数据，我们得出了一个总体假设，即BMTZ通过以下方式预防Pree 恢复胎盘RGS_2信号转导及减少G-Q-钙信号过量 与Pree相关的胎盘功能障碍有关。本提案的总体目标是：(一) 评价G--Q信号过量对胎盘滋养细胞功能和子痫前期的影响 表型，以及(Ii)表明BMTZ增加了RGS_2活性，导致G-Q-钙降低 信令，从而阻止Pree。目标1将研究胎盘GαQ信号过多对胎盘的作用 胎盘特异性hm3Dq(GαQ激活)Dredd受体小鼠模型中的功能障碍和Pre。 与此一致，我们将测试RGS2的减少通过过量的GαQ信号在一个 胎盘RGS2减少小鼠模型(WT DAMS×RGS2-KO雄性)。在分离的总滋养层细胞中 在这些小鼠模型和原发人类先兆子痫胎盘组织中，我们将研究是否增加钙 释放导致滋养层细胞迁移不良，与Pree一致。目标2将测试我们的假设，即 观察到的Pree中RGS2的减少是由于滋养层细胞cAMP-CREB信号的减少，这将在 (AVP)诱导的HTR-8/svNeo细胞和Pree妊娠的原代人滋养层细胞。我们将检查是否 这种cAMP-CREB-RGS2信号的减少将被BMTZ逆转，在i)AVP诱导 HTR-8/svNeo细胞，II)临床暴露于BMTZ的原代人滋养层细胞和III)在我们的慢性输注中 加压素(CIV)致Pree小鼠模型。总而言之，这些研究将极大地阐明 RGS2在子痫前期发病机制中的作用及调控RGS2表达的生理机制 胎盘滋养层细胞和BMTZ在预防子痫前期中的可能新用途。

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 Gαq signaling on placental dysfunction and PreE in a placental specific hm3Dq (Gαq-activating) DREDD receptor mouse model. Consistent with this, we will test that reduced RGS2 results in PreE through the excessive Gαq 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.