The Role of AT1-AA in Causing Adult Hypertension in Offspring Born with FGR

子痫前期（PE）是妊娠期新发高血压，与其他器官功能障碍相关， 以及慢性免疫激活，是母亲和胎儿发病和死亡的主要原因。 目前唯一有效的PE治疗方法是胎儿-胎盘单位的分娩。早产 胎儿是胎儿生长受限（FGR）的主要原因，并与以下风险升高相关： 心血管、代谢和神经系统疾病。PE女性表现出慢性免疫 通过增加辅助性T细胞和B细胞的激活来激活，产生针对 血管紧张素II I型受体（AT 1-AA）。AT 1-AA参与了许多导致高血压的途径 包括氧化应激、自然杀伤细胞激活和对血管紧张素II敏感性增加。我们实验室 通过阻断AT 1-AA的产生或活性，已证明对母亲有益。美罗华 临床上用于B细胞耗竭，已显示降低平均动脉压（MAP），循环B细胞， 和AT 1-AA在先兆子痫大鼠模型中的作用。我们的实验室还使用了一种加帽的七氨基酸序列肽， “n7 AAc”，以结合并阻断AT 1-AA的活性。这导致MAP，自然杀伤细胞 活化和氧化应激。虽然“n7 AAc”尚未在临床上使用， 患有类风湿性关节炎、多发性硬化症或非霍奇金淋巴瘤的孕妇接受过治疗， 在妊娠期间或妊娠前三个月使用利妥昔单抗，胎儿发病率未升高，或 报告的死亡人数。我们假设AT 1-AA在PE中发挥病理作用，导致高血压， 免疫激活不仅对母亲，而且对胎儿，母体治疗利妥昔单抗或 “n7 AAc”将长期改善孕产妇健康和后代健康。为了验证这一假设，怀孕的老鼠将 接受RUPP手术，用或不用利妥昔单抗或“n7 AAc”治疗，并允许分娩。的 这些窝仔的后代将被跟踪12周至1年的时间。根据我们初步的 研究结果，我们假设B细胞耗竭或AT 1-AA阻断妊娠先兆子痫的母体将改善 通过降低母体和胎儿循环AT 1-AA活性、炎症和后代血液， 压力以下具体目标将用于检验这一假设： 具体目的1：为了检验妊娠期间B细胞耗竭将改善后代存活率的假设， 生长和HTN对妊娠期间胎盘缺血的反应。 具体目的2：检验妊娠期间给予AT 1-AA会使后代恶化的假设 长期生存、生长和心血管健康。 具体目标3：为了检验怀孕期间“n7 AAc”治疗将改善后代存活率的假设， 生长和HTN对妊娠期间胎盘缺血的反应。

Preeclampsia (PE), new-onset hypertension during pregnancy, is associated with other organ dysfunction as well as chronic immune activation and is the leading cause of morbidity and mortality for the mother and fetus. The only currently effective treatment for PE is the delivery of the fetal-placental unit. Preterm delivery of the fetus is the primary cause of fetal growth restriction (FGR) and is associated with an elevated risk for cardiovascular, metabolic, and neurological disorders later in life. PE women demonstrate chronic immune activation through increased activation of T helper cells and B cells producing an agonistic autoantibody to the angiotensin II type I receptor (AT1-AA). AT1-A A is implicated in numerous pathways contributing to hypertension in PE including oxidative stress, natural killer cell activation, and increased sensitivity to angiotensin II. Our lab has demonstrated beneficial effects for the mother by blocking the production or activity of AT1-AA. Rituximab used clinically for B cell depletion, has been shown to decrease mean arterial pressure (MAP), circulating B cells, and AT1-AA in a rat model of preeclampsia. Our lab has also used a capped seven amino acid sequence peptide, ‘n7AAc’, to bind to and block the activity of AT1-AA. This has resulted in decreased MAP, natural killer cell activation, and oxidative stress in a rat model of preeclampsia. While ‘n7AAc’ has not been used clinically, pregnant women with rheumatoid arthritis, multiple sclerosis, or non-Hodgkin’s lymphoma have been treated with Rituximab during or up to the first trimester of their pregnancies with no elevation in fetal morbidities or mortalities reported. We hypothesize that AT1-AA plays a pathologic role in PE to cause hypertension and immune activation not only for the mother but also for the fetus and that maternal treatment with Rituximab or ‘n7AAc’ will improve maternal health and offspring health long-term. To test this hypothesis, pregnant rats will undergo the RUPP surgery with or without treatment with Rituximab or ‘n7AAc’ and be allowed to deliver. The offspring from these litters will be followed for a period of twelve weeks to one year. Based on our preliminary findings, we hypothesize that B cell depletion or AT1-AA blockade in pregnant preeclamptic dams will improve offspring health by reducing maternal and fetal circulating AT1-AA activity, inflammation, and offspring blood pressure. The following specific aims will be used to test this hypothesis: Specific Aim 1: To test the hypothesis that B cell depletion during pregnancy will improve offspring survival, growth, and HTN in response to placental ischemia during pregnancy. Specific Aim 2: To test the hypothesis that administration of AT1-AA during pregnancy will worsen offspring survival, growth, and cardiovascular health long-term. Specific Aim 3: To test the hypothesis that ‘n7AAc’ treatment during pregnancy will improve offspring survival, growth, and HTN in response to placental ischemia during pregnancy.