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

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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.