Friday, May 16, 2025
5/16/2025
B Cells in Preeclampsia: Long-term Effects on Offspring - Preeclampsia (PE), new-onset hypertension during pregnancy with multi-organ dysfunction, is associated with chronic immune activation and is the leading cause of morbidity and mortality for the mother and fetus. Delivery of the baby is the current treatment for PE. Today’s therapies focus on managing symptoms instead of preventing the occurrence. Preterm delivery of the fetus is a primary cause of fetal growth restriction (FGR) and this is associated with an elevated risk for cardiovascular, metabolic, and neurological disorders later in life. In fact, PE is associated with autism spectral disorder in offspring and early signs of cognitive disorders in the mother. PE women exhibit increased activated T helper cells and B cells producing agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) which have been implicated in oxidative stress, increased sensitivity to angiotensin II, and cerebrovascular dysfunction in the mother. Our lab has demonstrated that AT1-AA can be blocked with a novel inhibitory peptide ‘n7AAc’ that reduces blood pressure and cerebrovascular dysfunction in PE rat models. While ‘n7AAc’ has not been tested clinically, we have demonstrated its efficacy and safety in several preclinical models of PE and PE offspring. We hypothesize that AT1-AA produced by B cells stimulated in PE pregnancies contribute both to the PE syndrome during pregnancy as well as postpartum risk for neurovascular disease in previously PE women and their children. We will address this hypothesis by isolating B cells from the placentas of PE patients and adoptively transferring them into pregnant nude athymic rats and then examine blood pressure, immune cells, cerebrovascular function, and cognitive function. Additionally, we will allow a second group of animals to deliver and examine birth weight and growth in the offspring, as well as blood pressure, immune cells, cerebrovascular function, and cognitive function in the adult offspring and postpartum dams. Finally, we will treat the B cell recipients with the inhibitory peptide ‘n7AAc’ and measure the same outcomes during pregnancy as well as in the adult offspring and postpartum dams. Based on our preliminary findings we hypothesize that AT1-AA blockade will improve maternal outcomes in B cell recipients and reduce postpartum risks following PE in both the dams and offspring. The following specific aims will be used to test this hypothesis. Specific Aim 1: To test the hypothesis that CD20+ B cells from PE women are stimulated to produce AT1-AA and cause hypertension as well as cerebrovascular and cognitive dysfunction during pregnancy and in 12-week postpartum dams as well as male and female offspring. Specific Aim 2: To test the hypothesis that perinatal or postnatal blockade of AT1-AA in recipient dams of PE CD20+ B cells will improve hypertension as well as cerebrovascular and cognitive dysfunction during pregnancy and in postpartum dams and offspring.
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