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Hypoxia-ischemia is a serious perinatal complication affecting neonates globally. Animal models have increased the understanding of its pathophysiology and have been used to investigate potential therapies. Exenatide, clinically used for the treatment of type 2 diabetes mellitus, also protects the rodent brain from hypoxia-ischemia. The rabbit brain has an earlier neurodevelopmental maturation than rodents, as well as similar postnatal maturation to humans. We hereby introduce a new, reproducible hypoxia-ischemia model in rabbit kits at postnatal day (P) 3–4. Following hypoxia-ischemia, rabbit kits received different exenatide concentrations: 170 μg/g (2-dose) or 500 μg/g (1- or 2-dose), or vehicle. The brains were collected seven days later for histological assessment showing that 500 μg/g exenatide, either as a 1- or 2-dose regimen, reduced brain tissue loss by 90% in hypoxia-ischemia experiments both at P3 and P4. A second cohort received a 1-dose 500 μg/g of exenatide or vehicle, and were sacrificed at different early time-points for glucose, ketone bodies, body weight, and temperature measurements. Our results showed a transient 2-fold increase in ketone bodies (0.6 to 1.3 mmol/L) at 6 h. Exenatide did not affect glucose, body temperature or weight gain and appears to be safe and well tolerated in the rabbit model of hypoxia-ischemia.

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1) on gestation days (GD) 13–19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p < 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p < 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE.

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia.

Preeclampsia is a hypertensive disorder of major concern in pregnancy than can lead to intrauterine growth restriction, placental abruption and stillbirth. The pathophysiology of preeclampsia is multifactorial, including not only kidney dysfunction but also endothelial dysfunction, as the maternal endothelium becomes exposed to placental factors that are released into the circulation and increase systemic levels of vasoconstrictors, oxidative stress, anti-angiogenic factors and inflammatory mediators. Importantly, inflammation can lead to insufficient placental perfusion and low birthweight in offspring. Various innate and adaptive immune cells and mediators have been implicated in the development of preeclampsia, in which oxidative stress is associated with activation of the maternal inflammatory response. Immune cells such as regulatory T cells, macrophages, natural killer cells, and neutrophils are known to have major causative roles in the pathology of preeclampsia, but the contributions of additional immune cells such as B cells, inflammatory cytokines and anti-angiotensin II type 1 receptor autoantibodies are also now recognized. Immunological interventions, therefore, have therapeutic potential in this disease. Here, we provide an overview of the immune responses that are involved in the pathogenesis of preeclampsia, including the role of innate and adaptive immune cells and mediators.Immune dysregulation contributes to the pathogenesis of preeclampsia. Here, the authors examine the role of immune cells and mediators in driving the oxidative stress and endothelial dysfunction that characterize this hypertensive disorder of pregnancy.

Preeclampsia (PE) is new onset hypertension beyond the 20th week of gestation in conjunction with some type of end organ dysfunction. PE is one of the leading causes of maternal and fetal demise worldwide and effects roughly 5-8% of pregnancies each year. PE stems from placental ischemia which leads to release of placental factors and a chronic inflammatory environment in the placenta and the maternal circulation. The inflammation in PE is characterized by activated T helper (Th) cells, Natural Killer (NK) cells, B cells producing agonistic antibodies to the angiotensin II type 1 receptor (AT1-AA) and dysregulation of the complement system. Although these inflammatory mediators have been linked to hypertension in PE, there have been very few studies that have investigated a role of B cells, independent of the AT1-AA, in the pathophysiology of PE.B cells are divided into B1 and B2 subsets. B1 cells are innate-like B cells that spontaneously produce low-affinity antibodies independent of Th cell help. B2 cells are classical B cells that produce antigen specific, high-affinity antibodies and transform into memory B cells with the help of Th cells. B1 cells have previously been implicated in the pathophysiology of PE by producing AT1-AA; however, AT1-AA has been found 7 years postpartum thus suggesting that long-term memory mechanisms, such as those mediated by B2 cells, are involved in AT1-AA production. Our lab has previously shown that communication between Th cells and B cells leads to AT1-AA and hypertension in pregnant rats, suggesting that B2 cells are involved in the pathophysiology of PE. One aim of this work is to test if B2 cells are responsible for AT1-AA in response to placental ischemia in pregnant rats.B cells primarily induce inflammatory actions by producing antibodies. The AT1-AA was originally discovered in the serum of PE women. AT1-AA binds the second extracellular loop of the AT1 receptor, activates the AT1 receptor, induces anti-angiogenic factors, and induces endothelin and oxidative stress. Studies with the AT1-AA in animal models have also shown it sensitizes women to vasoconstrictors and can directly induce hypertension during pregnancy. As AT1-AA is an antibody, it also is an important activator of killer functions of the immune system. After AT1-AA binds its antigen, the FC region of the antibody can be bound by CD16 on human NK cells. CD16 activation on NK cells serves as a strong activating signal and induces cellular cytotoxicity which can contribute to cell mediated destruction and tissue dysfunction in PE. Antibodies can also activate the classical pathway of the complement system. After antibody binding, the C1 complex is built on the FC region of the antibody which starts a cascade of proteolytic cleavages that ultimately result in destruction of the antibody bound cell. Both NK cell activation and complement activation have been implicated in the pathophysiology of PE; but, there have not been any studies that directly studied the relationship between placental ischemiastimulated B cells and NK cell or complement activation. Thus, a second aim of this work was to examine the relationship between B cells in PE and complement activation or NK cell activation during pregnancy.Overall the goal of this dissertation is to further elucidate the role of AT1-AA producing B cells in the pathophysiology of PE. There have been little advancements in treatment strategies for PE over the last 50 years, so there is a dire need for new therapeutic options for clinicians. These studies could elucidate the direct role for B cells to induce hypertension, NK cell activation, complement dysregulation, or fetal growth restriction in PE. Data from these studies may provide insight into specific molecular targets to selectively inhibit known mechanisms of hypertension in women with PE.