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July 2013 - February 2016
Publications
Publications (90)
Problem
Preeclampsia (PE), new‐onset hypertension during pregnancy accompanied by organ dysfunction, is associated with chronic inflammation including elevated IL‐17, CD4+ T cells, B cells and natural killer (NK) cells. IL‐17 can serve as a signal for either the adaptive or innate immune activation. We have previously shown that IL‐17 contributes t...
Background
Preeclampsia, new‐onset hypertension during pregnancy alongside other organ dysfunction, is the leading cause of mortality for the mother and low birth weight for the baby. Low birth weight contributes to high risk of cardiovascular disorders later in life. Women with preeclampsia have activated B cells producing agonistic autoantibodies...
Preeclampsia (PE), new onset hypertension and significant end-organ dysfunction with or without proteinuria after 20 weeks of gestation, affects 8% of all pregnancies in the U.S. and it is associated with progesterone deficiency, chronic inflammation, elevated angiotensin II type 1 receptor agonistic autoantibody (AT1-AA) and endothelial dysfunctio...
Background:
Preeclampsia (PE), new-onset hypertension (HTN), and organ dysfunction during the second half of pregnancy, is associated with an increase in inflammatory immune cells, including T helper 17 (Th17) cells. Studies have demonstrated that mitochondrial (mt) dysfunction is important in the pathogenesis of PE though causative factors have y...
Problem:
Preeclampsia (PE), new-onset hypertension during pregnancy, is associated with a pro-inflammatory state with activated T cells, cytolytic natural killer (NK) cells, dysregulated complement proteins, and B cells secreting agonistic autoantibodies to the angiotensin II type-1 receptor (AT1-AA). The reduced uterine perfusion pressure (RUPP)...
Preeclampsia (PE), new onset hypertension during pregnancy, is associated with activated T Helper cells (Th), and B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA). The Reduced Uterine Perfusion Pressure (RUPP) model of placental ischemia recapitulates these characteristics. B2 cells are classical B cell...
BACKGROUND
Preeclampsia (PE), new-onset hypertension (HTN), and organ dysfunction during the second half of pregnancy, is associated with an increase in inflammatory immune cells, including T helper 17 (Th17) cells. Studies have demonstrated that mitochondrial (mt) dysfunction is important in the pathogenesis of PE though causative factors have yet...
Preeclampsia (PE) is characterized by new onset hypertension (HTN), fetal growth restriction (FGR), multi-organ dysfunction, and increased inflammatory cytokines. Moreover, we have shown offspring of RUPP rats develop hypertension at different stages of life based on sex. More recent studies demonstrate a role for mitochondrial (mt) dysfunction/mtR...
Two important clinical features of preeclampsia (PE) are hypertension and fetal growth restriction. The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE exhibits both of these features. Moreover, RUPP and PE women have elevated vasoconstrictor peptide endothelin-1 (ET-1) and inflammation. Interleukin-2 (IL-2) is a cytokine that...
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 infla...
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 duri...
Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity for the mother and low birth weight in offspring. PE women have activated B cells producing agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA). We have shown Rituximab (R), used clinically for B cell depletion, lowers mean ar...
Preeclampsia (PE) is characterized by new onset hypertension (HTN), intrauterine growth restriction (IUGR), multi-organ dysfunction, and is associated with increased inflammatory cytokines, such as interleukin 17 (IL-17). More recent studies demonstrate a role for mitochondrial (mt) dysfunction/mtROS in the pathogenesis of PE. Although we have show...
Preeclampsia (PE) is characterized by new onset hypertension, intrauterine growth restriction, multi-organ dysfunction, inflammatory cytokines and agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA). More recent studies demonstrate a role for mitochondrial (mt) dysfunction (decreased respiration and mt Reactive Oxygen Species) i...
Preeclampsia (PE) is characterized by new onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines which are likely culprits for decreased fetal weight during PE pregnancies. As progesterone increases during normal pregnancy, it stimulates Progesterone Induced Blocking Factor (PIBF). PIBF has been shown t...
Pre-eclampsia (PE) is a hypertensive disorder of pregnancy associated with chronic inflammation, mitochondrial (mt) dysfunction and fetal demise. Natural Killer cells (NK cells) are critical for the innate immune response against tumors or infection by disrupting cellular mt function and causing cell death. Although NK cells can be stimulated by Tu...
Problem
The Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia recapitulates many characteristics of preeclampsia including maternal hypertension, intrauterine growth restriction (IUGR), and increased cytolytic natural killer cells (cNKs). While we have previously shown a 5‐fold higher cytotoxicity of RUPP NKs vs normal pregn...
The Reduced Uterine Perfusion Pressure (RUPP) rat model and normal pregnant (NP) rat recipients of RUPP CD4+T cells recapitulate many characteristics of preeclampsia (PE) such as hypertension and oxidative stress. We have shown an important hypertensive role for NK cells to cause mitochondrial (mt) dysfunction in RUPP rats, however the role for RUP...
Introduction:Women with preeclampsia (PE) and reduced uterine perfusion pressure (RUPP) pre-clinical rat model of PE have elevated angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA) and cerebrovascular dysfunction.
Methods:Sprague Dawley rats had RUPP surgery with/without AT1-AA inhibitor (‘n7AAc’144 μg/day) osmotic minipumps. Mean ar...
Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and preproendothelin-1 (PPET-1) levels. Currently there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration...
Preeclampsia (PE), new onset hypertension during pregnancy, is associated with inflammation and B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA). Two recognized subsets of B Cells are B1 and B2 B Cells. B2 B Cells are involved in adaptive immune responses and produce specific antibodies. B1 B Cells prod...
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity in the U.S. While the pathogenesis remains unclear, PE is characterized by new onset hypertension associated with progesterone deficiency, elevated cytolytic natural killer cells (cNK), inflammation, and endothelial dysfunction. Progesterone is essential in the initiation and...
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). Infusion of sFlt-1 causes hypertension and other characteristics of PE in pregnant rodents. However a...
Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension associated with placental ischemia (PI), mitochondrial (mt) dysfunction, and an imbalance in T helper (TH) and Natural Killer (NK) cells during pregnancy. The reduced uterine perfusion pressure (RUPP) model is an established model for PE. We have previously shown an...
Preeclampsia (PE) is new onset hypertension during pregnancy and is associated with elevated inflammatory response such as CD4+ T cells, NK cells, and cytokines. We have previously shown women with PE exhibit increases in circulating and placental CD4+T cells and placental mitochondrial (mt) dysfunction/ROS compared to normal pregnant (NP) women. T...
Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity world-wide for the mother and fetus during pregnancy. The Reduced Uterine Perfusion Pressure Rat Model of PE (RUPP) exhibits many characteristics of PE including hypertension, suppressed regulatory T cells (T RegS ) associated with increased CD4+...
The RUPP rat model of Preeclampsia exhibits hypertension (MAP), cytolytic natural killer (cNK) cells, tumor necrosis factor alpha (TNF-α) and mitochondrial Reactive Oxygen Species (mt ROS). Objective: Does TNF-α blockade with ETAN (Etanercept) decrease cNK cell and mt ROS in RUPP rats.
Methods:
On gestational day 14, RUPP surgery was performed, E...
Preeclampsia (PE) is new onset hypertension during pregnancy and is associated with elevated inflammatory response such as CD4+ T cells, NK cells, and cytokines. We have previously shown that women with PE exhibit increases in placental mitochondrial (mt) dysfunction and ROS compared to normal pregnant (NP) women. The Reduced Uterine Perfusion Pres...
Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity world‐wide for the mother and fetus during pregnancy. The Reduced Uterine Perfusion Pressure Rat Model of Preeclampsia (RUPP) exhibits many characteristics of PE including hypertension, suppressed regulatory T cells (T RegS ) associated with incr...
Preeclampsia (PE), new onset hypertension during pregnancy, is associated with a pro‐inflammatory state and B lymphocytes secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1‐AA). Two recognized subsets of B Cells are B1 and B2 B Cells. B2 B Cells are the classical B cell involved in adaptive immune responses and produ...
Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension that is associated with placental ischemia, mitochondrial (mt) dysfunction, and an imbalance in T helper and Natural Killer (NK) cells during pregnancy. The reduced uterine perfusion pressure (RUPP) model is an established model for PE exhibiting hypertension in res...
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). Infusion of sFlt‐1 causes hypertension and endothelial and renal dysfunction in pregnant rodent model...
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity in the U.S. While the pathogenesis remains unclear, PE is characterized by new onset hypertension associated with progesterone deficiency, elevated cytolytic natural killer cells (cNK), inflammation, and endothelial dysfunction. Progesterone is essential in the initiation and...
Preeclampsia (PE) is new onset hypertension during pregnancy associated with increased uterine artery resistance (UARI) and an imbalance among CD4 + T lymphocytes and natural killer (NK) cells. We have shown an important role for 17-hydroxyprogesterone caproate (17-OHPC) to improve hypertension and fetal demise in the RUPP rat model of PE. However...
Preeclampsia (PE) is characterized by new onset hypertension that usually occurs in the 3rd trimester of pregnancy, and is associated with oxidative stress and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs). Inhibition of the AT1-AAs in the reduced uterine perfusion pressure (RUPP) rat, a model of PE, attenuates hypertension and...
Preeclamptic (PE) women have placental ischemia, hypertension (HTN), mitochondrial (mt) dysfunction, increased mt-reactive oxygen species (ROS), cytolytic natural killer (NK) cells, and pro-inflammatory cytokines, such as tumor necrosis factor (TNFα). The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE, is a well-established m...
Preeclampsia (PE) affects 5-7% of all pregnancies in the U.S and it is characterized by new onset hypertension in association with progesterone deficiency, elevated natural killer (NK) cells and inflammatory cytokines. Despite being a leading cause of maternal death and perinatal morbidity, the mechanisms responsible for the pathogenesis of PE are...
Women with preeclampsia (PE) have a risk of developing cardiovascular diseases (CVD) later in life. The angiotensin II type I receptor agonistic autoantibodies (AT1-AAs) are elevated in women with PE, PE women 2 years post-partum (PP), and the reduced uterine perfusion pressure (RUPP) rat model of PE. Blockade of the AT1-AA by using a specific bind...
Preeclampsia (PE), new onset hypertension, is associated with chronic inflammation, autoantibodies to the AT1 receptor (AT1‐AA) and placental ischemia. Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Evidence indicates a shift towards proinflammatory NK cell, C...
Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with immune activation and placental oxidative stress. Mitochondrial (mt) dysfunction is a major source of oxidative stress and may play a role in the pathology of PE. We have previously shown that placental ischemia is associated with mt oxidative stres...
Preeclampsia (PE) is characterized by chronic inflammation and elevated agonistic autoantibodies to the angiotensin type 1 receptor (AT1-AA), endothelin-1, and uterine artery resistance index (UARI) during pregnancy. Previous studies report an imbalance among immune cells, with T-helper type 2 (Th2) cells being decreased during PE. We hypothesized...
Preeclampsia (PE), new onset hypertension during pregnancy, is associated with a proinflammatory profile compared to normal pregnancy (NP). We hypothesize that CD4⁺ T cells from PE patient placentas cause PE symptoms during pregnancy compared to those from NP women. CD4⁺ T cells were isolated from placentas of PE and NP women using anti-CD4 magneti...
Women with preeclampsia (PE) have increased mean arterial pressure (MAP), natural killer (NK) cells, reactive oxygen species (ROS), and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA's administered to pregnant rodents produces a well-accepted model of PE. However, the role of NK cells and mitochondrial reactive oxyg...
Preeclampsia (PE) affects 7% of pregnancies in the United States and is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1). We and others have shown that infusion of sFlt-1 into pregnant rodents causes hypertension, indicating an important role for sFlt-1 in mediating the pathophysiology...
Preeclampsia (PE) is characterized by new onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines which are likely culprits for decreased fetal weight during PE pregnancies. Progesterone induced blocking factor (PIBF) increases during normal pregnancy and has been shown to decrease inflammation and cytol...
Women with preeclampsia (PE) have increased blood pressure (MAP), natural killer (NK) cells, reactive oxygen species (ROS), and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA’s administered to pregnant rodents produces a well-accepted model of PE. However, the role of NK cells and mitochondrial reactive oxygen speci...
Placental ischemia is believed to be the initial event in the development of preeclampsia. Mitochondrial dysfunction is a cause of reactive oxygen species (ROS) generation and oxidative stress, however, there are not many studies examining the role of mitochondrial ROS in the pathology of preeclampsia. The purpose of this study was to not only exam...
Previous studies have demonstrated that T-helper 17 cells (TH17s) and cytolytic NK cells (cNKs) are increased in women with preeclampsia (PE). In this study, we investigated the role of placental ischemia-stimulated TH17s to induce cNKs in pregnancy. We further assessed the role of TH17-mediated oxidative stress to facilitate cNK activation in preg...
The R educed U terine P erfusion P ressure (RUPP) rat model of placental ischemia mimics many of the characteristics of preeclampsia (PE) including hypertension, intrauterine growth restriction, and increases in circulating T H 17 cells (T H 17s), IL‐17 and placental cytolytic natural killer cells (cNKs). Although the stimulus for cNKs in PE is cur...
Women with preeclampsia (PE) have hypertension, placental ischemia, increased pro‐inflammatory cells (natural killer (NK) and Th1 cells) and cytokines, and intrauterine growth restriction (IUGR). Interleukin‐2 (IL‐2) is a Th1 cytokine that stimulates NK cell activation. We hypothesize that IL‐2 is one mechanism whereby Th1 cells, which are activate...
Introduction
Preeclampsia (PE), is characterized by new onset hypertension and is associated with placental ischemia and oxidative stress. Placental ischemia is believed to be the initial event in the development of PE. Mitochondria are the major source of oxidative stress, the mitochondrial (mt) dysfunction leads to decreased respiration and incre...
Preeclampsia (PE), new onset hypertension, is a progesterone deficient state and is associated with an imbalance among CD4 ⁺ T lymphocytes, natural killer (NK) cells, and inflammatory cytokines which are likely culprits for decreased fetal weight during PE pregnancies. During normal pregnancy activated lymphocytes express progesterone receptors, wh...
Women with preeclampsia produce AT1-AA (agonistic autoantibodies to the angiotensin II type 1 receptor), which stimulate reactive oxygen species, inflammatory factors, and hypertensive mechanisms (ET [endothelin] and sFlt-1 [soluble fms-like tyrosine kinase-1]) in rodent models of preeclampsia. The placental ischemic reduced uterine perfusion press...
Preeclampsia is characterized by elevated TNF-α (tumor necrosis factor-α), antiangiogenic factors, such as sFlt-1 (soluble vascular endothelial growth factor receptor 1), increased uterine artery resistance index, and decreased of NO during pregnancy. Previously we showed that 17-hydroxyprogesterone caproate (17-OHPC) administered into reduced uter...
Preeclampsia is associated with hypertension, small-for-gestational-age babies and increased cytolytic natural killer (NK) cells. The specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. We hypothesized that Reduced Uterine Perfusion Pressure (RUPP) stimulates proliferation and cytolytic activatio...
Preeclampsia (PE), hypertension in response to placental ischemia, is associated with angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA), oxidative stress, and neurological complications, such as headaches, blurred vision, and seizures which could lead to stroke and death. We hypothesize that AT1AAs play a role in the cerebral patholo...
Preeclampsia (PE), new onset hypertension during pregnancy, is associated with a proinflammatory profile compared to normal pregnancy (NP). We hypothesize that CD4 ⁺ T cells play an important role to cause much of the pathophysiology associated with PE. To determine if CD4 ⁺ T cells isolated from PE patients cause PE symptoms during pregnancy compa...
Introduction: Preeclampsia (PE) is associated with placental ischemia, new onset hypertension, oxidative stress and endothelial dysfunction. Factors linking placental ischemia with endothelial dysfunction and hypertension are not completely understood. Mitochondrial (mt) dysfunction (dys) is a major source of reactive oxygen species (ROS) and we ha...
Introduction: Preeclampsia (PE) is characterized by new onset hypertension in pregnancy and is associated with renal dysfunction, proteinuria and is believed to be initiated by placental ischemia. Mitochondrial dysfunction is an important source of reactive oxygen species (ROS) generation. To better understand the role of mitochondrial dysfunction...
Preeclampsia (PE), new onset hypertension in response to placental ischemia during pregnancy, is associated with chronic inflammation characterized by elevated tumor necrosis factor (TNF-α), interleukin-6 (IL-6), agonistic autoantibody to the Ang II type 1 receptor (AT1-AA). In addition, evidence for a shift towards proinflammatory CD4+TH1 vs CD4+T...
Preeclampsia (PE), a hypertensive disorder of pregnancy, is associated with increased circulating T H 17 cells (T H 17s), IL-17 and cytolytic Natural Killer cells (cNKs). Although the stimulus for cNKs in PE is currently unknown, recent in vitro studies suggest that IL-17 induces proliferation and cytotoxic activity in human NK cells. We have previ...
Problem:
Preeclampsia (PE) is associated with inflammation and decreased Treg cells and IL-10. The reduced uterine perfusion pressure (RUPP) rat model of PE exhibits these characteristics, and we hypothesized that induction of endogenous Tregs by a specific stimulus (CD28 superagonistic monoclonal antibody) would reduce inflammation, vasoactive fa...
Autoantibodies to the angiotensin II (ANGII) type I receptor (AT1-AA) are associated with preeclampsia (PE). We found that Vitamin D supplementation reduced AT1-AA and blood pressure (MAP) in the RUPP rat model of PE. However, it was undetermined if the decrease in AT1-AA was the mechanism whereby Vitamin D lowered MAP or if it was through factors...
Preeclampsia is a hypertensive disorder of pregnancy with limited therapeutic options. In healthy pregnancy, relaxin plays an important vasodilatory role to maintain vascular compliance; however, there is currently no preclinical evidence to support the use of relaxin during preeclampsia. Therefore, the goal of this study was to test the hypothesis...
Preeclampsia (PE), new onset hypertension during pregnancy, is associated with pro-inflammatory cytokines and decreased regulatory immune mechanisms such as Tregs, IL-10 and IL-4. We believe this decrease in immune regulatory mechanisms leads to an uncontrolled proinflammatory response which contributes to most of the pathophysiology associated wit...
Introduction: Placental ischemia is believed to be the initial event in the development of preeclampsia (PE). PE is characterized by new onset hypertension and is associated with reduced fetal weight and placental oxidative stress. Mitochondrial dysfunction is the major cause of reactive oxygen species (ROS) generation. We hypothesize that the plac...
Women with Preeclampsia (PE), a form of new onset hypertension during pregnancy, exhibit alterations in the renin angiotension system (RAS). These differences include angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA), ANG II sensitivity, and increased oxidation and levels of angiotensinogen (AGT). While antihypertensive drugs are use...
Preeclampsia (PE), new onset hypertension, is characterized by decreased fetal weight, elevated cytolytic natural killer (NK) cells and placental ischemia during pregnancy. Cytolytic NK are thought to play a role in fetal demise as they have also been shown to be increased in patients suffering from miscarriage.Currently, there is no effective trea...
Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small-for-gestational-age babies and demonstrate an increase in the cytolytic natural killer (NK) cell activation. The specific role of cytolytic NK cells in the pathophysiology of PE has not been clearly defined. The reduced uterine perfusion pr...
Deficiency of Vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine if VD supplementation would reduce the pathophysiology and hypertension associated with the Reduced Uterine Perfusion Pressure (RUPP) rat model of PE. Normal pregnant (NP)...
Studies in our lab have previously shown that Vitamin D supplementation in the RUPP rat model of preeclampsia lowers blood pressure and reduces autoantibodies to the AT1 receptor (AT1-AA). Therefore, we sought to determine if the effects of Vitamin D supplementation to inhibit endothelial dysfunction and hypertension during pregnancy were mediated...
Preeclampsia (PE), new onset hypertension during pregnancy, is associated with pro-inflammatory cytokines and decreased regulatory immune mechanisms such as Tregs, IL-10 and IL-4. We believe this decrease in immune regulatory mechanisms leads to an uncontrolled proinflammatory response which contributes to most of the pathophysiology associated wit...
The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia was used to determine the effects of added interleukin-10 (IL-10) on Tregs and hypertension in response to placental ischemia and how the decrease in these anti-inflammatory factors mediates the pathophysiology of preeclampsia.
IL-10 (2.5 ng/kg/d) was infused via osmotic mini-p...
: Preeclampsia is a multisystemic syndrome during pregnancy that is often associated with intrauterine growth retardation. Immunologic dysregulation, involving T cells, is implicated in the pathogenesis. The aim of this study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Appli...
Preeclampsia is characterized by hypertension, proteinuria and often associated with intrauterine growth retardation. There is a growing body of evidence that immunological dysregulation, involving T-cells, is implicated in causing preeclampsia. Proper recognition of paternal antigens by regulatory T cells is essential for successful outcome of pre...
Preeclampsia (PE), new onset of hypertension during pregnancy, is associated with pro-inflammatory cytokines and decreased regulatory immune responses including Tregs and decreased IL-10. We believe this decrease in immune regulatory mechanisms leads to much of the pathophysiology associated with PE such as elevated blood pressure and decrease in f...
