Preeclampsia (PE) affects 5-7% of all pregnancies in the United States and is the leading cause of maternal and prenatal morbidity. PE is associated with hypertension after week 20 of gestation, ...decreased renal function and small-for-gestational-age babies. Women with PE exhibit chronic inflammation and production of autoantibodies. It is hypothesized that during PE, placental ischaemia occurs as a result of shallow trophoblast invasion which is associated with an immune imbalance where pro-inflammatory CD4(+) T-cells are increased and T regulatory cells (Tregs) are decreased. This imbalance leads to chronic inflammation characterized by oxidative stress, pro-inflammatory cytokines and autoantibodies. Studies conducted in our laboratory have demonstrated the importance of this immune imbalance in causing hypertension in response to placental ischaemia in pregnant rats. These studies confirm that increased CD4(+) T-cells and decreased Tregs during pregnancy leads to elevated inflammatory cytokines, endothelin (ET-1), reactive oxygen species (ROS) and agonistic autoantibodies to the angiotensin II (Ang II), type 1 receptor (AT1-AA). All of these factors taken together play an important role in increasing the blood pressure during pregnancy. Specifically, this review focuses on the decrease in Tregs, and their associated regulatory cytokine interleukin (IL)-10, which is seen in response to placental ischaemia during pregnancy. This study will also examine the effect of regulatory immune cell repopulation on the pathophysiology of PE. These studies show that restoring the balance of the immune system through increasing Tregs, either by adoptive transfer or by infusing IL-10, reduces the blood pressure and pathophysiology associated with placental ischaemia in pregnant rats.
Preeclampsia (PE) is a pregnancy-specific syndrome and one of the leading causes of preterm birth, neonatal and maternal morbidity and mortality. This disease is characterized by new onset ...hypertension usually in the third trimester of pregnancy and is sometimes associated with proteinuria, although proteinuria is not a requirement for the diagnosis of PE. In developing countries, women have a higher risk of death due to PE than more affluent countries and one of the most frequent causes of death is high blood pressure and stroke. Although PE only affects approximately 2%-8% of pregnancies worldwide it is associated with severe complications such as eclampsia, hemorrhagic stroke, hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), renal failure and pulmonary edema. Importantly, there is no "cure" for the disease except for early delivery of the baby and placenta, leaving PE a health care risk for babies born from PE moms. In addition, PE is linked to the development of cardiovascular disease and stroke in women after reproductive age, leaving PE a risk factor for long-term health in women. This review will highlight factors implicated in the pathophysiology of PE that may contribute to long-term effects in women with preeclamptic pregnancies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
4.
Rebuttal from Mark O. Cunningham Cunningham, Mark O.
Journal of physiology,
1 November 2022, 2022-11-00, 20221101, Volume:
600, Issue:
21
Journal Article
Peer reviewed
Open access
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Preeclampsia is the leading cause of death and morbidity worldwide for the mother and fetus during pregnancy. Preeclampsia does not only affect the mother and the baby during pregnancy, but can also ...have long-term effects, such as the increased risk of hypertension and cardiovascular disease on the offspring and the postpartum mother later in life. The exact cause of preeclampsia is unknown, but women with preeclampsia have elevated concentrations of agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA). These AT1-AA's through multiple studies have shown to play a significant role in the pathology and possible genesis of preeclampsia. This review will discuss the discovery of AT1-AAs and the role of AT1-AAs in the pathophysiology of preeclampsia. This review will also discuss future therapeutic approaches towards the AT1-AA to prevent adverse pregnancy outcomes. Furthermore, we will examine the relationship between AT1-AA induced hypertension associated with increased oxidative stress, antiangiogenic factors (such as soluble fms-related tyrosine kinase-1 (sFlt-1), endothelin-1 (ET-1), inflammation, endothelial dysfunction, and reduced renal function. Understanding the pathological role of AT1-AAs in hypertensive pregnancies is important as we search for novel therapies to manage preeclampsia.
Women with hypertensive pregnancy complications are at greater risk of developing cardiovascular disease (CVD), metabolic diseases, stroke, and end-stage renal disease (ESRD) later in life. Pregnancy ...complications affect not only the mother's long-term health but also the health of the fetus immediately after delivery and into adulthood. The health of the fetus until adulthood can be influenced by developmental programming, in which the fetus is exposed to insults that will ultimately affect the growth of the offspring and increase the offspring's risk of developing hypertension, coronary heart disease, metabolic disease, and chronic kidney disease in adulthood. Preeclampsia, the onset of hypertension during pregnancy, is one of the major risk factors for the development of renal disease, cerebral disease, and CVD in the mother. Women with preeclampsia are at a 5-12-fold increased risk of developing ESRD, 2-fold increased risk of stroke, and 2-fold increased risk of developing CVD later in life. In this review article, we discuss 1) preeclampsia, 2) the risk of developing CVD, renal disease, or stroke later in life for women with hypertensive pregnancies, and 3) the effects of a hypertensive pregnancy on the offspring.
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 examine the effect of placental ischemia on mitochondrial-mediated oxidative stress in reduced uterine perfusion pressure (RUPP) rat model of preeclampsia but to also examine the role of mitochondrial ROS in contributing to hypertension in response to placental ischemia. Female pregnant Sprague Dawley rats were used in this study. On gestational day 14, RUPP surgery was performed. On gestational day 19, blood pressure (mean arterial pressure) was measured, placentas and kidneys were collected from normal pregnant and RUPP rats and processed for mitochondrial respiration, ROS, and oxidative phosphorylation enzyme activities. Renal and placental complex activities, expressions and respiration rates were significantly reduced and mitochondrial ROS was increased in RUPP versus normal pregnant mitochondria. Mean arterial pressure was elevated in RUPP (n=6) compared with normal pregnant rats (n=5; 126±4 versus 103±4 mm Hg; P<0.05) and treatment with mitochondrial-specific antioxidants (MitoQ/MitoTEMPO) significantly reduced mean arterial pressure in RUPPs (n=5–10). Mitochondrial ROS was significantly elevated in endothelial cells incubated with RUPP serum compared from with normal pregnant rats, whereas serum from mito antioxidant–treated RUPP rats attenuated this response. Impaired mitochondrial function and vascular, placental, and renal mitochondrial ROS play an important role in hypertension and reduced fetal weight in response to placental ischemia during pregnancy.
Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this ...vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin‐1β (IL‐1β) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL‐1β. Systemic LPS triggered microglial IL‐1β, astrocytic chemokines, IL‐6, and acute cognitive dysfunction, whereas IL‐1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL‐1β and IL‐6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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 pressure (RUPP) rat model of preeclampsia exhibits many of these features. In this study, we examined the maternal outcomes of AT1-AA inhibition (‵n7AAc′) in RUPP rats. Blood pressure was higher in RUPP rats versus normal pregnant (NP) rats (123±2 versus 99±2 mm Hg, P<0.05), which was reduced in RUPP+‵n7AAc′ (105±3 versus 123±2 mm Hg, P<0.05 versus RUPP). Uterine artery resistant index was increased in RUPP versus NP rats (0.71±0.02 versus 0.49±0.02, P<0.05) and normalized in RUPP+‵n7AAc′ rats (0.55±0.03). Antiangiogenic factor sFlt-1 was elevated in RUPP versus NP rats (176±37 versus 77±15 pg/mL, P<0.05) but normalized in RUPP+‵n7AAc′ (86±9, P=0.05 versus RUPP). Plasma nitrate and nitrite were decreased (14±1 versus 20±1 µMNO3, P<0.05) and isoprostanes were elevated (20 117±6304 versus 2809±1375 pg/mL, P<0.05) in RUPP versus NP rats; and normalized in RUPP+‵n7AAc′ rats; (18±2 µMNO3; 4311±1 pg/mL). PPET-1 (preproendothelin-1) expression increased 4-fold in RUPP versus NP rats which were prevented with ‵n7AAc′. Importantly, placental cytolytic natural killer cells were elevated in RUPP versus NP rats (8±2% versus 2±2% gated, P<0.05), which was prevented in RUPP+‵n7AAc′ total (3±1% gated, P<0.05) In conclusion, AT1-AA inhibition prevents the rise in maternal blood pressure and several pathophysiological factors associated with preeclampsia in RUPP rats and could be a potential therapy for preeclampsia.
Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of ...relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin human recombinant relaxin-2 (RLX) in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng·kg(-1)·min(-1) sc) for 6 wk or shams. RLX was administered (4 μg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg·day(-1)·100 g(-1), P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects.
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