Reduced uterine perfusion pressure as a model for preeclampsia and fetal growth restriction in murine: a systematic review and meta-analysis.

The reduced uterine perfusion pressure (RUPP) model is frequently used to study preeclampsia and fetal growth restriction. An improved understanding of influential factors might improve reproducibility and reduce animal use considering the variability in RUPP phenotype. We performed a systematic review and meta-analysis by searching Medline and Embase (until 28 March, 2023) for RUPP studies in murine.

Luteolin prevents TNF-α-induced NF-κB activation and ROS production in cultured human placental explants and endothelial cells.

Introduction: Preeclampsia (PE) is a serious hypertensive pregnancy disorder and a leading cause of maternal and perinatal morbidity and mortality. Despite the prevalence and complications, there are no approved therapeutics to relieve PE symptoms. Inflammation, oxidative stress, and angiogenic imbalance have been shown to contribute to the PE pathophysiology, though there is a lack of understanding in how best to target these pathways in PE.

Bioflavonoid luteolin prevents sFlt-1 release via HIF-1α inhibition in cultured human placenta.

Preeclampsia (PE) is a serious hypertensive complication of pregnancy and is a leading cause of maternal death and major contributor to maternal and perinatal morbidity, including establishment of long-term complications. The continued prevalence of PE stresses the need for identification of novel treatments which can target prohypertensive factors implicated in the disease pathophysiology, such as soluble fms-like tyrosine kinase 1 (sFlt-1). We set out to identify novel compounds to reduce placental sFlt-1 and determine whether this occurs via hypoxia-inducible factor (HIF)-1α inhibition.

Long-Term Impacts of Preeclampsia on the Cardiovascular System of Mother and Offspring.

Preeclampsia is a pregnancy-specific complication that is associated with an increased postpartum risk of cardiovascular disease (CVD) in both women and their offspring, although the underlying mechanisms have yet to be fully elucidated. Nevertheless, differential methylation of cytosine-phosphate-guanosine islands and alterations in the expression of microRNA, associated with an elevated risk of CVD, have been observed in women and their children following preeclampsia. Among this specific population, genetic and epigenetic factors play crucial roles in the development of CVD in later life.

Epithelial sodium channels in macrophage migration and polarization: role of proinflammatory cytokines TNFα and IFNγ.

Migration of monocytes-macrophages plays an important role in phagocytosis of pathogens and cellular debris in a variety of pathophysiological conditions. Although epithelial Na channels (ENaCs) are required for normal migratory responses in other cell types, their role in macrophage migration signaling is unknown. To address this possibility, we determined whether ENaC message is present in several peripheral blood monocyte cell populations and tissue-resident macrophages in healthy humans using the Human Protein Atlas database (www.

Is there a role of proinflammatory cytokines on degenerin-mediated cerebrovascular function in preeclampsia?

Preeclampsia (PE) is associated with adverse cerebrovascular effects during and following parturition including stroke, small vessel disease, and vascular dementia. A potential contributing factor to the cerebrovascular dysfunction is the loss of cerebral blood flow (CBF) autoregulation. Autoregulation is the maintenance of CBF to meet local demands with changes in perfusion pressure.

Sustained Elevated Circulating Activin A Impairs Global Longitudinal Strain in Pregnant Rats: A Potential Mechanism for Preeclampsia-Related Cardiac Dysfunction.

Mediators of cardiac injury in preeclampsia are not well understood. Preeclamptic women have decreased cardiac global longitudinal strain (GLS), a sensitive measure of systolic function that indicates fibrosis and tissue injury. GLS is worse in preeclampsia compared to gestational hypertension, despite comparable blood pressure, suggesting that placental factors may be involved.

Placental Ischemia Says "NO" to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia.

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO) and/or nitrate (NO), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum.

Expression of Exogenous Epithelial Sodium Channel Beta Subunit in the Mouse Middle Cerebral Artery Increases Pressure-Induced Constriction.

Background: Pressure-induced constriction (PIC) is inherent to small arteries and arterioles, in which intraluminal pressure-induced vascular smooth muscle cell stretch elicits vasoconstriction. Degenerin (Deg) proteins, such as beta-epithelial Na+ channel (βENaC), have been studied in the PIC response because they are evolutionarily linked to known mechanosensors. While loss of Deg function phenotypes are plentiful, a gain-of-function phenotype has not been studied.

Macula Densa NOS1β Modulates Renal Hemodynamics and Blood Pressure during Pregnancy: Role in Gestational Hypertension.

Background: Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease.

Animal models of preeclampsia: investigating pathophysiology and therapeutic targets.

Animal models have been critical in investigating the pathogenesis, mediators, and even therapeutic options for a number of diseases, including preeclampsia. Preeclampsia is the leading cause of maternal and fetal morbidity and mortality worldwide. The placenta is thought to play a central role in the pathogenesis of this disease because it releases antiangiogenic and proinflammatory factors into the maternal circulation, resulting in the maternal syndrome.

Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats.

The prevalence of preeclampsia and obesity have increased. Although obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass.

Interleukin-17 induces hypertension but does not impair cerebrovascular function in pregnant rats.

Preeclampsia affects 5-8% of pregnancies and is characterized by hypertension, placental ischemia, neurological impairment, and an increase in circulating inflammatory cytokines, including Interleukin-17 (IL17). While placental ischemia has also been shown to impair cerebrovascular function, it is not known which placental-associated factor(s) drive this effect. The purpose of this study was to examine the effects of IL17 on cerebrovascular function during pregnancy.

Long-Term Postpartum Cardiac Function and Its Association With Preeclampsia.

Background Preeclampsia is a prominent risk factor for long-term development of cardiovascular disease. Although existing studies report a strong correlation between preeclampsia and heart failure, the underlying mechanisms are poorly understood. One possibility is the glycoprotein growth factor activin A.

Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction.

Preeclampsia (PE), a hypertensive disorder, occurs in 3% to 8% of pregnancies in the United States and affects over 200,000 women and newborns per year. The United States has seen a 25% increase in the incidence of PE, largely owing to increases in risk factors, including obesity and cardiovascular disease. Although the etiology of PE is not clear, it is believed that impaired spiral artery remodeling of the placenta reduces perfusion, leading to placental ischemia.

Luteolin-induced vasorelaxation in uterine arteries from normal pregnant rats.

Background: The flavonoid, luteolin, promotes vasorelaxation in various arteries through endothelial-dependent and independent mechanisms. Although there is growing interest in the vasoactive effects of flavonoids on maternal vascular function during pregnancy, it is unknown whether luteolin elicits vasorelaxation in the uterine circulation. We tested the hypothesis that luteolin induces vasorelaxation via endothelial-dependent mechanisms in uterine arteries from normal pregnant rats during late gestation.

Antepartum Aspirin Administration Reduces Activin A and Cardiac Global Longitudinal Strain in Preeclamptic Women.

Background Approximately 60% of women have Stage B heart failure 1 year after a preeclamptic delivery. Emerging evidence suggests that the profibrotic growth factor activin A, which has been shown to induce cardiac fibrosis and hypertrophy, is elevated in preeclampsia and may be inhibited by aspirin therapy. We hypothesized that preeclamptic women receiving aspirin would have lower activin A levels and reduced global longitudinal strain (GLS), a sensitive measure of cardiac dysfunction, than women who do not receive aspirin.

Pressure-induced constriction of the middle cerebral artery is abolished in TrpC6 knockout mice.

Pressure-induced constriction (PIC) is an inherent response of small arteries and arterioles in which increases in intraluminal pressure evoke vasoconstriction. It is a critical mechanism of blood flow autoregulation in the kidney and brain. Degenerin (Deg) and transient receptor potential (Trp) protein families have been implicated in transduction of PIC because of evolutionary links to mechanosensing in the nematode and fly.

Interleukin-17 Reduces βENaC via MAPK Signaling in Vascular Smooth Muscle Cells.

Degenerin proteins, such as the beta epithelial Na channel (βENaC), are essential in the intracellular signaling of pressure-induced constriction, an important vascular smooth muscle cell (VSMC) function. While certain cytokines reduce ENaC protein in epithelial tissue, it is unknown if interleukin-17 (IL-17), a potent pro-inflammatory cytokine, directly mediates changes in membrane-associated βENaC in VSMCs. Therefore, we tested the hypothesis that exposure to IL-17 reduces βENaC in VSMCs through canonical mitogen-activated protein kinase (MAPK) signaling pathways.

Utero-placental vascular remodeling during late gestation in Sprague-Dawley rats.

Background: Remodeling of the uterine spiral arteries and blood vessels within the placenta allows delivery of nutrients to the growing utero-fetal-placental unit. While abnormal remodeling of these vessels is thought to play an important role in syndromes including intrauterine growth restriction and preeclampsia, there are a lack of studies that have quantified vascular remodeling in normal pregnant rats. Thus, the purpose of this study was to quantify time-dependent remodeling of the utero-placental vasculature during late gestation in normal pregnant rats.

Tumor necrosis factor-α impairs cerebral blood flow in pregnant rats: role of vascular β-epithelial Na channel.

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with ) increased circulating TNF-α, ) attenuated pressure-induced cerebral vascular tone, and ) suppression of β-epithelial Na channel (βENaC) protein in cerebral vessels. In addition to its role in epithelial Na and water transport, βENaC is an essential signaling element in transduction of pressure-induced (aka "myogenic") constriction, a critical mechanism of blood flow autoregulation.

The angiotensin II type I receptor contributes to impaired cerebral blood flow autoregulation caused by placental ischemia in pregnant rats.

Background: Placental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined.

The Reduced Uterine Perfusion Pressure (RUPP) rat model of preeclampsia exhibits impaired systolic function and global longitudinal strain during pregnancy.

Background: Preeclampsia (PE) is a disorder prevalent in 3-8% of pregnancies, characterized by hypertension, endothelial dysfunction and cardiac dysfunction, including hypertrophy and impaired global longitudinal strain (GLS), which indicates reduced contractility and tissue injury. Despite several clinical studies highlighting impaired cardiac function in these women, the underlying mechanisms have not been studied, in part, due to lack of an appropriate animal model. The Reduced Uterine Perfusion Pressure (RUPP) rat model produces a PE-like phenotype, including adverse cardiac remodeling.