Severe, early-onset fetal growth restriction is a leading cause of medically indicated preterm birth and substantially increases the risk for perinatal death or disability. No treatments exist to ...improve fetal growth or safely prolong pregnancy. Furthermore, wide-ranging phenotypes limit the accurate prediction of pregnancy outcome. In this issue of the JCI, Spencer and colleagues combine a discovery-science approach with ultrasound parameters to identify the most discriminative models for predicting either the primary outcome of fetal or neonatal death, or a secondary outcome of death or delivery at 28 weeks of gestation or earlier. Their findings can better individualize patient counseling but, just as compellingly, provide the capacity to identify those pregnancies that are at such considerable risk as to justify enrollment in paradigm-shifting interventional trials that are in the pipeline.
Summary
The coronavirus disease 2019 (COVID‐19) pandemic is a rapidly evolving global emergency that continues to strain healthcare systems. Emerging research describes a plethora of patient ...factors—including demographic, clinical, immunologic, hematological, biochemical, and radiographic findings—that may be of utility to clinicians to predict COVID‐19 severity and mortality. We present a synthesis of the current literature pertaining to factors predictive of COVID‐19 clinical course and outcomes. Findings associated with increased disease severity and/or mortality include age > 55 years, multiple pre‐existing comorbidities, hypoxia, specific computed tomography findings indicative of extensive lung involvement, diverse laboratory test abnormalities, and biomarkers of end‐organ dysfunction. Hypothesis‐driven research is critical to identify the key evidence‐based prognostic factors that will inform the design of intervention studies to improve the outcomes of patients with COVID‐19 and to appropriately allocate scarce resources.
Fetal growth restriction (FGR), which most commonly results from suboptimal placental function, substantially increases risks for adverse perinatal and long-term outcomes. The only "treatment" that ...exists is delivery, which averts stillbirth but does not improve outcomes in survivors. Furthermore, the potential long-term consequences of FGR to the fetus, including cardiometabolic disorders, predispose these individuals to developing FGR in their future pregnancies. This creates a multi-generational cascade of adverse effects stemming from a single dysfunctional placenta, and understanding the mechanisms underlying placental-mediated FGR is critically important if we are to improve outcomes and overall health. The mechanisms behind FGR remain unknown. However, placental insufficiency derived from maldevelopment of the placental vascular systems is the most common etiology. To highlight important mechanistic interactions within the placenta, we focus on placental vascular development in the setting of FGR. We delve into fetoplacental angiogenesis, a robust and ongoing process in normal pregnancies that is impaired in severe FGR. We review cellular models of FGR, with special attention to fetoplacental angiogenesis, and we highlight novel integrin-extracellular matrix interactions that regulate placental angiogenesis in severe FGR. In total, this review focuses on key developmental processes, with specific focus on the human placenta, an underexplored area of research.
Growth-restricted fetuses with absent or reversed end-diastolic velocities in the umbilical artery are at substantially increased risk for adverse perinatal and long-term outcome, even in comparison ...to growth-restricted fetuses with preserved end-diastolic velocities. Translational studies show that this Doppler velocimetry correlates with fetoplacental blood flow, with absent or reversed end-diastolic velocities signifying abnormally elevated resistance within the placental vasculature. The fetoplacental vasculature is unique in that it is not subject to autonomic regulation, unlike other vascular beds. Instead, humoral mediators, many of which are synthesized by local endothelial cells, regulate placental vascular resistance. Existing data demonstrate that in growth-restricted pregnancies complicated by absent or reversed umbilical artery end-diastolic velocities, an imbalance in production of these vasoactive substances occurs, favoring vasoconstriction. Morphologically, placentas from these pregnancies also demonstrate impaired angiogenesis, whereby vessels within the terminal villi are sparsely branched, abnormally thin, and elongated. This structural deviation from normal placental angiogenesis restricts blood flow and further contributes to elevated fetoplacental vascular resistance. Although considerable work has been done in the field of fetoplacental vascular development and function, much remains unknown about the mechanisms underlying impaired development and function of the human fetoplacental vasculature, especially in the context of severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities. Fetoplacental endothelial cells are key regulators of angiogenesis and vasomotor tone. A thorough understanding of their role in placental vascular biology carries the significant potential of discovering clinically relevant and innovative approaches to prevention and treatment of fetal growth restriction with compromised umbilical artery end-diastolic velocities.
Pregnancies complicated by severe fetal growth restriction with
bnormal umbilical artery
oppler
elocimetry (FGRadv) are at substantial risk for adverse perinatal and long-term outcomes. Impaired ...angiogenesis of the placental vasculature in these pregnancies results in a sparse, poorly branched vascular tree, which structurally contributes to the abnormally elevated fetoplacental vascular resistance that is clinically manifested by absent or reversed umbilical artery Doppler indices. Previous studies have shown that aryl hydrocarbon receptor nuclear translocator (ARNT) is a key mediator of proper placental angiogenesis, and within placental endothelial cells (ECs) from human FGRadv pregnancies, low expression of ARNT leads to decreased vascular endothelial growth factor A (VEGFA) expression and deficient tube formation. Thus, the aim of the present study was to determine the effect of VEGFA administration or ARNT overexpression on angiogenic potential of FGRadv ECs. ECs were isolated and cultured from FGRadv or gestational age-matched control placentas and subjected to either vehicle vs VEGFA treatment or transduction with adenoviral-CMV (ad-CMV) vs adenoviral-ARNT (ad-ARNT) constructs. They were then assessed via wound scratch and tube formation assays. We found that VEGFA administration nominally improved FGRadv EC migration (
<0.01) and tube formation (
<0.05). ARNT overexpression led to significantly enhanced ARNT expression in FGRadv ECs (
<0.01), to a level similar to control ECs. Despite this, FGRadv EC migration (
<0.05) and tube formation (
<0.05) were still only partially rescued. This suggests that although ARNT does play a role in fetoplacental EC migration, other factors in addition to ARNT are likely also important in placental angiogenesis.
During human pregnancy, the fetal circulation is separated from maternal blood in the placenta by two cell layers - the fetal capillary endothelium and placental trophoblast. This placental barrier ...plays an essential role in fetal development and health by tightly regulating the exchange of endogenous and exogenous materials between the mother and the fetus. Here we present a microengineered device that provides a novel platform to mimic the structural and functional complexity of this specialized tissue
in vitro
. Our model is created in a multilayered microfluidic system that enables co-culture of human trophoblast cells and human fetal endothelial cells in a physiologically relevant spatial arrangement to replicate the characteristic architecture of the human placental barrier. We have engineered this co-culture model to induce progressive fusion of trophoblast cells and to form a syncytialized epithelium that resembles the syncytiotrophoblast
in vivo
. Our system also allows the cultured trophoblasts to form dense microvilli under dynamic flow conditions and to reconstitute expression and physiological localization of membrane transport proteins, such as glucose transporters (GLUTs), critical to the barrier function of the placenta. To provide a proof-of-principle for using this microdevice to recapitulate native function of the placental barrier, we demonstrated physiological transport of glucose across the microengineered maternal-fetal interface. Importantly, the rate of maternal-to-fetal glucose transfer in this system closely approximated that measured in
ex vivo
perfused human placentas. Our "placenta-on-a-chip" platform represents an important advance in the development of new technologies to model and study the physiological complexity of the human placenta for a wide variety of applications.
We present a microengineered cell culture device designed to mimic the maternal-fetal interface in the human placenta.
Objective To assess whether cord blood biomarkers associated with placental maternal vascular underperfusion (MVU) are predictive of bronchopulmonary dysplasia-associated pulmonary hypertension ...(BPD-PH). Study design Premature infants enrolled in a longitudinal cohort study were randomly sampled from 4 gestational age strata (n = 190, range 23-36 weeks). Fifteen factors from a human angiogenesis panel were measured in cord blood using multiplex immunoassay. Multivariate linear regression was used to compare biomarker levels according to placental histologic MVU, taking into account acute/chronic inflammation and fetal vascular pathology. Biomarkers associated with MVU were further evaluated in the subgroup of extremely low gestational age infants (gestational age ≤ 28 weeks; n = 48), and measured by enzyme-linked immunoassay in an additional 39 infants to determine associations with BPD (defined using the National Institutes of Health workshop criteria) and PH (identified by echocardiogram at 36 weeks of gestation). Results Cord blood placental growth factor (PIGF), granulocyte-colony stimulating factor (G-CSF), and vascular endothelial growth factor-A were decreased with MVU ( P < .003), and decreased with BPD-PH ( P < .05). The findings were validated for PIGF and G-CSF in 39 additional extremely low gestational age infants. In the combined group (n = 87), PIGF was decreased in infants with BPD-PH (n = 21) versus controls without PH (median 3 pg/mL IQR 2-7 vs median 15 pg/mL IQR 6-30, respectively; P < .001). G-CSF was similarly decreased with BPD-PH (median, 55 pg/mL IQR 38-85 vs median 243 pg/mL IQR 48-1593, respectively; P = .001). Receiver operator curve analysis revealed that decreased PIGF and G-CSF were predictive of BPD-PH (area under the curve 0.83 and 0.76, respectively). Conclusions Cord blood angiogenic factors that are decreased with placental MVU may serve as predictors of BPD-PH.
Role of Estrogen Receptor-β in Endometriosis Bulun, Serdar E.; Monsavais, Diana; Pavone, Mary Ellen ...
Seminars in reproductive medicine,
01/2012, Letnik:
30, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., ...pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local aromatase expression. The question remains, then, what mediates estradiol action. Because estrogen receptor (ER)β levels in endometriosis are >100 times higher than those in endometrial tissue, this review focuses on this nuclear receptor. Deficient methylation of the ERβ promoter results in pathological overexpression of ERβ in endometriotic stromal cells. High levels of ERβ suppress ERα expression. A severely high ERβ-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor and increased cyclo-oxygenase-2 levels contributing to progesterone resistance and inflammation. ERβ-selective estradiol antagonists may serve as novel therapeutics of endometriosis in the future.
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