Impaired Spiral Artery Remodeling Research Articles

The Deubiquitinating Enzyme USP4 Promotes Trophoblast Dysfunction by Stabilizing RYBP.

Previous studies have suggested that impaired spiral artery remodeling, placental dysfunction, and insufficient trophoblast infiltration are the etiology and pathogenesis of Preeclampsia (PE). Ring 1 and YY1 binding protein (RYBP) has been reported to be associated with trophoblast dysfunction. However, the molecular mechanism of RYBP involved in trophoblasts in the pathogenesis of PE is poorly defined. RYBP and Ubiquitin-specific peptidase 4 (USP4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). RYBP, USP4, p-PI3K, PI3K, p-AKT, and AKT protein levels were measured using western blot assay. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay. RYBP and USP4 expression were upregulated in placental tissues from PE patients. By using JEG-3 and HTR-8/SVneo trophoblast cells, RYBP overexpression or USP4 upregulation could hinder cell viability, proliferation, invasion, migration, and promote apoptosis. Mechanistically, USP4 could trigger the deubiquitination of RYBP and prevent its degradation. In addition, USP4 repressed the PI3K/AKT signaling pathway by regulating RYBP. In total, Decreased USP4-mediated ubiquitination results in an adverse impact on trophoblast function by enhancing RYBP expression, providing a novel therapeutic target for PE.

DOCK1 deficiency drives placental trophoblast cell dysfunction by influencing inflammation and oxidative stress, hallmarks of preeclampsia.

Preeclampsia (PE) is a globally prevalent obstetric disorder, pathologically characterized by abnormal placental development. Dysfunctions of angiogenesis, vasculogenesis and spiral artery remodeling are demonstrated to be involved in PE pathogenesis; however, the underlying mechanisms remain largely unknown. Here, we investigated the role of the dedicator of cytokinesis 1 (DOCK1), crucial molecule in various cellular processes, in PE progression using HTR-8 cells derived from first-trimester placental extravillous trophoblasts. Our analysis revealed an aberrant DOCK1 expression in the placental villi of PE patients and its impact on essential cellular functions for vascular network formation. A deficiency of DOCK1 in HTR-8 cells impaired the vascular network formation, exacerbated the expression of anti-angiogenic factor ENG, and reduced VEGF levels. Moreover, DOCK1 knockout amplified apoptosis, as indicated by an altered BCL2: BAX ratio and enhanced levels of cleaved PARP. DOCK1 depletion also boosted NF-κB activation and pro-inflammatory cytokine production (IL-6 and TNF-α). Furthermore, the mice treated with DOCK1 inhibitor, TBOPP, exhibited PE-like symptoms. These findings highlight the multifaceted roles of DOCK1 in the pathophysiology of PE, demonstrating that its deficiency can lead to placental dysfunction by orchestrating inflammatory responses and oxidative stress. These insights emphasize the pathogenic role of DOCK1 in PE development and suggest potential treatment strategies that require further exploration. In the graphical abstract, a split image of placental villi contrasts the effects of normal and reduced DOCK1 expression on preeclampsia. The left side illustrates adequate DOCK1 levels supporting healthy trophoblast function and effective spiral artery remodeling. The right side highlights the consequences of DOCK1 deficiency, leading to trophoblast dysfunction and impaired spiral artery remodeling, accompanied by angiogenic imbalance, increased inflammation, oxidative stress, and apoptosis, contributing to placental dysfunction and the development of preeclampsia.

Prevalence of placental bed spiral artery pathology in preeclampsia and fetal growth restriction: A prospective cohort study

BackgroundPreeclampsia and fetal growth restriction (PE/FGR) are pregnancy complications known to be associated with poor utero-placental function due to abnormal “physiological” remodeling of spiral arteries and unfavorable maternal cardiovascular health. However, the prevalence and degree of impaired spiral artery remodeling has not been clearly established. MethodProspective, multi-center observational cohort study to assess the prevalence of lesions associated with abnormal development of spiral arteries in placental bed biopsies systematically obtained from 121 women undergoing Caesarian section for PE/FGR compared with a reference group of 149 healthy controls. ResultsPE/FGR was associated with a high prevalence of impaired spiral artery remodeling compared with controls (63.6 vs 10.1 %, p < 0.001), and a higher prevalence of non-remodeled spiral arteries without the presence of intramural trophoblast (45.5 vs 6.7 %, p < 0.001), despite abundant interstitial trophoblast invasion in surrounding decidua and myometrium. Normal remodeling was associated with circumferential presence of intramural trophoblast and hardly any trophoblast in surrounding tissue. Acute atherosis (28.9 vs 3.4 %, p < 0.001) and thrombosis (16.5 vs 5.4 %, p = 0.003) lesions were significantly more prevalent in PE/FGR. Impaired remodeling, acute atherosis and thrombosis lesions were equally present in both decidual and myometrial segments of the spiral arteries in both groups. Impaired remodeling was most prominent in the groups with FGR (with or without PE) and thrombosis was most often seen in the group with PE and FGR. ConclusionPE/FGR is associated with a high prevalence of impaired physiological remodeling and vascular lesions of the uterine spiral arteries in the placental bed.

RNA-binding protein SORBS2 increases human trophoblast cell migration via stabilizing HK2 mRNA in preeclampsia.

SORBS2, an RNA-binding protein, is identified as a regulator of aerobic glycolysis, which is essential for trophoblast migration and placental development. Reduced SORBS2 expression in preeclampsia may impair trophoblast migration by affecting mRNA stability and glycolysis, suggesting its role in the disease's pathogenesis. Insufficient trophoblast migration and impaired uterine spiral artery remodeling are implicated in the pathogenesis of preeclampsia, contributing to inadequate placentation. However, the molecular mechanism underlying this process remains unclear. Aerobic glycolysis, which produces substantial lactate, is crucial for establishing a favorable microenvironment for early uterine preparation and supporting embryo implantation and trophoblast migration. In the present study, we have demonstrated that SORBS2, an RNA-binding protein, regulated aerobic glycolysis and significantly improved trophoblast migration in vitro. Our results showed that SORBS2 expression was significantly reduced in human PE placentas and trophoblasts during hypoxia. Overexpression of SORBS2 enhanced cell proliferation and migration, whereas knockdown of SORBS2 decreased these functions in HTR-8/SVneo cells. Mechanistic studies have demonstrated that SORBS2 directly interacts with the 3' untranslated regions (UTRs) of key glycolysis-related genes, specifically HK2. This interaction results in enhanced stability of HK2 and activation of glycolysis. Moreover, silencing HK2 abrogated the enhancement of proliferation and migration of HTR-8/SVneo cells induced by SORBS2. In conclusion, our findings suggest that the downregulation of SORBS2 may contribute to the pathogenesis of preeclampsia by regulating mRNA stability and inhibiting trophoblast migration during placentation.

B-Flow/Spatiotemporal Image Correlation M-Mode and Contrast-Enhanced/Microbubble Ultrasonography Quantification of Spiral Artery Distensibility and Placental Intervillous Perfusion in the First Trimester in a Primate Model of Impaired Spiral Artery Remodeling.

During early human pregnancy, placental trophoblasts remodel spiral arteries into distensible low-resistance vessels to promote placental perfusion. We have established a model of impaired spiral artery remodeling (SAR) by elevating estradiol levels in the first trimester of baboon pregnancy. In the present study, B-flow/spatiotemporal image correlation (STIC) M-mode ultrasonography, a non-Doppler technology for sharp rendering of vessel dimensions, was used to determine whether spiral artery distensibility was altered in SAR-suppressed baboons. Contrast-enhanced ultrasound/microbubble imaging was also performed to determine whether it detected changes in placenta intervillous space perfusion in SAR-suppressed baboons. The two imaging procedures were performed in the first trimester in baboons not treated or treated with estradiol to suppress SAR. Spiral artery distensibility, that is, luminal diameter at systole minus diameter at diastole, and volume flow as quantified by B-flow/STIC M-mode were 26% (p=0.03) and 55% (p=0.059) lower, respectively, in SAR-suppressed baboons. However, placental intervillous space flow rate and video intensity plateau levels reflecting blood perfusion, quantified by contrast-enhanced ultrasound/microbubble imaging, were unaltered in SAR-suppressed baboons. The results indicate that B-flow/STIC M-mode ultrasonography provides a non-invasive method to detect reduced distensibility and, thus, function of spiral arteries across the cardiac cycle in the first trimester in a primate model of impaired SAR. This study represents a first step in determining whether B-flow/STIC M-mode detects a similar defect in SAR early in adverse human pregnancy. This would provide an avenue to develop therapeutic modalities to prevent the devastating consequences of impaired SAR.

Elevated gestational testosterone impacts vascular and uteroplacental function

Maternal vascular adaptations to establish an adequate blood supply to the uterus and placenta are essential for optimal nutrient and oxygen delivery to the developing fetus in eutherian mammals, including humans. Numerous factors contribute to maintaining appropriate hemodynamics and placental vascular development throughout pregnancy. Failure to achieve or sustain these pregnancy-associated changes in women is strongly associated with an increased risk of antenatal complications, such as preeclampsia, a hypertensive disorder of pregnancy. The precise etiology of preeclampsia is unknown, but emerging evidence points to a potential role for androgens. The association between androgens and maternal cardiovascular and placental function merits particular attention due to the notable 2- to 3-fold elevated plasma testosterone (T) levels observed in preeclampsia. T levels in preeclamptic women positively correlate with vascular dysfunction, and preeclampsia is associated with increased androgen receptor (AR) levels in placental tissues. Moreover, animal studies replicating the pattern and magnitude of T increase observed in preeclamptic pregnancies have reproduced key features of preeclampsia, including gestational hypertension, endothelial dysfunction, heightened vasoconstriction to angiotensin II, impaired spiral artery remodeling, placental hypoxia, reduced nutrient transport, and fetal growth restriction. Collectively, these findings suggest that AR-mediated activity plays a significant role in the clinical presentation of preeclampsia. This review critically evaluates this hypothesis, considering both clinical and preclinical evidence.

Decreased PPP1R3G in pre-eclampsia impairs human trophoblast invasion and migration via Akt/MMP-9 signaling pathway.

Pre-eclampsia (PE) is a severe pregnancy complication characterized by impaired trophoblast invasion and spiral artery remodeling and can have serious consequences for both mother and child. Protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is involved in numerous tumor-related biological processes. However, the biological action and underlying mechanisms of PPP1R3G in PE progression remain unclear. We used western blotting and immunohistochemistry to investigate PPP1R3G expression in gestational age-matched pre-eclamptic and normal placental tissues. After lentivirus transfection, wound-healing, Transwell, cell-counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and TdT mediateddUTP Nick End Labeling (TUNEL) assays were used to assess trophoblast migration, invasion, proliferation, and apoptosis, respectively. The relative expression levels of PPP1R3G and the proteins involved in the Akt signaling pathway were determined using western blotting. The results showed that PPP1R3G levels were significantly lower in the placental tissues and GSE74341 microarray of the PE group than those of the healthy control group. We also found that neonatal weight and Apgar score were lower at birth, and peak systolic blood pressure and diastolic blood pressure were higher in the PE group than in the non-PE group. In addition, PPP1R3G knockdown decreased p-Akt/Akt expression and inhibited migration, invasion, and proliferation in HTR-8/SVneo trophoblasts but had no discernible effect on cell apoptosis. Furthermore, PPP1R3G positively regulated matrix metallopeptidase 9 (MMP-9), which was downregulated in placental tissues of pregnant women with PE. These results provided the first evidence that the reduced levels of PPP1R3G might contribute to PE by suppressing the invasion and migration of trophoblasts and targeting the Akt/MMP-9 signaling pathway.

Runx1 regulates critical factors that control uterine angiogenesis and trophoblast differentiation during placental development.

During early pregnancy in humans and rodents, uterine stromal cells undergo a remarkable differentiation to form the decidua, a transient maternal tissue that supports the growing fetus. It is important to understand the key decidual pathways that orchestrate the proper development of the placenta, a key structure at the maternal-fetal interface. We discovered that ablation of expression of the transcription factor Runx1 in decidual stromal cells in a conditional Runx1-null mouse model (Runx1d/d) causes fetal lethality during placentation. Further phenotypic analysis revealed that uteri of pregnant Runx1d/d mice exhibited severely compromised decidual angiogenesis and a lack of trophoblast differentiation and migration, resulting in impaired spiral artery remodeling. Gene expression profiling using uteri from Runx1d/d and control mice revealed that Runx1 directly controls the decidual expression of the gap junction protein connexin 43 (also known as GJA1), which was previously shown to be essential for decidual angiogenesis. Our study also revealed that Runx1 controls the expression of insulin-like growth factor (IGF) 2 and IGF-binding protein 4 (IGFBP4) during early pregnancy. While Runx1 deficiency drastically reduced the production of IGF2 by the decidual cells, we observed concurrent elevated expression of the IGFBP4, which regulates the bioavailability of IGFs, thereby controlling trophoblast differentiation. We posit that dysregulated expression of GJA1, IGF2, and IGFBP4 in Runx1d/d decidua contributes to the observed defects in uterine angiogenesis, trophoblast differentiation, and vascular remodeling. This study therefore provides unique insights into key maternal pathways that control the early phases of maternal-fetal interactions within a critical window during placental development.

Alterations in the Gut Microbiome and Metabolisms in Pregnancies with Fetal Growth Restriction.

Fetuses diagnosed with fetal growth restriction (FGR) are at an elevated risk of stillbirth and adulthood morbidity. Gut dysbiosis has emerged as one of the impacts of placental insufficiency, which is the main cause of FGR. This study aimed to characterize the relationships among the intestinal microbiome, metabolites, and FGR. Characterization was conducted on the gut microbiome, fecal metabolome, and human phenotypes in a cohort of 35 patients with FGR and 35 normal pregnancies (NP). The serum metabolome was analyzed in 19 patients with FGR and 31 normal pregnant women. Multidimensional data was integrated to reveal the links between data sets. A fecal microbiota transplantation mouse model was used to determine the effects of the intestinal microbiome on fetal growth and placental phenotypes. The diversity and composition of the gut microbiota were altered in patients with FGR. A group of microbial species altered in FGR closely correlated with fetal measurements and maternal clinical variables. Fecal and serum metabolism profiles were distinct in FGR patients compared to those in the NP group. Altered metabolites were identified and associated with clinical phenotypes. Integrated multi-omics analysis revealed the interactions among gut microbiota, metabolites, and clinical measurements. Microbiota from FGR gravida transplanted to mice progestationally induced FGR and placental dysfunction, including impaired spiral artery remodeling and insufficient trophoblast cell invasion. Taken together, the integration of microbiome and metabolite profiles from the human cohort indicates that patients with FGR endure gut dysbiosis and metabolic disorders, which contribute to disease pathogenesis. IMPORTANCE Downstream of the primary cause of fetal growth restriction are placental insufficiency and fetal malnutrition. Gut microbiota and metabolites appear to play an important role in the progression of gestation, while dysbiosis induces maternal and fetal complications. Our study elaborates the significant differences in microbiota profiles and metabolome characteristics between women with FGR and normal pregnancies. This is the first attempt so far that reveals the mechanistic links in multi-omics in FGR, providing a novel insight into host-microbe interaction in placenta-derived diseases.

Mitochondrial ROS Accumulation Contributes to Maternal Hypertension and Impaired Remodeling of Spiral Artery but Not IUGR in a Rat PE Model Caused by Maternal Glucocorticoid Exposure.

Increased maternal glucocorticoid levels have been implicated as a risk factor for preeclampsia (PE) development. We found that pregnant rats exposed to dexamethasone (DEX) showed hallmarks of PE features, impaired spiral artery (SA) remodeling, and elevated circulatory levels of sFlt1, sEng IL-1β, and TNFα. Abnormal mitochondrial morphology and mitochondrial dysfunction in placentas occurred in DEX rats. Omics showed that a large spectrum of placental signaling pathways, including oxidative phosphorylation (OXPHOS), energy metabolism, inflammation, and insulin-like growth factor (IGF) system were affected in DEX rats. MitoTEMPO, a mitochondria-targeted antioxidant, alleviated maternal hypertension and renal damage, and improved SA remodeling, uteroplacental blood flow, and the placental vasculature network. It reversed several pathways, including OXPHOS and glutathione pathways. Moreover, DEX-induced impaired functions of human extravillous trophoblasts were associated with excess ROS caused by mitochondrial dysfunction. However, scavenging excess ROS did not improve intrauterine growth retardation (IUGR), and elevated circulatory sFlt1, sEng, IL-1β, and TNFα levels in DEX rats. Our data indicate that excess mitochondrial ROS contributes to trophoblast dysfunction, impaired SA remodeling, reduced uteroplacental blood flow, and maternal hypertension in the DEX-induced PE model, while increased sFlt1 and sEng levels and IUGR might be associated with inflammation and an impaired energy metabolism and IGF system.

Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis

BackgroundPre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood.MethodsHuman placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague–Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors.ResultsIn this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFβ1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats.ConclusionsOur data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization.

ANP promotes HTR-8/SVneo cell invasion by upregulating protein kinase N 3 via autophagy inhibition.

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.

The long noncoding RNA TARID regulates the CXCL3/ERK/MAPK pathway in trophoblasts and is associated with preeclampsia

BackgroundThe widely accepted explanation of preeclampsia (PE) pathogenesis is insufficient trophoblast invasion and impaired uterine spiral artery remodeling. However, the underlying molecular mechanism remains unclear.MethodsWe performed transcriptome sequencing on placentas of normal and PE patients and identified 976 differentially expressed long noncoding RNAs (lncRNAs). TCF21 antisense RNA inducing demethylation (TARID) was one of the most significantly differentially expressed lncRNAs and was negatively correlated with the systolic and diastolic blood pressure in PE patients. Furthermore, we verified the effect of TARID on the biological behavior of trophoblasts and performed UID mRNA-seq to identify the effectors downstream of TARID. Then, co-transfection experiments were used to better illustrate the interaction between TARID and its downstream effector.ResultsWe concluded that the downregulation of TARID expression may inhibit trophoblast infiltration and spiral artery remodeling through inhibition of cell migration, invasion, and tube formation mediated through the CXCL3/ERK/MAPK pathway.ConclusionsOverall, these findings suggested that TARID may be a therapeutic target for PE through the CXCL3/ERK/MAPK pathway.

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms–like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

BCAM Deficiency May Contribute to Preeclampsia by Suppressing the PIK3R6/p-STAT3 Signaling.

Preeclampsia is a pregnancy syndrome that may utilize multiple pathogenic mechanisms. Insufficient trophoblast invasion and impaired uterine spiral artery remodeling are believed to be the pathological basis; yet the underlying mechanisms remain largely unclear. The placental BCAM (basal cell adhesion molecule) expression and important clinical indicators were detected and correlation analysis was performed. MiRNAs directly targeting BCAM were predicted and further verified by dual-luciferase reporter gene, and the downstream molecular mechanisms of BCAM were investigated in both HTR-8/SVneo and JAR cells. In addition, pregnant/nonpregnant rats were treated with adenoviruses containing BCAM shRNA genes (Ad-shBCAM) on gestational 9.5 days to detect the preeclamptic features. The BCAM is highly expressed on the trophoblast membrane and decreased in the preeclamptic placentae. In HTR-8/SVneo and JAR cells, BCAM knockdown inhibited trophoblast proliferation, migration, and invasion, and suppressed phosphorylation on Y705 of STAT3 dependent on the downregulation of PIK3R6. Moreover, miR-199a-5p mediated the degradation of BCAM and also inhibited trophoblast proliferation, migration, and invasion. In vivo, BCAM deficiency induced a preeclampsia-like phenotype included elevated systolic blood pressure, proteinuria, impaired morphology and function of multiple organs (placenta, liver, and kidney), and fetal growth restriction. The expression of placenta BCAM/PIK3R6/p-STAT3 signaling was also downregulated in this preeclampsia rat model. MiR-199a-5p mediated-BCAM deficiency contributes to the suppression of trophoblast proliferation, migration, and invasion by inhibiting PIK3R6/p-STAT3 signaling, which may lead to poor placentation and result in preeclampsia-like phenotypes. Our study provides a new academic perspective on the pathogenesis of preeclampsia.

Porphyromonas gingivalis-mediated disruption in spiral artery remodeling is associated with altered uterine NK cell populations and dysregulated IL-18 and Htra1

Impaired spiral artery remodeling (IRSA) underpins the great obstetrical syndromes. We previously demonstrated that intrauterine infection with the periodontal pathogen, Porphyromonas gingivalis, induces IRSA in rats. Since our previous studies only examined the end stage of arterial remodeling, the aim of this study was to identify the impact of P. gingivalis infection on the earlier stages of remodeling. Gestation day (GD) 11 specimens, a transition point between trophoblast-independent remodeling and the start of extravillous trophoblast invasion, were compared to late stage GD18 tissues. P. gingivalis was found in decidual stroma of GD11 specimens that already had reduced spiral artery remodeling defined as smaller arterial lumen size, increased retention of vascular smooth muscle, and decreased invasion by extravillous trophoblasts. At GD11, P. gingivalis-induced IRSA coincided with altered uterine natural killer (uNK) cell populations, decreased placental bed expression of interleukin-18 (IL-18) with increased production of temperature requirement A1 (Htra1), a marker of oxidative stress. By GD18, placental bed IL-18 and Htra1 levels, and uNK cell numbers were equivalent in control and infected groups. However, infected GD18 placental bed specimens had decreased TNF + T cells. These results suggest disturbances in placental bed decidual stroma and uNK cells are involved in P. gingivalis-mediated IRSA.

Maternal exposure to ambient PM2.5 causes fetal growth restriction via the inhibition of spiral artery remodeling in mice

BackgroundMaternal exposure to ambient fine particulate matters (PM2.5) is associated with low birth weight (LBW) in offspring, but the underlying biological mechanisms are not yet fully understood. As the bridge that connects mother and fetus, the placenta plays a crucial role in fetal development by providing the fetus with nutrients and oxygen. However, whether PM2.5 exposure would impact the placental development and the related mechanisms are unclear. ResultsIn the present study, female C57Bl/6j mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during pregestational and gestational periods, and the fetal development and placental structure were investigated. Our results showed that maternal exposure to CAP induced fetal growth restriction (FGR) and LBW. The placenta from CAP-exposed mice exhibited abnormal development including significant decrease of surface area, smaller junctional zone and impaired spiral artery remodeling. Meanwhile, CAP exposure altered trophoblast lineage differentiation and disrupted the balance between angiogenic and angiostatic factors in placenta. In addition, the inflammatory cytokines levels in lung, placenta and serum were significantly increased after ambient PM2.5 exposure. ConclusionOur findings indicate that maternal exposure to PM2.5 disrupts normal structure and spiral artery remodeling of placenta and further induces FGR and LBW. This effect may be caused by the placental inflammation response subsequent to the pulmonary and systemic inflammation induced by ambient PM2.5 exposure.

B-flow/spatiotemporal image correlation M-mode: novel ultrasound method that detects decrease in spiral artery luminal diameter in first trimester in primate model of impaired spiral artery remodeling.

ABSTRACTObjectiveTo determine if B‐flow/spatiotemporal image correlation (STIC) M‐mode ultrasonography detects a decrease in spiral artery luminal diameter and volume flow during the first trimester in a non‐human primate model of impaired spiral artery remodeling (SAR).MethodsPregnant baboons were treated daily with estradiol benzoate on days 25–59 of the first trimester (term, 184 days), or remained untreated. On day 60 of gestation, spiral artery luminal diameter (in seven untreated and 12 estradiol‐treated baboons) and volume flow (in four untreated and eight estradiol‐treated baboons) were quantified by B‐flow/STIC M‐mode ultrasonography. In addition, in 15 untreated and 18 estradiol‐treated baboons, the percent of spiral arteries remodeled by extravillous trophoblasts was quantified ex vivo by immunohistochemical image analysis on placental basal plate tissue collected via Cesarean section on day 60. Findings were compared between treated and untreated animals. The correlation between spiral artery luminal diameter and percent of SAR was assessed in three untreated and six estradiol‐treated baboons which underwent both B‐flow/STIC M‐mode ultrasound and quantification of SAR.ResultsThe proportion of spiral arteries greater than 50 µm in diameter remodeled by extravillous trophoblasts was 70% lower in estradiol‐treated baboons than in untreated animals (P = 0.000001). Spiral artery luminal diameter in systole and diastole, as quantified by B‐flow/STIC M‐mode in the first trimester of pregnancy, was 31% (P = 0.014) and 50% (P = 0.005) lower, respectively, and volume flow was 85% lower (P = 0.014), in SAR‐suppressed baboons compared with untreated animals. There was a significant correlation between spiral artery luminal diameter as quantified by B‐flow/STIC M‐mode ultrasonography and the percent of SAR (P < 0.05).ConclusionB‐flow/STIC M‐mode ultrasonography provides a novel real‐time non‐invasive method to detect a decrease in uterine spiral artery luminal diameter and volume flow during the cardiac cycle, reflecting decreased distensibility of the vessel wall, in the first trimester in a non‐human primate model of defective SAR. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Effect Study of Physiological changes of a Pregnant Woman

Understating these changes and their profound impact on the pharmacokinetic properties of drugs in pregnancy isessential to optimize maternal and fetal health. During normal pregnancy, the renin–angiotensin system (RAS) plays avitally important role in salt balance and subsequent well-being of mother and fetus. In this balance, one must consider notonly the classical renal RAS but also that of the uteroplacental unit, where both maternal and fetal tissues contribute to thesignaling cascade. Many studies have shown that in normal pregnancy there is an increase in almost all of the componentsof the RAS. In derangements of pregnancy this delicate equilibrium can become unbalanced. Preeclampsia is one suchcase. It is a disorder of pregnancy characterized by hypertension, proteinuria and placental abnormalities associated withshallow trophoblast invasion and impaired spiral artery remodeling. Changes in the cardiovascular system in pregnancyare profound and begin early in pregnancy, such that by eight weeks’ gestation, the cardiac output has already increasedby 20%. The primary event is probably peripheral vasodilatation. This is mediated by endothelium-dependent factors,including nitric oxide synthesis, upregulated by oestradiol and possibly vasodilatory prostaglandins (PGI2). There is asignificant increase in oxygen demand during normal pregnancy. This is due to a 15% increase in the metabolic rate anda 20% increased consumption of oxygen.

SIRT1: A Novel Protective Molecule in Pre-eclampsia.

Pre-eclampsia is a severe pregnant complication, mainly characterized by insufficient trophoblast invasion, impaired uterine spiral artery remodeling, placental hypoxia and ischemia, and endothelial dysfunction. However, the potential mechanisms of pre-eclampsia remain unclear. SIRT1 is a NAD+-dependent deacetylase, involving in multiple biological processes, including energy metabolism, oxidative stress, inflammatory response, and cellular autophagy. Several studies showed that SIRT1 might play a vital role in the pathogenesis of pre-eclampsia. In this review, we aim to integrate the latest research on SIRT1 and pre-eclampsia to explore the comprehensive mechanisms of SIRT1 in pre-eclampsia. More specifically, SIRT1 might affect placental development and trophoblast invasion through autophagy and senescence in pre-eclampsia, and SIRT1 protects vascular endothelial cells from oxidative stress, inflammatory response, autophagy, and senescence. Furthermore, SIRT1 deficiency mice showed typical pre-eclampsia-like performances, which can be reversed via direct SIRT1 supplement or SIRT1 agonist treatment. Additionally, resveratrol, a SIRT1 agonist, attenuates vascular endothelial injury and placental dysfunction, and exerts protective effect on decreasing blood pressure. In this review, we provide new insights into the development of pre-eclampsia, which can establish a theoretical basis for prevention and treatment for pre-eclampsia. Besides, we also propose questions that still need to be further addressed in order to elucidate the comprehensive molecular mechanisms of pre-eclampsia in the future.