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Yanyu Zhong,1,&ast; Nan Wang,1,&ast; Sihui Lu,2 Yaqian Lu,2 Xin Pan,3 Ying Zhou1 1Reproductive Medicine Centre, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Obstetrics and Gynecology, The Fourth Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Zhou, Reproductive Medicine Centre, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Gusu District, Suzhou, Jiangsu Province, 215008, People’s Republic of China, Tel +86-0512-67973182, Email zhouyingzzzyyy@163.com Xin Pan, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Gusu District, Suzhou, Jiangsu Province, 215008, People’s Republic of China, Tel +86-0512-67973182, Email panxinxin9@outlook.comObjective: This study aimed to analyze uterine artery and spiral artery hemodynamics in patients with unexplained recurrent pregnancy loss (URPL) with varying pregnancy outcomes.Methods: 174 pregnant women with URPL and 144 pregnant women without adverse pregnancy histories were enrolled in this retrospective study. Based on pregnancy outcomes, these patients were divided into two groups: normal pregnancy outcomes (URPL-N, n=138) and adverse pregnancy outcomes (URPL-A, n=36). Control group participants were categorized into normal pregnancy outcomes (CON-N, n=129) and adverse pregnancy outcomes (CON-A, n=15). We compared uterine artery and spiral artery hemodynamics during different stages of gestation and the predictive value of these parameters for pregnancy outcomes.Results: URPL-N group had fewer pregnancy losses and lower BMI compared to URPL-A group (P< 0.05). Spiral artery hemodynamics in URPL-N and CON-N groups were lower than those in URPL-A and CON-A groups during the mid-luteal phase, 11– 13 weeks, 15– 17 weeks, and 19– 21 weeks of gestation, respectively. Uterine artery hemodynamics ((Pulsatility index (mPI), resistive index (mRI), and systolic-to-diastolic ratio (mS/D)) in the mid-luteal period were lower in URPL-N group than URPL-A group. Similarly, in CON-N group were lower than CON-A group. The URPL-A and CON-A groups had higher uterine artery and spiral artery hemodynamics when compared to the URPL-N and CON-N groups. Spiral artery hemodynamics exhibited larger areas under the ROC curve compared to uterine artery parameters.Conclusion: Abnormal hemodynamics in these arteries may contribute to URPL and adverse pregnancy outcomes. Spiral artery hemodynamics are more reliable predictors of pregnancy outcomes than uterine artery parameters.Keywords: unexplained recurrent pregnancy loss, spiral artery, uterine artery, blood flow, pregnancy outcome

The mammalian placenta's interface with the parent is a richly vascularized tissue whose development relies upon communication between many different cell types within the uterine microenvironment. The uterine blood vessels of the interface are reshaped during pregnancy into wide‐bore, flaccid vessels that convey parental blood to the exchange region of the placenta. Invasive trophoblast as well as parental uterine macrophages and Natural Killer cells are involved in the stepwise remodeling of these vessels and their respective contributions to this crucial process are still being delineated. However, the earliest steps in arteriole remodeling are understudied as they are difficult to study in humans, and other species lack the deep trophoblast invasion that is so prominent a feature of placentation in humans. Here, we further characterize the rat, with deep hemochorial placentation akin to humans, as a model system in which to tease apart the earliest, relatively understudied events in spiral arteriole remodeling. We show that the rat uterine−placental interface increases in size and vascularity rapidly, before trophoblast invasion. The remodeling stages in the arterioles of the rat uterine–placental interface follow a sequence of anatomical changes similar to those in humans, and there are changes to the arterioles' muscular tunica media prior to the marked influx of immune cells. The rat is a tractable model in which to better understand the cell/cell interactions occurring in vivo in an intact tissue microenvironment over time. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles? SUMMARY ANSWER Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. WHAT IS KNOWN ALREADY First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. STUDY DESIGN, SIZE, DURATION This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). MAIN RESULTS AND THE ROLE OF CHANCE Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints β  = 0.017, 95% CI [0.009; 0.025], bifurcation points β  = 0.012, 95% CI [0.006; 0.018], crossing points β  = 0.017, 95% CI [0.008; 0.025], vessel points β  = 0.01, 95% CI [0.002; 0.008], and total vascular length β  = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P -values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV β = −94.972, 95% CI [−185.245; −3.698], bifurcation points: uPVV β = −192.601 95% CI [−360.532; −24.670]) and birth weight percentiles (endpoints: uPVV β = −20.727, 95% CI [−32.771; −8.683], bifurcation points: uPVV β −51.097 95% CI [−72.257; −29.937], and crossing points: uPVV β = −48.604 95% CI [−74.246; −22.961])), all P -values < 0.05. After stratification, the associations were observed in natural conceptions specifically. LIMITATION, REASONS FOR CAUTION Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. WIDER IMPLICATIONS OF THE FINDINGS Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER Registered at the Dutch Trial Register (NTR6854). [ABSTRACT FROM AUTHOR]

Preeclampsia, poses significant risks to both maternal and fetal well‐being. Exosomes released by the placenta play a crucial role in intercellular communication and are recognized as potential carriers of essential information for placental development. These exosomes transport a payload of proteins, nucleic acids, and lipids that mirror the placental microenvironment. This review delves into the functional roles of placental exosomes and its contents shedding light on their involvement in vascular regulation and immune modulation in normal pregnancy. Discernible changes are reported in the composition and quantity of placental exosome contents in pregnancies affected by preeclampsia. The exosomes from preeclamptic mothers affect vascularization and fetal kidney development. The discussion also explores the implications of utilizing placental exosomes as biomarkers and the prospects of translating these findings into clinical applications. In conclusion, placental exosomes hold promise as a valuable avenue for deciphering the complexities of preeclampsia, providing crucial diagnostic and prognostic insights. As the field progresses, a more profound comprehension of the distinct molecular signatures carried by placental exosomes may open doors to innovative strategies for managing and offering personalized care to pregnancies affected by preeclampsia. [ABSTRACT FROM AUTHOR]

Purpose: In the first of two companion papers, we comprehensively reviewed the recent evidence in the primary literature, which addressed the increased prevalence of hypertensive disorders of pregnancy, late-onset or term preeclampsia, fetal overgrowth, postterm birth, and placenta accreta in women conceiving by in vitro fertilization. The preponderance of evidence implicated frozen embryo transfer cycles and, specifically, those employing programmed endometrial preparations, in the higher risk for these adverse maternal and neonatal pregnancy outcomes. Based upon this critical appraisal of the primary literature, we formulate potential etiologies and suggest strategies for prevention in the second article. Methods: Comprehensive review of primary literature. Results: Presupposing significant overlap of these apparently diverse pathological pregnancy outcomes within subjects who conceive by programmed autologous FET cycles, shared etiologies may be at play. One plausible but clearly provocative explanation is that aberrant decidualization arising from suboptimal endometrial preparation causes greater than normal trophoblast invasion and myometrial spiral artery remodeling. Thus, overly robust placentation produces larger placentas and fetuses that, in turn, lead to overcrowding of villi within the confines of the uterine cavity which encroach upon intervillous spaces precipitating placental ischemia, oxidative and syncytiotrophoblast stress, and, ultimately, late-onset or term preeclampsia. The absence of circulating corpus luteal factors like relaxin in most programmed cycles might further compromise decidualization and exacerbate the maternal endothelial response to deleterious circulating placental products like soluble fms-like tyrosine kinase-1 that mediate disease manifestations. An alternative, but not mutually exclusive, determinant might be a thinner endometrium frequently associated with programmed endometrial preparations, which could conspire with dysregulated decidualization to elicit greater than normal trophoblast invasion and myometrial spiral artery remodeling. In extreme cases, placenta accreta could conceivably arise. Though lower uterine artery resistance and pulsatility indices observed during early pregnancy in programmed embryo transfer cycles are consistent with this initiating event, quantitative analyses of trophoblast invasion and myometrial spiral artery remodeling required to validate the hypothesis have not yet been conducted. Conclusions: Endometrial preparation that is not optimal, absent circulating corpus luteal factors, or a combination thereof are attractive etiologies; however, the requisite investigations to prove them have yet to be undertaken. Presuming that in ongoing RCTs, some or all adverse pregnancy outcomes associated with programmed autologous FET are circumvented or mitigated by employing natural or stimulated cycles instead, then for women who can conceive using these regimens, they would be preferable. For the 15% or so of women who require programmed FET, additional research as suggested in this review is needed to elucidate the responsible mechanisms and develop preventative strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To use superb microvascular imaging (SMI) to evaluate longitudinally spiral artery (SA) and uterine artery (UtA) vascular adaptation in normal human pregnancy, and to develop reference ranges for use at various gestational ages throughout pregnancy. Methods: The data for this study were obtained from the National Institutes of Health (NIH)‐funded Human Placenta Project. Women aged 18–35 years, with a body mass index < 30 kg/m2, without comorbidities, with a singleton gestation conceived spontaneously, and gestational age at or less than 13 + 6 weeks were eligible for inclusion. The current analysis was restricted to uncomplicated pregnancies carried to term. Exclusion criteria included maternal or neonatal complications, fetal or umbilical cord anomalies, abnormal placental implantation or delivery < 37 weeks. Women who fulfilled the inclusion criteria formed the reference population of the Human Placenta Project study. Each participant underwent eight ultrasound examinations during pregnancy. The pulsatility index (PI) of both the left and right UtA were obtained twice for each artery and the presence or absence of a notch was noted. Using SMI technology, the total number of SA imaged was recorded in a sagittal placental section at the level of cord insertion. The PI and peak systolic velocity (PSV) were also measured in a total of six SA, including two in the central portion of the placenta, two peripherally towards the uterine fundal portion, and two peripherally towards the lower uterine segment. Results: A total of 90 women fulfilled the study criteria. Maternal UtA‐PI decreased throughout the first half of pregnancy from a mean ± SD of 1.39 ± 0.50 at 12–13 weeks' gestation to 0.88 ± 0.24 at 20–21 weeks' gestation. The mean number of SA visualized in a sagittal plane of the placenta increased from 8.83 ± 2.37 in the first trimester to 16.99 ± 3.31 in the late‐third trimester. The mean SA‐PI was 0.57 ± 0.12 in the first trimester and decreased progressively during the second trimester, reaching a nadir of 0.40 ± 0.10 at 24–25 weeks, and remaining constant until the end of pregnancy. SA‐PSV was highest in early pregnancy with a mean of 57.16 ± 14.84 cm/s at 12–13 weeks' gestation, declined to a mean of 49.38 ± 17.88 cm/s at 20–21 weeks' gestation and continued to trend downward for the remainder of pregnancy, reaching a nadir of 34.50 ± 15.08 cm/s at 36–37 weeks' gestation. A statistically significant correlation was noted between SA‐PI and UtA‐PI (r = 0.5633; P < 0.001). Multilevel regression models with natural cubic splines were used to create reference ranges of SA‐PSV and SA‐PI for given gestational ages. Conclusion: From early gestation, we have demonstrated the ability to image and quantify SA blood flow in normal pregnancy, and have developed reference ranges for use at various gestational ages throughout pregnancy. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

A fused triplet placenta was observed in a Wistar Hannover rat on gestation day 15. Each placenta (referred to as PL-A, PLB, and PL-C) of this fused placenta was attached to one fetus each, but their fetal weights were lower than that of the fetus attached to the only normal placenta (referred to as PL-N) in this dam. Histopathologically, thinning of the trophoblastic septa and dilatation of the maternal sinusoid in the labyrinth zone were observed in PL-B and PL-C, but not in PL-A or PL-N. The points of placental fusion were at the junctional zone derived from each side of the placenta without connective tissues, and the septum was composed of trophoblastic giant cells. Although PL-A had a solitary metrial gland, PL-B and PL-C shared one metrial gland with one spiral artery terminus branching towards each labyrinth zone. [ABSTRACT FROM AUTHOR]

Spiral artery remodeling is the process by which the uterine vessels become large bore low resistance conduits, allowing delivery of high volumes of maternal blood to the placenta to nourish the developing fetus. Failure of this process is associated with the pathophysiology of most of the major obstetric complications, including late miscarriage, fetal growth restriction and pre-eclampsia. However, the point at which remodeling 'fails' in these pathological pregnancies is not yet clear. Spiral artery remodeling has predominantly been described in terms of its morphological features, however we are starting to understand more about the cellular and molecular triggers of the different aspects of this process. This review will discuss the current state of knowledge of spiral artery remodeling, in particular the processes involved in loss of the vascular smooth muscle cells, and consider where in the process defects would lead to a pathological pregnancy. • Spiral artery remodeling is key for a successful pregnancy. • The morphological aspects of spiral artery remodeling are well described. • Understanding of the cellular and molecular mediators is becoming clearer. [ABSTRACT FROM AUTHOR]

Background: Progesterone is essential for maintaining pregnancy. Spiral arteries, providing blood flow to the placenta, undergo changes in early pregnancy, reducing uteroplacental resistance. Our study was aimed at investigating the relationship between the first trimester serum progesterone levels, spiral artery Doppler findings and pregnancy outcome. Methods: This observational retrospective cohort study included 126 pregnant women at 11–14 weeks of gestation, confirmed by last menstrual period and ultrasonography. Between 11–14 weeks, serum progesterone levels were measured and spiral artery pulsatility index (PI), resistive index (RI), peak systolic velocity (PSV) and systolic/diastolic ratio (S/D) values were recorded. Pregnant women were followed up until delivery, and serum progesterone levels and spiral artery Doppler findings were compared between patients with poor perinatal outcomes and others. Results: This study included 126 pregnancies, of which 13 patients were lost to follow-up. Miscarriage occurred in 2 of the pregnant women, stillbirth in 1, intrauterine growth retardation in 10 and preeclampsia in 5 of them. 6 infants developed respiratory problems and 3 infants developed jaundice. Seventeen of the infants were hospitalized in the neonatal intensive care unit. There was no statistically significant difference between serum progesterone, spiral artery PI, RI and S/D values of 86 uncomplicated and 27 complicated pregnant women. Conclusions: It is known that there is a strong relationship between the first trimester serum levels of progesterone, which is an important hormone for the healthy continuation of pregnancy, and the risk of miscarriage. The quantity and quality of placental and fetal circulation is determined by the changes that occur in the spiral arteries with pregnancy. Although a close relationship is known between both variables and pregnancy outcomes, no correlation could be established between them in terms of early detection of poor perinatal outcomes.

The importance of uterine microvascular adaptations during placentation in pregnancy has been well established for decades. Inadequate dilatation of spiral arteries is associated with gestational complications, such as preeclampsia and/or intrauterine growth restriction. More recently, it has become clear that trophoblast cells invade and adapt decidual veins and lymphatic vessels 1 month before spiral arteries become patent and before intervillous space perfusion starts. Normal intervillous space hemodynamics is characterized by high volume flow at low velocity and pressure in the interseptal compartments surrounding the chorionic villi, hereby facilitating efficient maternal-fetal exchange. In case of shallow decidual vein dilatation, intervillous arterial supply exceeds venous drainage. This will cause congestion in the interseptal compartments with subsequently reduced perfusion and increased pressure. An efficient mechanism to counteract venous congestion and safeguard the viability of the conceptus is by reducing arterial inflow via shallow dilatation of the spiral arteries. This review made the case for intervillous space congestion as an unexplored trigger for inadequate spiral artery dilatation during the placentation process, eventually leading to abnormal systemic circulatory dysfunctions. An abnormal maternal venous function can result from an abnormal maternal immune response to paternal antigens with an imbalanced release of vasoactive mediators or can exist before conception. To get the full picture of abnormal placentation, maternal veins must not be forgotten. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) in the endometrium plays a crucial role in mammalian pregnancy. We have shown that versican secreted from the endometrial epithelium promotes embryo implantation. Versican is a proteoglycan, a major player in the provisional matrix, and versikine, its N-terminal fragment cleaved by ADAMTS proteinases, serves as a bioactive molecule. Here, since versican expression in the placenta was dynamically altered in humans and mice, we investigated the role of versican in pregnancy using uterine-specific Vcan deletion mice (uKO mice) and ADAMTS-resistant versican expressing mice (V1R mice). uKO mice exhibited insufficient spiral artery dilation, followed by fetal growth restriction and maternal hypertension. Further analysis revealed impaired proliferation of tissue-resident natural killer cells required for spiral artery dilation. V1R mice showed the same results as the control, eliminating the involvement of versikine. Our results provide a new concept that versican, one factor of ECM, contributes to placentation and following fetal growth. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: The latest treatments do not sufficiently prevent miscarriage and fetal growth restriction (FGR) in pregnant women. Here, we assessed the effects of a human protein, CTRP6, that specifically inhibits the activation of the alternative complement pathway on miscarriage, fetal and placental development. Methods: Pregnant CBA/J mice mated with DBA/2 male mice as a model of spontaneous abortion and FGR were randomly divided into the control and CTRP6 groups. In the CTRP6 group, the mice were intravenously administered CTRP6 on days 4.5 and 6.5 post-conception (dpc). The abortion rate and fetal and placental weights on 14.5 dpc were examined. Remodeling of the spiral artery was also assessed. Results: The abortion rate in the CTRP6 group (13%) was reduced compared to the control group (21%), but there was no statistical difference. The placental and fetal weights in the CTRP6 group were also heavier than those in the control (P < 0.05). Moreover, the thickness of the blood vessel wall in the CTRP6 group was significantly thinner than that in the control (P < 0.05) and comparable to that in the non-abortion model (CBA/J x BALB). The ratio of the inner-per-the-outer diameter of the spiral artery increased more in the CTRP6 group than that in the control (P < 0.05). As well, the Th1/Th2 cytokine ratio was significantly reduced by CTRP6 treatment. Conclusions: Taken together, the supplementation with a protein that regulates the alternative complement pathway in vivo improves FGR and promotes spiral artery remodeling in a mouse model of miscarriage and FGR. [ABSTRACT FROM AUTHOR]

Introduction: Hyperglycemic conditions achieved during pregnancy have been shown to have detrimental effects to fetal development and increase the prevalence of childhood comorbidities. However, the mechanisms in which diabetic pregnancies affect placental development and subsequently contribute to adverse health effects on the mother and offspring remain unclear. Research design and methods: Streptozotocin was used to induce gestational diabetes in mice. In this model, hyperglycemia was established at embryonic day 3.5 (E3.5). Pregnancy mass was collected at E10.5, E12.5, E14.5, and E16.5 for different assessments. Results: Both placental and embryonic weights were found to be significantly elevated at E16.5. At E14.5, a significantly larger junctional zone with increased number of glycogen trophoblasts was found in the placentas from hyperglycemic pregnancies (HG group) compared to the placentas from normoglycemic pregnancies (NG group). Importantly, the HG placenta exhibited decreased trophoblast giant cell (TGC) association and TUNEL+ cells, and increased expression of α-SMA on the spiral artery, suggesting arterial remodeling was impacted. Moreover, the interhemal membrane of the labyrinth layer, was found to be thicker in the HG placentas. Furthermore, hyperglycemia resulted in more offspring congenital defects, which were associated with a thicker interhemal membrane. Conclusions: Together, these results suggest that gestational diabetes perturbs proper placental development and function, specifically spiral artery remodeling and angiogenesis, thereby negatively impacting embryonic development.

Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia. [Display omitted] • Endothelial progenitor cells control uterine spiral artery (uSpA) remodeling • CD117highKDRhigh cells with AMPK deficiency release excessive sEng via HO-1 inhibition • Excessive sEng induces stenosis in remodeled uSpAs Tan et al. demonstrate that the suppressive AMPK/HO-1 regulatory axis in endothelial progenitor cells overproduces sEng, which contributes to the narrowing of remodeled uterine spiral arteries. The mechanism holds promise in elucidating the pathogenesis of preeclampsia. [ABSTRACT FROM AUTHOR]

Uterine spiral artery remodeling is one of the key maternal adaptations of pregnancy, allowing delivery of the large volumes of maternal blood required for both placental and fetal growth. Failure of this process is associated with obstetric complications including preeclampsia, fetal growth restriction and miscarriage. Spiral artery remodeling is characterized by loss of the musculoelastic wall which is replaced by fibrinoid and intramural extravillous trophoblast cells (EVT). In recent years attention has focused on the initial stages of spiral artery remodeling which include separation of the vascular smooth muscle cells (VSMCs) and their phenotypic switch to a more synthetic phenotype, facilitating their migration away from the vessel wall. However, less is known about the final fate of the VSMCs. In vitro studies suggested that EVT could induce VSMC apoptosis, though VSMC apoptosis is not seen within the wall of the spiral arteries undergoing remodeling. However, apoptotic VSMCs have been observed amongst those cells which had migrated away from the vessel wall. This review article gives a brief overview of the current state of knowledge of the processes involved in spiral artery remodeling, and then concentrates on the mechanisms involved in VSMC apoptosis, drawing on knowledge from other vascular beds. [ABSTRACT FROM AUTHOR]

Objective: Superb microvascular imaging (SMI) has been shown to improve visualization of small vessels by suppressing global motions while preserving low-flow components, such as the microvessels in the placenta. We sought to determine if SMI-aided visualization of flow velocity waveforms in the spiral arteries (SA) and intravillous fetal arterioles (IVA) could predict fetal growth restriction (FGR), gestational hypertension (GH) and/or pre-eclampsia (PE).Methods: This was a prospective longitudinal study of singleton pregnancies without fetal anomaly, receiving prenatal care in one of two medical centers over a 5-year period. Using SMI-aided color Doppler, SA and IVA flow velocity was measured at three timepoints: 11 + 0 to 14 + 0, 18 + 0 to 22 + 6 and 28 + 0 to 34 + 6 weeks of gestation. SA and IVA flow velocity waveforms were reported as resistance indices (RI). RI values were analyzed using multilevel modeling; individual regression curves were estimated and combined to obtain the reference intervals for SA-RI and IVA-RI in uncomplicated pregnancies. The primary clinical outcome was FGR and secondary outcomes were PE and GH. FGR was defined as estimated fetal weight < 10th percentile. Student's t-test was used to compare deviation from expected RI between normal and complicated pregnancies.Results: Among 540 pregnancies included in the analysis, 18 (3.3%) had FGR, 31 (5.7%) PE and 61 (11.3%) GH. In uncomplicated pregnancies, the SA-RI decreased progressively with advancing gestation, whereas the IVA-RI increased with gestational age. In the third trimester, the mean SA-RI and IVA-RI values were significantly higher in the FGR group compared with pregnancies that did not develop FGR, while the mean SA-RI was significantly higher in PE compared with non-PE pregnancies. There was no significant difference in mean SA-RI or IVA-RI between pregnancies with vs those without GH at any gestational age. When all three adverse outcomes were combined, SA-RI was significantly higher in pregnancies with these outcomes when compared to uncomplicated pregnancies in the third trimester (mean ± SD, 0.29 ± 0.12 vs 0.26 ± 0.12; P = 0.02). In screening for FGR using SA-RI, the areas under the receiver-operating-characteristics curves (AUC) were 0.68, 0.73 and 0.73 in the first, second and third trimesters, respectively. The respective AUCs for IVA-RI were 0.72, 0.72 and 0.73 for each trimester.Conclusions: SA-RI and IVA-RI, measured using SMI technology, were significantly higher in pregnancies at risk for FGR in late gestation. Larger studies are needed to determine if SA and IVA flow are reliable predictors of adverse pregnancy outcome. © 2021 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

During formation of the mammalian placenta, trophoblasts invade the maternal decidua and remodel spiral arteries to bring maternal blood into the placenta. This process, known as endovascular invasion, is thought to involve the adoption of functional characteristics of vascular endothelial cells (ECs) by trophoblasts. The genetic and molecular basis of endovascular invasion remains poorly defined, however, and whether trophoblasts utilize specialized endothelial proteins in an analogous manner to create vascular channels remains untested. Vascular endothelial (VE-)cadherin is a homotypic adhesion protein that is expressed selectively by ECs in which it enables formation of tight vessels and regulation of EC junctions. VE-cadherin is also expressed in invasive trophoblasts and is a prime candidate for a molecular mechanism of endovascular invasion by those cells. Here, we show that VE-cadherin is required for trophoblast migration and endovascular invasion into the maternal decidua in the mouse. VE-cadherin deficiency results in loss of spiral artery remodeling that leads to decreased flow of maternal blood into the placenta, fetal growth restriction, and death. These studies identify a non-endothelial role for VE-cadherin in trophoblasts during placental development and suggest that endothelial proteins may play functionally unique roles in trophoblasts that do not simply mimic those in ECs.

Physiological transformation with remodeling of the uteroplacental spiral arteries is key to a successful placentation and normal placental function. It is an intricate process that involves, but is not restricted to, complex interactions between maternal decidual immune cells and invasive trophoblasts in the uterine wall. In normal pregnancy, the smooth muscle cells of the arterial tunica media of uteroplacental spiral arteries are replaced by invading trophoblasts and fibrinoid, and the arterial diameter increases 5- to 10-fold. Poor remodeling of the uteroplacental spiral arteries is linked to early-onset preeclampsia and several other major obstetrical syndromes, including fetal growth restriction, placental abruption, and spontaneous preterm premature rupture of membranes. Extravillous endoglandular and endovenous trophoblast invasions have recently been put forth as potential contributors to these syndromes as well. The well-acknowledged disturbed extravillous invasion of maternal spiral arteries in preeclampsia is summarized, as are briefly novel concepts of disturbed extravillous endoglandular and endovenous trophoblast invasions. Acute atherosis is a foam cell lesion of the uteroplacental spiral arteries associated with poor remodeling. It shares some morphologic features with early stages of atherosclerosis, but several molecular differences between these lesions have also recently been revealed. Acute atherosis is most prevalent at the maternal-fetal interface, at the tip of the spiral arteries. The localization of acute atherosis downstream of poorly remodeled arteries suggests that alterations in blood flow may trigger inflammation and foam cell development. Acute atherosis within the decidua basalis is not, however, confined to unremodeled areas of spiral arteries or to hypertensive disorders of pregnancy and may even be present in some clinically uneventful pregnancies. Given that foam cells of atherosclerotic lesions are known to arise from smooth muscle cells or macrophages activated by multiple types of inflammatory stimulation, we have proposed that multiple forms of decidual vascular inflammation may cause acute atherosis, with or without poor remodeling and/or preeclampsia. Furthermore, we propose that acute atherosis may develop at different gestational ages, depending on the type and degree of the inflammatory insult. This review summarizes the current knowledge of spiral artery remodeling defects and acute atherosis in preeclampsia. Some controversies will be presented, including endovascular and interstitial trophoblast invasion depths, the concept of 2-stage trophoblast invasion, and whether the replacement of maternal spiral artery endothelium by fetal endovascular trophoblasts is permanent. We will discuss the role of acute atherosis in the pathophysiology of preeclampsia and short- and long-term health correlates. Finally, we suggest future opportunities for research on this intriguing uteroplacental interface between the mother and fetus. [ABSTRACT FROM AUTHOR]

Abstract Background Downstream remodeling of the spiral arteries (SpA) decreases utero-placental resistance drastically, allowing sustained and increased blood flow to the placenta under all circumstances. We systematically evaluated available reports to visualize adaptation of spiral arteries throughout pregnancy by ultra-sonographic measurements and evaluated when this process is completed. Methods A systematic review and meta-analysis of spiral artery flow (pulsatility index (PI), resistance index (RI) and peak systolic velocity (PSV)) was performed. English written articles were obtained from Pubmed, EMBASE and Cochrane Library and included articles were assessed on quality and risk of bias. Weighted means of Doppler indices were calculated using a random-effects model. Results In healthy pregnancies, PI and RI decreased from 0.80 (95% CI: 0.70–0.89) and 0.50 (95% CI: 0.47–0.54) in the first trimester to 0.50 (95% CI: 0.45–0.55, p

Introduction: The aim of the study was to evaluate and compare the spiral artery flow in mid first trimester (4–8 weeks) in cases of threatened abortion and in normal pregnancies. Material and methods: Spiral artery was sonographically evaluated in 50 patients comprising two groups of 25 women each. The first group included patients presenting with threatened miscarriage (vaginal bleeding/spotting with or without abdominal pain). The second group comprised of females who had no complications, but had no desire to continue the pregnancy. Spiral artery flow velocity measurements were performed using Color Doppler (Pulsatility Indices, Resistive Indices and Systolic/diastolic values) in mid first trimester (between 4–8 weeks of gestation), each measurement was performed twice. Statistical analysis was performed using Statistical package for social sciences software. Values were rounded off to two digits after decimal point. Results: Significant differences were noted in the spiral artery Doppler values in the two groups. In particular, the Resistive Indices was higher in cases of women with threatened miscarriage. The difference in Pulsatility Indices was also statistically significant between the two groups. Conclusion: Doppler values of spiral artery may be used as a useful parameter in assessing the prognosis in cases presenting with threatened miscarriage.

Introduction: Uteroplacental acute atherosis is frequently observed in preeclampsia, and shares features with early atherosclerotic lesions, including artery wall foam cells. The lipid-associated proteins FABP4 (fatty acid binding protein 4), perilipin-2, and LOX-1 (lectin-like oxidized LDL-receptor 1) are involved in atherosclerotic foam cell formation. Increased levels of these proteins have been associated with preeclampsia systemically and in placental tissue. Their role in acute atherosis is yet unidentified. Our aim was to describe the presence of these proteins in acute atherosis, and compare our findings to what is known in early atherosclerotic lesions.Methods: Serial sections of decidua basalis tissue from 12 normotensive (4 with acute atherosis) and 23 preeclamptic pregnancies (16 with acute atherosis) were stained with HE and immunostained for CK7, CD68, FABP4, perilipin-2, and LOX-1. Artery wall and perivascular protein expression was assessed in 190 spiral artery sections; 55 with acute atherosis.Results: Acute atherosis foam cells were commonly positive for perilipin-2 (55%), less often for FABP4 (13%), and never for LOX-1. LOX-1 was frequently observed in intramural trophoblasts of normal spiral arteries. Perivascularly, LOX-1 positivity of decidual stromal cells surrounding arteries with acute atherosis was significantly increased as compared to arteries lacking acute atherosis (38% vs. 15%, p < 0.001).Discussion: We found that perilipin-2 and FABP4 are expressed by acute atherosis foam cells, similar to atherosclerosis, supporting possible shared pathways for foam cell generation. Unlike atherosclerosis, LOX-1 is not present in acute atherosis, possibly explained by pregnancy-specific routes to decidua basalis foam cell generation. [ABSTRACT FROM AUTHOR]

Study Question: Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles?, Summary Answer: Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles., What Is Known Already: First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown., Study Design, Size, Duration: This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018., Participants/materials, Setting, Methods: We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no)., Main Results and the Role of Chance: Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints β = 0.017, 95% CI [0.009; 0.025], bifurcation points β = 0.012, 95% CI [0.006; 0.018], crossing points β = 0.017, 95% CI [0.008; 0.025], vessel points β = 0.01, 95% CI [0.002; 0.008], and total vascular length β = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV β = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV β = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV β = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV β -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV β = -48.604 95% CI [-74.246; -22.961])), all P-values < 0.05. After stratification, the associations were observed in natural conceptions specifically., Limitation, Reasons for Caution: Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship., Wider Implications of the Findings: Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction., Study Funding/competing Interest(s): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest., Trial Registration Number: Registered at the Dutch Trial Register (NTR6854)., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

An adequately sized placenta at a suitable site with appropriate depth and centripetal progression of implantation are the major factors for optimal fetal development. The cytotrophoblasts surround the blastocyst fuses at the site of the uterine attachment. This forms a second layer of multinucleated syncytiotrophoblasts that constitutes the inner epithelial boundary of the chorionic villous against the intervillous space. In a normal pregnancy, extravillous cytotrophoblasts (EVT) invade and obstruct the spiral arteries and remodel them. Vacuoles in the syncytial cell layer fuse and develop the intervillous space. The inner cell mass (embryoblast) gives rise to the umbilical cord and the mesenchyme in the chorionic villi. Vasculogenesis starts with the formation of hemangioblastic cords in this mesenchyme. The trophoblastic cell columns anchor the placenta. A variety of molecular pathways participate in the placentation process. Placental morphogenesis occurs mainly through complex cellular interactions between the chorionic villous and the extravillous cytotrophoblasts. The formation of the normal structure of the chorionic villi, syncytiotrophoblast layer and vasculature is essential for placental function, hormone production, and regulation of fetal growth. At each stage of placental development, genetic variants, exposure to infection, poor vascular function, oxidative stress, or failure of normal development can all lead to abnormal formation resulting in the clinical complications of pregnancy such as fetal growth disorders, neonatal neurologic abnormalities, placental adhesions, and inflammatory problems as well as maternal disease such as preeclampsia. [ABSTRACT FROM AUTHOR]

Background: Miscarriage is a common event in the first half of pregnancy. Improvements in Ultrasound and Doppler technology, have led to a better understanding of early pregnancy development. Such a facility may be used in turn to predict pregnancy outcome in threatened miscarriage. Objective: To assess the ability of the Uterine artery RI and Spiral artery RI to predict outcome in cases of Threatened miscarriage Patients and methods: Prospective observational study was conducted in the Department of Obstetrics and Gynecology at Menoufia University Hospital. The study included 90 women with gestational age between 5 - 13 w. divided into three groups; Group (A): involved (30) women diagnosed with threatened miscarriage and was followed up and got aborted before pregnancy completed 24weeks. Group (B): (30) women diagnosed with threatened miscarriage and were followed up and the pregnancy continued till 24weeks. Group (C): 30 women having singleton normal ongoing pregnancy till 24 weeks of gestation as a control group. Results: In this study, the Doppler study of uterine arteries the subchorionic blood flow revealed that (RI) was significantly higher in the miscarried group than both continued and control groups. Conclusion: Uterine artery RI and Subchorionic blood flow RI can predict the fate of pregnancy in cases with threatened miscarriage with high accuracy. [ABSTRACT FROM AUTHOR]

L-Arginine is a semi-essential amino acid, which is one of the nitric oxide (NO) synthesis substrates. This compound has a role in the L-Arginine-NO pathway in preeclampsia. This study determined the effect of LArginine on the diameter of the spiralis artery and fetal weight in normal pregnant mice and preeclampsia mice model. A true experimental study with randomized post-test-only control group using Swiss Mus musculus divided into 3 groups. There were normal pregnant mice group (K-), preeclampsia mouse model group (K+), and preeclampsia mouse models with L-Arginine group (P). The mean of fetal weight of each mouse was calculated and measured the diameter of the spiralis artery from placental. The mean diameter of the spiral arteries of the groups (K-), (K+) and (P) was 221.7500±70.2498µm, 159.4333±30.2653µm, and 277.3222±54.5503µm, respectively. There were significant differences between groups (K-) and (K+) (p = 0.024), groups (K-) and (P) (p = 0.047), and between groups (K+) and (P) (p = 0.000). Meanwhile, the mean fetal weight of the groups (K-), (K+) and (P) was 0.6733±0.3145g, 0.6222±0.2838g, and 0.7589±0.3444g, respectively. There were no significant differences between groups (K-) and (K+) (p = 0.722), between groups (K-) and (P) (p = 0.590), and between groups (K +) and (P) (p = 0.372). L-Arginine has been proven effective in repairing endothelial damage and was seen from the diameter of the spiralis artery and fetal weight in preeclampsia mouse models. [ABSTRACT FROM AUTHOR]

Accumulating evidence has shown that preeclampsia (PE) was associated with an aberrant maternal-fetal inflammatory response. In the present study, we first found that in human PE placentas levels of toll-like receptor 4 (TLR4), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and inflammatory cytokines IL-6 and MCP-1 were significantly upregulated. Next, we demonstrated a notable increase in systolic blood pressure (SBP) and proteinuria in lipopolysaccharide (LPS)-treated pregnant rats and concomitant high levels of TLR4 and p-p38 in these PE-like rat placentas, which led to aberrant overexpression of both IL-6 and MCP-1, as well as deficient trophoblast invasion and spiral artery (SA) remodeling, and these abnormalities were ameliorated by SB203580, a reported inhibitor of p38. In vitro we further confirmed that LPS triggered the activation of TLR4/p38 signaling pathway, which promoted trophoblast apoptosis and damaged trophoblastic invasion via downstream effectors IL-6 and MCP-1; these mutations were rectified by silencing this signaling pathway. These findings elaborated potential mechanisms that aberrant TLR4/p38 signaling might contribute to PE and LPS-induced PE-like symptom by damaging trophoblast invasion and SA remodeling via activating inflammatory cytokines including IL-6 and MCP-1.

Preeclampsia (PE) is a multiorgan disorder that complicates around 2-8% of pregnancies and is a major cause of perinatal and maternal morbidity and mortality. PE is a clinical syndrome characterized by hypertension secondary to systemic inflammation, endothelial dysfunction, and syncytiotrophoblast stress leading to hypertension and multiorgan dysfunction. The uterine arteries are the main blood vessels that supply blood to the uterus. They give off branches and plays an important role in maintaining blood supply during pregnancy. The arcuate artery originates from the uterine artery and runs medially through the myometrium. The arcuate arteries divide almost directly into anterior and posterior branches, from which the radial artery leads directly to the uterine cavity during their course. Near the endometrium-myometrium junction, the radial artery generates spiral arteries within the basal layer and functional endometrium. The walls of radial and spiral arteries are rich in smooth muscle, which is lost when trophoblast cells invade and become large-caliber vessels. This physiological transformation of uteroplacental spiral arteries is critical for successful placental implantation and normal placental function. In normal pregnancy, the luminal diameter of the spiral arteries is greatly increased, and the vascular smooth muscle is replaced by trophoblast cells. This process and changes in the spiral arteries are called spiral artery remodeling. In PE, this genetically and immunologically governed process is deficient and therefore there is decreased vascular capacitance and increased resistance in the uteroplacental circulation. Furthermore, this defect in uteroplacental spiral artery remodeling is not only associated with early onset PE, but also with fetal growth restriction, placental abruption, and spontaneous premature rupture of membranes. Doppler ultrasound allows non-invasive assessment of placentation, while the flow impedance decreases as the pregnancy progresses in normal pregnancies, in those destined to develop preeclampsia the impedance is increased., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The aim of the study was to evaluate and compare the spiral artery flow in mid first trimester (4-8 weeks) in cases of threatened abortion and in normal pregnancies. Material and methods: Spiral artery was sonographically evaluated in 50 patients comprising two groups of 25 women each. The first group included patients presenting with threatened miscarriage (vaginal bleeding/spotting with or without abdominal pain). The second group comprised of females who had no complications, but had no desire to continue the pregnancy. Spiral artery flow velocity measurements were performed using Color Doppler (Pulsatility Indices, Resistive Indices and Systolic/diastolic values) in mid first trimester (between 4-8 weeks of gestation), each measurement was performed twice. Statistical analysis was performed using Statistical package for social sciences software. Values were rounded off to two digits after decimal point. Results: Significant differences were noted in the spiral artery Doppler values in the two groups. In particular, the Resistive Indices was higher in cases of women with threatened miscarriage. The difference in Pulsatility Indices was also statistically significant between the two groups. Conclusion: Doppler values of spiral artery may be used as a useful parameter in assessing the prognosis in cases presenting with threatened miscarriage. [ABSTRACT FROM AUTHOR]

• Early-onset preeclampsia with poor placentation fitted well with the original two-stage model. • A revised model suggests a late form of placental malperfusion fitting with late-onset disease. • Major immunological preeclampsia findings are summarized and fit with the updated model. • "Maternal" preeclampsia does not exist, as all preeclampsia requires a placenta. Early-onset preeclampsia has been linked to poor placentation and fetal growth restriction, whereas late-onset preeclampsia was suggested to result from maternal factors. We have proposed an alternative model, suggesting that both early- and late-onset preeclampsia result from placental syncytiotrophoblast stress. This stress represents a common endpoint of several Stage 1 processes, promoting the clinical stage 2 of preeclampsia (new-onset hypertension and proteinuria or other signs of end-organ dysfunction), but the causes and timing of placental malperfusion differ. We have suggested that late-onset preeclampsia, without evidence of poor spiral artery remodelling, may be secondary to intraplacental (intervillous) malperfusion due to mechanical restrictions. As the growing placenta reaches its size limit, malperfusion and hypoxia occurs. This latter pathway reflects what is observed in postmature or multiple pregnancies. Our revised two-stage model accommodates most risk factors for preeclampsia including primiparity, chronic pre-pregnancy disease (e.g. obesity, diabetic-, chronic hypertensive-, and some autoimmune diseases), and pregnancy risk factors (e.g. multiple or molar pregnancies, gestational diabetes or hypertension, and low circulating Placental Growth Factor). These factors may increase the risk of progressing to the second stage of preeclampsia (both early- and late-onset) by affecting one of or both pathways leading to Stage 1, as well as potentially accelerating the steps towards Stage 2, including priming the maternal cardiovascular susceptibility to inflammatory factors shed by the placenta. This paper reviews previous preeclampsia findings and concepts, which fit with the revised two-stage model, and argues that "maternal" preeclampsia does not exist, as all preeclampsia requires a placenta. [ABSTRACT FROM AUTHOR]

Accumulating evidence has shown that preeclampsia (PE) was associated with an aberrant maternal-fetal inflammatory response. In the present study, we first found that in human PE placentas levels of toll-like receptor 4 (TLR4), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and inflammatory cytokines IL-6 and MCP-1 were significantly upregulated. Next, we demonstrated a notable increase in systolic blood pressure (SBP) and proteinuria in lipopolysaccharide (LPS)-treated pregnant rats and concomitant high levels of TLR4 and p-p38 in these PE-like rat placentas, which led to aberrant overexpression of both IL-6 and MCP-1, as well as deficient trophoblast invasion and spiral artery (SA) remodeling, and these abnormalities were ameliorated by SB203580, a reported inhibitor of p38. In vitro we further confirmed that LPS triggered the activation of TLR4/p38 signaling pathway, which promoted trophoblast apoptosis and damaged trophoblastic invasion via downstream effectors IL-6 and MCP-1; these mutations were rectified by silencing this signaling pathway. These findings elaborated potential mechanisms that aberrant TLR4/p38 signaling might contribute to PE and LPS-induced PE-like symptom by damaging trophoblast invasion and SA remodeling via activating inflammatory cytokines including IL-6 and MCP-1. [ABSTRACT FROM AUTHOR]