Attenuated retinoic acid signaling is among the early responses in mouse uterus approaching embryo attachment.

The uterus is transiently receptive for embryo implantation. It remains to be understood why the uterus does not reject a semi-allogeneic embryo (to the biological mother) or an allogeneic embryo (to a surrogate) for implantation. To gain insights, we examined uterine early response genes approaching embryo attachment on day 3 post coitum (D3) at 22 hours when blue dye reaction, an indication of embryo attachment, had not manifested in mice. C57BL/6 pseudo-pregnant (control) and pregnant mouse uteri were collected on D3 at 22 hours for microarray analysis. The self-assembling-manifold (SAM) algorithm identified 21,858 unique probesets. Principal component analysis indicated a clear separation between the pseudo-pregnant and pregnant groups. There were 106 upregulated and five downregulated protein-coding genes in the pregnant uterus with fold change (fc) >1.5 and q value <5%. Gene ontology (GO) analysis of the 106 upregulated genes revealed 38 significant GO biological process (GOBP) terms (P <0.05), and 32 (84%) of them were associated with immune responses, with a dominant natural killer (NK) cell activation signature. Among the top eight upregulated protein-coding genes, Cyp26a1 inactivates retinoic acid (RA) while Lrat promotes vitamin A storage, both of which are expected to attenuate RA bioavailability; Atp6v0d2 and Gjb2 play roles in ion transport and transmembrane transport; Gzmb, Gzmc, and Il2rb are involved in immune responses; and Tdo2 is important for kynurenine pathway. Most of these genes or their related pathways have functions in immune regulations. RA signaling has been implicated in immune tolerance and immune homeostasis, and uterine NK cells have been implicated in immunotolerance at the maternal-fetal interface in the placenta. The mechanisms of immune responses approaching embryo attachment remain to be elucidated. The coordinated effects of the early response genes may hold the keys to the question of why the uterus does not reject an implanting embryo.

Complete transverse transection of the normal-sized non-pregnant uterus associated with wearing a safety belt in abdominal blunt trauma: Narrative review and case study.

This review and case study illustrates a patient with a complete transverse transection of a non-pregnant uterus caused by blunt trauma associated with wearing a safety belt. The 31-year-old patient, who had a previous cesarean section, presented with impending hypovolemic shock caused by intra-abdominal hemorrhage secondary to blunt trauma while wearing a safety belt. On physical examination, a transverse straight line of ecchymosis along the line of a fastened safety belt was noted without any other external injury. The operative findings revealed a complete transverse transection which had cut through the lower part of the non-pathological, normal-sized uterus with active bleeding and mild injury to the small bowel without active bleeding. Total hysterectomy and simple closure of the small bowel were performed with successful outcomes. We hypothesize that transection was caused by the enormous pressure produced by blunt trauma transmitted through the abdomen by the fastened safety belt and the weakness of the uterine wall caused by the previous low transverse cesarean section which facilitated the separation and extension to the entire wall. In conclusion, this case study provides the following learning points: (1) Enormous forces produced by a fixed fastened safety belt during a car accident can cause complete transverse transection of a normal-sized, non-pathological uterus, leading to life-threatening intra-abdominal hemorrhage. (2) A previous cesarean section may potentiate the transection, especially when the uterus is repositioned above the pelvic brim. (3) The gynecologic condition should also be included in the differential diagnoses in cases of intra-abdominal hemorrhage. If highly suspected, gynecologists should be notified for early recognition and avoidance of delayed actions.

Monitoring uterine contractions during labor: current challenges and future directions.

Organ-level models are used to describe how cellular and tissue-level contractions coalesce into clinically observable uterine contractions. More importantly, these models provide a framework for evaluating the many different contraction patterns observed in laboring patients, ideally offering insight into the pitfalls of currently available recording modalities and suggesting new directions for improving recording and interpretation of uterine contractions. Early models proposed wave-like propagation of bioelectrical activity as the sole mechanism for recruiting the myometrium to participate in the contraction and increase contraction strength. However, as these models were tested, the results consistently revealed that sequentially propagating waves do not travel long distances and do not encompass the gravid uterus. To resolve this discrepancy, a model using 2 mechanisms, or a "dual model," for organ-level signaling has been proposed. In the dual model, the myometrium is recruited by action potentials that propagate wave-like as far as 10 cm. At longer distances, the myometrium is recruited by a mechanotransduction mechanism that is triggered by rising intrauterine pressure. In this review, we present the influential models of uterine function, highlighting their main features and inconsistencies, and detail the role of intrauterine pressure in signaling and cervical dilation. Clinical correlations demonstrate the application of organ-level models. The potential to improve the recording and clinical interpretation of uterine contractions when evaluating labor is discussed, with emphasis on uterine electromyography. Finally, 7 questions are posed to help guide future investigations on organ-level signaling mechanisms.

The ontogenies of endometrial and myometrial leptin and adiponectin receptors in pregnant rats: Their putative impact on uterine contractility.

AIMS: Limited data are available about the functions and expressions of leptin and adiponectin receptors (LEPR, AdipoRs) in the uterus. Our aim was to investigate the effects of leptin and adiponectin on the contractions of intact and denuded nonpregnant and pregnant uteri, as well as the changes in mRNA and protein expressions of LEPR and AdipoRs during the gestational period. MAIN METHODS: Contractions of nonpregnant and 5-, 15-, 18-, 20- or 22-day pregnant uterine rings were measured in an isolated organ bath system. The tissue contractions were stimulated with KCl and modified by cumulative concentrations of leptin or adiponectin. The mRNAs, protein expressions and localizations of LEPR and AdipoRs were determined by RT-PCR, Western blot and immunohistochemistry, respectively. KEY FINDINGS: Both adipokines relaxed the nonpregnant intact uterus more effectively than the denuded myometrium. Leptin inhibited the contractions of endometrium-denuded uteri throughout pregnancy, while its action was weakened on intact uteri towards term. The changes in LEPR receptor densities were independent of the relaxing effect. Adiponectin inhibited contractions, but this effect ceased on pregnancy day 22, while a gradual decrease was detected towards term on denuded myometria. These modifications were in harmony with changes in the expressions of AdipoRs. SIGNIFICANCE: Both leptin and adiponectin play a role in the relaxation of the pregnant uterus, but their efficacy significantly decreases towards the end of gestation. Their endometrial receptors may have a fine-tuning role in uterine contractions, predicting the importance of these adipokines in uterine contractions under altered adipokine level conditions.

Uterine torsion and intrauterine growth restriction: Case report and systematic literature review.

PURPOSE: Uterine torsion (UT) in pregnancy is a rare condition in obstetric practice. It is defined as a rotation of the uterus of more than 45° around its long axis. Presentations are varied and, most of the time, this condition is recognized at laparotomy or cesarean section (CS). The aim of this study is to summarize the latest evidence about UT in pregnancy. METHODS: A systematic research of the literature was conducted fetching all papers published from March 2006 to June 2020. We collected data regarding clinical features, treatment, and feto-maternal outcomes. Finally, we reported data of a case of UT associated with intrauterine growth restriction (IUGR) diagnosed and treated at our institution. RESULTS: According to our search strategy, 38 articles were included. In 66% of the cases, acute symptomatology was present at the onset, most frequently abdominal pain was reported. In one-third of the cases, UT was diagnosed during CS without clinical suspicion. Only in two cases, including our case, IUGR was reported. Most (66%) of the cases presented a 180° torsion. In the majority of the cases, a CS was performed also with a deliberate or accidental posterior hysterotomy. One and six cases of maternal and fetal death were, respectively, reported. CONCLUSION: UT is an infrequent obstetric condition but should be considered in case of abdominal pain, vomiting, or shock presentation during pregnancy. It could lead to a reduction in uterine blood flow contributing to poor placental perfusion, even though more evidence is needed to clarify this link.

Increased uterine androgen receptor protein abundance results in implantation and mitochondrial defects in pregnant rats with hyperandrogenism and insulin resistance.

In this study, we show that during normal rat pregnancy, there is a gestational stage-dependent decrease in androgen receptor (AR) abundance in the gravid uterus and that this is correlated with the differential expression of endometrial receptivity and decidualization genes during early and mid-gestation. In contrast, exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) or DHT alone significantly increased AR protein levels in the uterus in association with the aberrant expression of endometrial receptivity and decidualization genes, as well as disrupted implantation. Next, we assessed the functional relevance of the androgen-AR axis in the uterus for reproductive outcomes by treating normal pregnant rats and pregnant rats exposed to DHT and INS with the anti-androgen flutamide. We found that AR blockage using flutamide largely attenuated the DHT and INS-induced maternal endocrine, metabolic, and fertility impairments in pregnant rats in association with suppressed induction of uterine AR protein abundance and androgen-regulated response protein and normalized expression of several endometrial receptivity and decidualization genes. Further, blockade of AR normalized the expression of the mitochondrial biogenesis marker Nrf1 and the mitochondrial functional proteins Complexes I and II, VDAC, and PHB1. However, flutamide treatment did not rescue the compromised mitochondrial structure resulting from co-exposure to DHT and INS. These results demonstrate that functional AR protein is an important factor for gravid uterine function. Impairments in the uterine androgen-AR axis are accompanied by decreased endometrial receptivity, decidualization, and mitochondrial dysfunction, which might contribute to abnormal implantation in pregnant PCOS patients with compromised pregnancy outcomes and subfertility. KEY MESSAGES: The proper regulation of uterine androgen receptor (AR) contributes to a normal pregnancy process, whereas the aberrant regulation of uterine AR might be linked to polycystic ovary syndrome (PCOS)-induced pregnancy-related complications. In the current study, we found that during normal rat pregnancy there is a stage-dependent decrease in AR abundance in the gravid uterus and that this is correlated with the differential expression of the endometrial receptivity and decidualization genes Spp1, Prl, Igfbp1, and Hbegf. Pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin (INS) or to DHT alone show elevated uterine AR protein abundance and implantation failure related to the aberrant expression of genes involved in endometrial receptivity and decidualization in early to mid-gestation. Treatment with the anti-androgen flutamide, starting from pre-implantation, effectively prevents DHT + INS-induced defects in endometrial receptivity and decidualization gene expression, restores uterine mitochondrial homeostasis, and increases the pregnancy rate and the numbers of viable fetuses. This study adds to our understanding of the mechanisms underlying poor pregnancy outcomes in PCOS patients and the possible therapeutic use of anti-androgens, including flutamide, after spontaneous conception.

Interaction analysis of a pregnant female uterus and fetus in a vehicle passing a speed bump.

Pregnant vehicle occupants experience relatively large acceleration when the vehicle passes a speed-bump. In this paper, the effect of such sudden acceleration on a pregnant uterus is investigated. A biomechanical model representing the fundamental dynamic behaviors of a pregnant uterus has been developed. The model relates to the 32nd week of gestation when the fetus is in head-down, occipito-anterior position. Considering the drag and squeeze effects of the amniotic fluid, we derive a comprehensive differential equation that represents the interaction of the uterus and fetus. Solving the governing equation, we obtain the system response to different speed-bump excitations. Using the fetal head injury criterion (HIC = 390), we evaluate the model response. Three risk zones (Low, Medium, and High) are introduced, and the effects of excitation characteristics on HIC are investigated. HIC enhances, sub-exponentially, as the excitation amplitude (width) increases (decreases). Three risk-bounds, corresponding to 25%, 75%, and 100% risk of injury, are developed in the "width-amplitude" and the "frequency-amplitude" planes. Considering a typical speed-bump of width and excitation amplitude of 0.5 m and 0.12 m, respectively, the driver should not hit the speed-bump at 42 km/h or more. We advise hitting such speed-bumps under 25 km/h, based on this paper's findings. According to the risk-bounds, the injury risk of an arbitrary speed-bump excitation, at any desired vehicle speed, can be determined. The findings can help to understand how a pregnant uterus and fetus are subjected to risk caused by a vehicle passing a speed-bump and to expand our knowledge to improve safety during pregnancy.

Angiopoietin-2 regulated by progesterone induces uterine vascular remodeling during pregnancy.

During pregnancy, the uterus undergoes intense neovascularization and vascular remodeling to supply oxygen and nutrients to the embryo. During this period, progesterone secreted from the ovary has effects on vascular remodeling in the endometrium and interacts with angiogenic factors. However, the exact mechanism of uterine vascular remodeling during pregnancy is poorly understood. Therefore, the aim of the present study was to investigate the association between angiopoietin-2 (Ang-2), one of the angiopoietins, and intrauterine vessel remodeling during pregnancy, and to determine the effect of progesterone on Ang-2 levels. Changes in Ang-2 expression were observed according to quantitative modification of progesterone using pregnant mice and human uterine microvascular endothelial cells. As a result, Ang-2 was observed mainly in the mesometrial region (MR) of the uterus during the period between implantation and placentation. Furthermore, a substantial amount of Ang-2 also appeared in endothelial cells, particularly of the venous sinus region (VSR). Interestingly, Ang-2 expression was increased by progesterone, whereas estrogen had limited effects. To confirm the association between Ang-2 and progesterone, the function of the progesterone receptor (PR) was inhibited using RU486, a blocker of PR. Ang-2 expression and vascular remodeling of the VSR in the uterus were decreased when the functions of progesterone were inhibited. Overall, the regulation of Ang-2 by progesterone/PR was associated with vascular remodeling in the VSR during pregnancy. The present study proposed a solution to prevent pregnancy failure due to a lack of vascularity in the uterus in advance.

Diffusion Tensor Imaging (DTI) of the Cesarean-Scarred Uterus in vivo at 3T: Comparison Study of DTI Parameters Between Nonpregnant and Pregnant Cases.

BACKGROUND: Fiber architecture of the human uterus can be depicted in vivo using 3T MR-DTI (diffusion tensor imaging). PURPOSE: To investigate the differences in fibrous structure and DTI-related parameters between nonpregnant and pregnant cases in vivo. STUDY TYPE: Prospective case-control study. SUBJECTS: Thirty-one subjects were divided into two groups; 18 nonpregnant volunteers with previous cesarean deliveries (Group 1) and 13 patients in early pregnancy also with previous cesarean section (Group 2). FIELD STRENGTH/SEQUENCE: 3T Ssh-EPI (single-shot echo planar imaging) fast sequence with b values of 0 and 600 s/mm2 along 30 directions. ASSESSMENT: Fiber density, fiber length, apparent diffusion coefficient (ADC) value, and the fractional anisotropy (FA) value measured in the mid-sagittal plane of the uterus were obtained from the outer myometrium (OM), junctional zone (JZ), and the cesarean section scar (CSS). Fiber architecture in vivo was depicted by 3D diffusion tensor tractography (DTT). STATISTICAL TESTS: A t-test of independent sample or Wilcoxon rank sum test were used for comparison. RESULTS: Pregnant scarred-uterus (Group 2) showed a decrease in fiber density, FA value, and an increase in fiber length, ADC value than the nonpregnant scarred-uterus (Group 1) on OM, JZ, and CSS. Among the above parameters between the two groups, for OM, significant differences were found in fiber density (P < 0.001), length (P = 0.0306), and ADC (P = 0.0039). For JZ, significant differences were found in fiber density (P = 0.0093), FA (P = 0.0002), and ADC (P < 0.001). The scar's fiber density (P = 0.0794), length (P = 0.6167), FA (P = 0.6305), and ADC value (P = 0.1865) showed no statistically significant difference during early pregnancy. DATA CONCLUSION: Our results indicate considerable diffusional changes in uterine fiber architecture during pregnancy. The microenvironment of scar tissue appears to change little during early pregnancy. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:124-130.

Rigid-bar loading on pregnant uterus and development of pregnant abdominal response corridor based on finite element biomechanical model.

During pregnancy, traumas can threaten maternal and fetal health. Various trauma effects on a pregnant uterus are little investigated. In the present study, a finite element model of a uterus along with a fetus, placenta, amniotic fluid, and two most effective ligament sets is developed. This model allows numerical evaluation of various loading on a pregnant uterus. The model geometry is developed based on CT-scan data and validated using anthropometric data. Applying Ogden hyper-elastic theory, material properties of uterine wall and placenta are developed. After simulating the "rigid-bar" abdominal loading, the impact force and abdominal penetration are investigated. Findings are compared with the experimental abdominal response corridor, previously developed for a nonpregnant abdomen. "Response corridor" denotes a bounded envelope in response space, within which the system responses usually lie. Results show that at low abdominal penetrations (less than 45 mm), the pregnant abdomen response is highly compatible with the nonpregnant case. While, at large penetrations, the pregnant abdomen demonstrates stiffer behavior. The reason must be the existence of a fetus in the model. This reveals that the existing response corridors would not be reliable to be extended for a pregnant abdomen. Hence, response corridor development for a pregnant abdomen is a crucial task. In this study, a new fixed-back rigid-bar loading response corridor is proposed for a pregnant abdomen using the load-penetration behavior of the developed model. This model and response corridor can help to study the pregnant uterus response to environmental loading and investigate the injury risk to the uterus and fetus.

Histerocele gravídico umbilical. Reporte de un caso / Umbilical gravid hysterocele. A case report

Resumen ANTECEDENTES: Aunque la hernia umbilical es relativamente frecuente en la población africana, la mayoría de los casos cursan asintomáticos. La situación en la que un útero grávido entra en un saco herniario representa una complicación excepcional de la hernia umbilical. CASO CLÍNICO: Paciente de 30 años, con antecedentes médicos de hernia umbilical y obstétricos de 5 embarazos, 4 partos y 1 aborto espontáneo. Acudió a consulta por dolor en la parte baja del vientre, de tres días de evolución. En el interrogatorio refirió amenorrea de 5 meses; 2 semanas antes percibió movimientos fetales y ausencia de los mismos 3 días previos a la consulta médica. Al examen físico se observó el abdomen con aumento de volumen irreductible, de 30 cm de diámetro, de forma pendular, que se protruía a través de un gran anillo herniario umbilical y llegaba hasta la mitad de los muslos; se palpó el feto, pero no se escucharon latidos cardiacos. Por los antecedentes médicos, hallazgos clínicos y ecográficos se estableció el diagnosticó de muerte fetal intrauterina, como complicación de útero grávido en una hernia umbilical. Se decidió la interrupción del embarazo mediante cesárea de urgencia. La hernia umbilical se reparó con reforzamiento del defecto mediante colgajos fascio-aponeuróticos, según la técnica de Mayo. La evolución de la paciente fue satisfactoria. CONCLUSIONES: El tratamiento de pacientes embarazadas con hernia umbilical incluye una conducta conservadora, control prenatal estricto, colocación de un corsé para rectificar el útero grávido, programación de la cesárea y reparación del defecto herniario.

Abstract BACKGROUND: Although umbilical hernia is relatively common in African patients, the majority of cases are asymptomatic. The situation in which a gravid uterus enters a hernia sac is one of the rarest complications of umbilical hernia. CLINICAL CASE: 30-year-old pregnant woman with a history of umbilical hernia and obstetric of 5 pregnancies, 4 deliveries and 1 spontaneous abortion. She reported pain in the abdomen that appeared 3 days ago, absence of menstruation 5 months ago, with fetal movements referred 2 weeks ago and absence of them 3 days ago. At the physical examination, an irreducible volume increase of approximately 30 cm in diameter with a pendulum shape that protruded through a large umbilical hernia ring and reached the middle of the thighs, fetal parts were palpated and absence of fetal heartbeats. Due to the antecedents, the clinic and the obstetric ultrasound, an intrauterine fetal death was diagnosed as a complication of a gravid uterus in an umbilical hernia. The interruption of pregnancy was performed by emergency caesarean section. The umbilical hernia was repaired with reinforcement of the defect using fascio-aponeurotic flaps, according to the Mayo technique. The evolution was satisfactory until hospital discharge. CONCLUSIONS: The treatment of pregnant patients with umbilical hernia includes a conservative behavior, strict prenatal control, placement of a brace to rectify the pregnant uterus, programming of the cesarean and repair of the hernia defect.

The location of pacemakers in the uteri of pregnant guinea pigs and rats.

The pregnant uterus is a smooth muscle organ whose pattern of contraction is dictated by the propagation of electrical impulses. Such electrical activity may originate from one or more pacemakers, but the location of these sites has not yet been determined. To detect the location of the pacemaker in the gravid uterus, two approaches were used: 1) determine the site from where the contraction started using isolated uteri from the pregnant guinea pig, and videotape their contractions; and 2) record, in isolated uteri from pregnant term rats, with 240 extracellular electrodes simultaneously, and determine where the electrical bursts started. In both the contractile and electrophysiological experiments, there was not a single, specific pacemaker area. However, most contractions (guinea pig 87%) and bursts (rat 76%) started close to the mesometrial border (mean 2.7 ± 4.0 mm SD in guinea pigs and 1.3 ± 1.4 mm in rats). In addition, in the rat, most sites of initiations were located closer to the ovarial end of the horn (mean distance from the ovarial end 6.0 ± 6.2 mm SD), whereas such an orientation was not seen in the guinea pig. In both guinea pig and rat uteri at term, there is not one specific pacemaker area. Rather, contractile and electrical activity may arise from any site, with the majority starting close to the mesometrial border. Furthermore, in the rat, most activities started at the ovarial end of the horn. This may suggest a slightly different pattern of contraction in both species.

Uterine Telocytes: A Review of Current Knowledge.

Telocytes (TCs), a novel cell type, are briefly defined as interstitial cells with telopodes (Tps). However, a specific immunocytochemical marker has not yet been found; therefore, electron microscopy is currently the only accurate method for identifying TCs. TCs are considered to have a mesenchymal origin. Recently proteomic analysis, microarray-based gene expression analysis, and the micro-RNA signature clearly showed that TCs are different from fibroblasts, mesenchymal stem cells, and endothelial cells. The dynamics of Tps were also revealed, and some electrophysiological properties of TCs were described (such as membrane capacitance, input resistance, membrane resting potential, and absence of action potentials correlated with different ionic currents characteristics), which can be used to distinguish uterine TCs from smooth muscle cells (SMCs). Here, we briefly present the most recent findings on the characteristics of TCs and their functions in human pregnant and nonpregnant uteri.

Designing artificial environments for preterm infants based on circadian studies on pregnant uterus.

Using uterine explants from Per1::Luc rats and in situ hybridization, we recently reported that the circadian property of the molecular clock in the uterus and placenta is stably maintained from non-pregnancy, right through to the end stage of pregnancy under regular light-dark (LD) cycles. Despite long-lasting increases in progesterone during gestation and an increase in estrogen before delivery, the uterus keeps a stable Per1::Luc rhythm throughout the pregnancy. The study suggests the importance of stable circadian environments for fetuses to achieve sound physiology and intrauterine development. This idea is also supported by epidemiological and animal studies, in which pregnant females exposed to repeated shifting of the LD cycles have increased rates of reproductive abnormalities and adverse pregnancy outcomes. Leading from this, we introduced artificial circadian environments with controlled lighting conditions to human preterm infants by developing and utilizing a specific light filter which takes advantage of the unique characteristics of infants' developing visual photoreceptors. In spite of growing evidence of the physiological benefits of nighttime exposure to darkness for infant development, many Japanese Neonatal Intensive Care Units (NICUs) still prefer to maintain constant light in preparation for any possible emergencies concerning infants in incubators. To protect infants from the negative effects of constant light on their development in the NICU, we have developed a new device similar to a magic mirror, by which preterm infants can be shielded from exposure to their visible wavelengths of light even in the constant light conditions of the NICU while simultaneously allowing medical care staff to visually monitor preterm infants adequately. The device leads to significantly increased infant activity during daytime than during night time and better weight gains.

VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy.

The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. Here we show that dynamic and variable decidual angiogenesis (sprouting, intussusception and networking), and active vigorous vascular remodelling such as enlargement and elongation of 'vascular sinus folding' (VSF) and mural cell drop-out occur distinctly in a spatiotemporal manner in the rapidly growing mouse uterus during early pregnancy - just after implantation but before placentation. Decidual angiogenesis is mainly regulated through VEGF-A secreted from the progesterone receptor (PR)-expressing decidual stromal cells which are largely distributed in the anti-mesometrial region (AMR). In comparison, P4 -PR-regulated VEGF-A-VEGFR2 signalling, ligand-independent VEGFR3 signalling and uterine natural killer (uNK) cells positively and coordinately regulate enlargement and elongation of VSF. During the postpartum period, Tie2 signalling could be involved in vascular maturation at the endometrium in a ligand-independent manner, with marked reduction of VEGF-A, VEGFR2 and PR expressions. Overall, we show that two key vascular growth factor receptors - VEGFR2 and Tie2 - strikingly but differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri in an organotypic manner.