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Uterine-enhanced myometrial vascularity (EMV) is a rare complication following abortion/medical termination of pregnancy or postuterine instrumentation, which can lead to severe anaemia and could even be life-threatening in some cases. Several invasive surgical treatment methods are available for management. Recently, minimally invasive embolisation of uterine arteries has been emerging as an effective alternative management method with promising results. In this case report, we aim to describe a case of uterine EMV in a young female presenting with bleeding, which was successfully managed with uterine artery embolisation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The differentiation between conditions such as uterine arteriovenous malformation, pseudoaneurysm, gestational trophoblastic disease, and retained trophoblastic tissue can be challenging. Ultrasound imaging and Doppler interrogation are the primary diagnostic tools to assess cases of enhanced myometrial vascularity and differentiate intrauterine vascular anomalies. However, some cases remain of difficult differentiation. This study aims to analyze suspected cases and describe their diagnostic management and outcomes., Methods: We reviewed post-abortion cases that underwent pelvic transvaginal U/S imaging and Doppler examinations due to suspected uterine vascular anomalies. CT scans were performed in cases in which ultrasound did not reach a diagnosis. Simple follow-up, medical or surgical therapy, or embolization of uterine arteries were performed according to the final diagnosis., Results: From 2015 to 2022, we retrieved from electronic ultrasound records 22 cases of suspected vascular malformations. In eight cases, first-line U/S at admission excluded the suspected anomaly. In Five of the remaining 14 patients, uterine vascular anomalies were excluded upon a second-level  U/S based on angio-Doppler imaging and Doppler peak velocity interrogation. Nine cases underwent CT scan, and a digital angiography and embolization were performed in eight of these cases, of whom only two had a documented uterine arteriovenous malformation., Conclusion: Our triage proved that only two out of 22 suspected cases had a uterine arteriovenous malformation. This diagnosis is frequently misused in clinical practice. Our data confirm that enhanced myometrial vascularity should be used to encompass the spectrum of possible differential diagnosis. A precise step-by-step diagnostic method is of paramount importance to prevent unnecessary interventions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To assess the ultrasonographic, epidemiological, clinical and evolutive characteristics of enhanced myometrial vascularity (EMV) following a first-trimester termination of pregnancy (TOP) or management of non-viable pregnancy., Methods: This prospective study included women who underwent follow-up ultrasound examination 5-6 weeks after a first-trimester TOP or after management of a first-trimester non-viable pregnancy at the University Hospital Polyclinic San Martino of Genoa between March 2021 and March 2022. EMV was characterized using two- and three-dimensional ultrasound and Virtual Organ Computer-aided Analysis. Ultrasonographic diagnosis of EMV was made when an unusual, tortuous myometrial vessel structure, with high-velocity blood flow, protruding towards the endometrium was observed, while an abnormal junctional zone, absent endometrial midline and heterogeneous endometrium supported the diagnosis. Patients with EMV underwent expectant management with planned ultrasonographic follow-up every 2 weeks until resolution., Results: During the study period, 305 women underwent TOP, of whom 132 attended the initial follow-up 5-6 weeks later, at which 52 were diagnosed with EMV. Ninety-six women were managed for a non-viable pregnancy, of whom 32 presented for follow-up, at which six had a diagnosis of EMV. Thus, overall, 164 of 401 women were included in the study and EMV was identified in 58 (35%) of these. The prevalence of EMV 5-6 weeks after a TOP was therefore between 52/305 (17%) and 52/132 (39%), and that after management of a non-viable pregnancy was between 6/96 (6%) and 6/32 (19%). Bleeding/pelvic pain was present in half (29/58) of the women with EMV, and serum human chorionic gonadotropin was detectable in 29% (17/58) at the first follow-up examination. At ultrasound assessment, all cases with EMV presented abundant tortuous myometrial vessels with high-velocity flow projecting from the myometrium towards the endometrium, along with non-uniform heterogeneous endometrium in 97% of cases, which often (67% of these) contained cystic areas, absence of the endometrial midline in 98% of cases and an abnormal junctional zone in 97% of cases (64% interrupted, 33% irregular). Most (67%) women with EMV were parous and 90% of them had undergone TOP rather than management for a non-viable pregnancy. Medical management of the TOP or non-viable pregnancy was more frequent in women with than those without EMV (93% vs 77%, P = 0.023). Multiple regression analysis showed the risk of EMV to be increased following TOP vs non-viable pregnancy (odds ratio (OR), 3.67 (95% CI, 1.16-11.56), P = 0.026) and in parous compared with nulliparous women (OR, 2.95 (95% CI, 1.45-6.01), P = 0.002). All women with EMV underwent expectant management. Eleven women did not return for subsequent follow-up examinations and did not present to our outpatient or emergency facilities, so were lost to further follow-up. Spontaneous resolution of the lesion was observed within 7-16 weeks after the procedure in 96% (45/47) of the remaining cases. Two women chose to undergo surgery for pelvic discomfort, and histology showed the presence of neovessels mixed with retained chorionic villi., Conclusions: EMV is a transient and common finding 5-6 weeks following first-trimester TOP or management of non-viable pregnancy. TOP and being parous are risk factors for EMV. Expectant management of EMV is appropriate, because, in almost all cases, this resolves spontaneously, without complications, within 2-4 months. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To describe the etiology of arteriovenous malformations (AVM) and enhanced myometrial vascularity (EMV), and review updates in management for patients with retained products of conception (RPOC) associated with EMV through a case presentation., Design: A 6-minute narrated video discusses the recent distinction between EMV and AVM. The etiology, symptoms, imaging findings/interpretation, and management based on symptoms are reviewed in detail. As this represents a single case report, it does not meet the definition of research according to the regulations at 45 CFR 46.102(l); therefore, institutional review board approval was not required., Setting: Tertiary referral center., Patient(s): Eight weeks after suction dilation and curettage (D&C) for an incomplete abortion, a 28-year-old gravida 1, para 0 patient presented to an outside facility with RPOC, menorrhagia, and an acute decrease in hemoglobin. After uterine AVM was diagnosed, she was transferred to our facility for further care., Intervention(s): After transfer to our center, ultrasound demonstrated RPOC, with prominent internal vasculature containing peak systolic velocity >20 cm/s. A diagnosis of EMV was made. Magnetic resonance imaging confirmed a prominent serpentine vessel at the endometrium and RPOC within the uterine cavity (Fig. 1). Due to her anemia, she underwent uterine artery embolization (UAE) followed by suction D&C (Fig. 2). Hysteroscopy was performed before and after suction D&C and after curettage, a large vascular bundle was appreciated at the surface of the endometrium., Main Outcome Measure(s): None., Result(s): The patient presented to the clinic 2 weeks postoperatively with the resolution of abnormal uterine bleeding symptoms and a negative β-human chorionic gonadotropin test., Conclusion(s): Management of patients with EMV is dependent on the extent of their symptoms. If significant bleeding is present, surgical management is required. Previous reports suggested that patients with EMV and RPOC should undergo UAE before D&C, but more recent studies suggest that D&C may be initiated without UAE, as EMV associated with RPOC may be a normal transient placentation phenomenon and have less risk of hemorrhage than previously suspected. However, in patients with significant preoperative bleeding and/or anemia, we propose that UAE should still be considered. Each patient requires individualized management based on symptoms, signs, imaging, and plans for future fertility. The ideal management of patients with RPOC and EMV remains to be determined., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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Purpose: To assess the value of various grey-scale ultrasound, 2D color Doppler, and 3D power Doppler sonographic markers in predicting major intraoperative blood loss during planned cesarean hysterectomy for cases diagnosed with placenta accreta spectrum (PAS) disorders., Methods: 50 women diagnosed with PAS were scanned the day before planned delivery and hysterectomy for various sonographic markers indicative of placental invasion. These women were then later divided according to blood loss in two groups: group A (minor hemorrhage, < 2500 ml), and group B (major hemorrhage, > 2500 ml), and the data were analyzed., Results: The odds ratio (OR) for major hemorrhage was as follows for the following sonographic markers: 'number of lacunae > 4' OR 3.8 95% CI (1.0-13.8) (p = 0.047); 'subplacental hypervascularity' OR 10.8 95% CI (1.2-98.0) (p = 0.035); 'tortuous vascularity with 'chaotic branching' OR 10.8 95%CI (1.2-98.0) (p = 0.035); 'numerous coherent vessels involving the serosa-bladder interface OR 14.6 95% CI (2.7-80.5) (p = 0.002); and 'presence of bridging vessels OR 2.9 95% CI (1.4-6.9) (p = 0.005). Only the presence of numerous coherent vessels involving the bladder-serosal interface (p = 0.002) was proven to be independent predictor of major hemorrhage during hysterectomy., Conclusion: The use of 2D color Doppler and 3D power Doppler can help predict massive hemorrhage in cases of PAS disorders.

High-altitude (>2,500 m) residence increases the incidence of intrauterine growth restriction (IUGR) due, in part, to reduced uterine artery blood flow and impaired myometrial artery (MA) vasodilator response. A role for the AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR is suggested by genomic and transcriptomic studies in humans and functional studies in mice. AMPK is a hypoxia-sensitive metabolic sensor with vasodilatory properties. Here we hypothesized that AMPK-dependent vasodilation was increased in MAs from high versus low-altitude (<1,700 m) Colorado women with appropriate for gestational age (AGA) pregnancies and reduced in IUGR pregnancies regardless of altitude. Vasoreactivity studies showed that, in AGA pregnancies, MAs from high-altitude women were more sensitive to vasodilation by activation of AMPK with A769662 due chiefly to increased endothelial nitric oxide production, whereas MA responses to AMPK activation in the low-altitude women were endothelium independent. MAs from IUGR compared with AGA pregnancies had blunted vasodilator responses to acetylcholine at high altitude. We concluded that 1 ) blunted vasodilator responses in IUGR pregnancies confirm the importance of MA vasodilation for normal fetal growth and 2 ) the increased sensitivity to AMPK activation in AGA pregnancies at high altitude suggests that AMPK activation helped maintain MA vasodilation and fetal growth. These results highlight a novel mechanism for vasodilation of MAs under conditions of chronic hypoxia and suggest that AMPK activation could provide a therapy for increasing uteroplacental blood flow and improving fetal growth in IUGR pregnancies. NEW & NOTEWORTHY Intrauterine growth restriction (IUGR) impairs infant well- being and increases susceptibility to later-in-life diseases for mother and child. Our study reveals a novel role for AMPK in vasodilating the myometrial artery (MA) from women residing at high altitude (>2,500 m) with appropriate for gestational age pregnancies but not in IUGR pregnancies at any altitude.

Objectives: Our primary aim was to report the incidence of enhanced myometrial vascularity (EMV) in consecutive women attending our early pregnancy assessment unit, following first-trimester miscarriage. We aimed further to evaluate the clinical presentation and complications associated with expectant and surgical management of EMV in these women., Methods: This was a prospective cohort study conducted in a London teaching hospital between June 2015 and June 2018, including consecutive patients with an observation of EMV on transvaginal ultrasonography following first-trimester miscarriage. The diagnosis was made following the subjective identification of EMV using color Doppler ultrasonography and a peak systolic velocity (PSV) ≥ 20 cm/s within the collection of vessels. Women were followed up with repeat scans every 14 days. Management was expectant unless intervention was indicated because of excessive or prolonged bleeding, persistent presence of retained tissue in the endometrial cavity or patient choice. The final clinical outcome was recorded. Time to resolution of EMV was defined as the interval from detection of EMV until resolution., Results: During the study period, there were 2627 first-trimester fetal losses in the department and, of these, 40 patients were diagnosed with EMV, hence the incidence of EMV following miscarriage was 1.52%. All cases were associated with ultrasound evidence of retained products of conception (RPOC) at presentation (mean dimensions, 22 × 20 × 20 mm). Thirty-one patients opted initially for expectant management, of which 18 had successful resolution without intervention, five were lost to follow-up and eight subsequently had surgical evacuation due to patient choice. No expectantly managed case required emergency intervention. Nine patients chose surgical evacuation as primary treatment. No significant correlation was seen between PSV within the EMV at presentation and blood loss at surgery. Median PSV was 47 (range, 20-148) cm/s. The estimated blood loss in all cases managed surgically ranged from 20-300 mL. Presence of RPOC was confirmed in all specimens that were sent for analysis following surgery. For cases successfully managed expectantly, the mean time to resolution was 48 (range, 21-84) days. In the nine cases managed surgically from the beginning, the mean time to resolution of EMV was 10.6 (range, 3-29) days., Conclusions: This study suggests that EMV is an uncommon finding following miscarriage and is associated with the presence of RPOC. Expectant management was a safe option in our cohort, with minimal bleeding, although it was associated with protracted time to resolution. In patients who opted for surgery, the maximum blood loss was 300 mL and no patient required blood transfusion or embolization. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To describe the role of hysteroscopy in diagnosis and subsequent follow-up of uterine enhanced myometrial vascularity (EMV). Uterine EMV, previously known as arteriovenous malformation (AVM), is a rare but cannot-miss finding often associated with prior pregnancy or uterine surgery and is typically suspected when a vascular mass is found on ultrasound. Color Doppler imaging will demonstrate high-velocity, low-impedance flow, with more significant shunts demonstrating higher peak systolic velocity (PSV). If not already diagnosed by ultrasound, accurate recognition during hysteroscopy is mandatory prior to any uterine instrumentation, as biopsy or curettage can lead to unanticipated massive hemorrhage. While many cases of EMV may resolve spontaneously, actively bleeding patients may require treatment with embolization, a procedure that may decrease ovarian reserve and impair fertility, though favorable reproductive outcomes have been reported. Others have reported success with hysteroscopic management using a bipolar electrosurgical loop., Design: Case report., Setting: Academic hospital system., Patient(s): We describe a 22-year-old G2P1011 who presented to the emergency department with heavy vaginal bleeding and a negative urine human chorionic gonadotropin 9 weeks following a first-trimester termination of pregnancy. Her ultrasound demonstrated a heterogeneous 2.6×2.3×2.6 cm vascular mass in the endometrial canal that was initially interpreted as retained products of conception. Unfortunately, PSV in the lesion was not measured. During observation, bleeding continued, and her hemoglobin dropped from 8.3 g/dL to 6.9 g/dL the next morning. She was transfused 2 units of blood and taken to the operating room for hysteroscopic evaluation and possible uterine curettage., Intervention(s): Hysteroscopy revealed a large pulsating 2cm bluish vascular mass that was recognized as a uterine EMV and the procedure was terminated with the plan for embolization. Given fertility concerns, the diagnosis was confirmed with MRI/MRA, which identified a 2.7cm mass-like process with early post-contrast enhancement in the arterial phase. An angiogram demonstrated bilaterally enlarged tortuous uterine arteries perfusing a hypervascular EMV that was treated with selective bilateral uterine artery embolization., Main Outcome Measure(s): Further bleeding or evidence of EMV., Result(s): Follow-up office hysteroscopy at 2 weeks demonstrated a 2 cm raised area of tissue without pulsations. At 6 weeks post-procedure, bleeding had ceased, and office hysteroscopy revealed only a small 0.5 cm calcified nodule with a circumferential pseudo-decidual reaction., Conclusion(s): Hysteroscopy may be used to diagnose EMV when ultrasound is not conclusive. Recognition of the pulsating vascular appearance of EMV on hysteroscopy is critical in preventing hemorrhage from inappropriate curettage. Resolution of the lesion following embolization can be readily demonstrated with office hysteroscopy., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

We present a case of diffuse skin immune reaction, diagnosed as cutaneous small-vessel vasculitis, following assessment of tubal patency by contrast ultrasound, which appears to be the first reported case of hypersensitivity reaction to sonographic tubal patency testing, based on a literature search. A 32-year-old woman presented with non-thrombocytopenic palpable purpura the day after assessment of tubal patency by two-/three-dimensional hysterosalpingo-foam sonography (HyFoSy) using ExEm® Foam. During real-time ultrasound, the observer identified flow in only the right tube when using saline with air as contrast medium; however, the same observer identified flow in both tubes after injecting ExEm Foam and the woman left the clinic without any complications. The next day, the patient was admitted with a complaint of a red-purple skin rash noticed the same morning, associated with moderate leg pain. Slow-motion analysis of the recorded videos and three-dimensional ultrasound datasets showed previously unnoticed venous intravasation of ExEm Foam into the myometrial vessels. Palpable purpura is typically found in vasculitis as a result of extravasation of red cells outside the inflamed blood vessel. This previously unreported side effect of tubal patency testing by HyFoSy, its potential rare organ consequences, as well as unknown consequences of venous intravasation by foam, should be included in the informed consent prior to the examination. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To assess the complication rate, including estimated amount of blood loss, in patients undergoing dilation and curettage (D&C) for the treatment of retained products of conception with markedly enhanced myometrial vascularity mimicking arteriovenous malformation., Methods: This was a retrospective medical-records review study of patients with retained products of conception with enhanced myometrial vascularity presenting to our ultrasound unit between August 2015 and August 2017. Color/power Doppler imaging was used subjectively to identify the degree and extent of vascularity. All patients underwent D&C, and their operative reports and medical records were reviewed to see if ultrasound guidance was used, to ascertain estimated blood loss and to identify complications during or after the procedure., Results: The study group included 31 patients, of whom seven had retained products of conception after a vaginal delivery and 24 had retained products of conception after a first-trimester termination or miscarriage. The largest dimension of the region of enhanced myometrial vascularity ranged from 10 mm to 53 mm, with 14/31 having a width of ≥ 20 mm. Fifteen patients underwent a standard D&C procedure, 13 an ultrasound-guided procedure and three hysteroscopy. Estimated operative blood loss varied from negligible to a maximum of 400 mL. There were no intraoperative complications, although one patient was treated for presumed endometritis., Conclusions: An increasing number of studies describe the enhanced myometrial vascularity associated with retained products of conception as 'acquired arteriovenous malformation', with some recommending management with uterine-artery embolization. Our study demonstrates that the enhanced myometrial vascularity is associated with retained products of conception, and surgical removal by D&C, possibly with the aid of ultrasound guidance or hysteroscopy, is a safe treatment option. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

The aim of this study is to evaluate the clinical outcomes of conservative adenomyomectomy with TOUA for diffuse uterine adenomyosis and to determine the feasibility and safety. One hundred and sixteen patients with symptomatic diffuse uterine adenomyosis underwent adenomyomectomy with TOUA by a single surgeon at Ulsan University Hospital between May 2011 and March 2016. Surgical outcomes included operative time, intraoperative injury and operative blood loss. We assessed the degree of improvement in dysmenorrhea and menorrhagia at the 7-month follow-up visit after the operation. The mean age of patients was 37.49 years (range: 26-49). The mean total surgical time was 116.12 min (range: 60-300, SD: 37.27). The mean estimated blood loss was 207.22 mL (range: 30-1200, SD: 161.08) and there were no cases of injury to the uterine arteries or pelvic nerves. The mean duration of hospital stay was 5.05 days (range: 4-7, SD: 0.68) and the mean follow-up period of 16.67 months (range: 6-49, SD: 12.77). At the 7-month follow-up after adenomyomectomy with TOUA, dysmenorrhea and menorrhagia were improved in 100% and 89% of the patients, respectively. In patients with diffuse uterine adenomyosis, even when the whole uterus is involved, for relief of severe adenomyosis-related symptoms, adenomyomectomy with TOUA could be a safe and effective surgical treatment option for those who want to preserve their fertility., (Copyright © 2018. Published by Elsevier Taiwan.)

Study Question: Are there any phenotypic and structural/architectural changes in the vessels of endometrium and superficial myometrium during the normal menstrual cycle in healthy women and those with heavy menstrual bleeding (HMB)?, Summary Answer: Spatial and temporal differences in protein levels of endothelial cell (EC) markers and components of the extracellular matrix (ECM) were detected across the menstrual cycle in healthy women and these are altered in HMB., What Is Known Already: HMB affects 30% of women of reproductive age with ~50% of cases being idiopathic. We have previously shown that the differentiation status of endometrial vascular smooth muscle cells (VSMCs) is altered in women with HMB, suggesting altered vessel maturation compared to controls. Endometrial arteriogenesis requires the co-ordinated maturation not only of the VSMCs but also the underlying ECs and surrounding ECM. We hypothesized that there are spatial and temporal patterns of protein expression of EC markers and vascular ECM components in the endometrium across the menstrual cycle, which are altered in women with HMB., Study Design, Size, Duration: Biopsies containing endometrium and superficial myometrium were taken from hysterectomy specimens from both healthy control women without endometrial pathology and women with subjective HMB in the proliferative (PP), early secretory (ESP), mid secretory (MSP) and late secretory (LSP) phases (N = 5 for each cycle phase and subject group). Samples were fixed in formalin and embedded in paraffin wax., Participants/materials, Setting, Methods: Serial sections (3μm thick) were immunostained for EC markers (factor VIII related antigen (F8RA), CD34, CD31 and ulex europaeus-agglutinin I (UEA-1) lectin), structural ECM markers (osteopontin, laminin, fibronectin and collagen IV) and for Ki67 to assess proliferation. Immunoreactivity of vessels in superficial myometrium, endometrial stratum basalis, stratum functionalis and luminal region was scored using either a modified Quickscore or by counting the number of positive vessels., Main Results and the Role of Chance: In control samples, all four EC markers showed a dynamic expression pattern according to the menstrual cycle phase, in both endometrial and myometrial vessels. EC protein marker expression was altered in women with HMB compared with controls, especially in the secretory phase in the endometrial luminal region and stratum functionalis. For example, in the LSP expression of UEA-1 and CD31 in the luminal region decreased in HMB (mean quickscore: 1 and 5, respectively) compared with controls (3.2 and 7.4, respectively) (both P = 0.008), while expression of F8RA and CD34 increased in HMB (1.4 and 8, respectively) compared with controls (0 and 5.8, respectively) (both P = 0.008). There was also a distinct pattern of expression of the vascular structural ECM protein components osteopontin, laminin, fibronectin and collagen IV in the superficial myometrium, stratum functionalis and stratum basalis during the menstrual cycle, which was altered in HMB. In particular, compared with controls, osteopontin expression in HMB was higher in stratum functionalis in the LSP (7.2 and 11.2, respectively P = 0.008), while collagen IV expression was reduced in stratum basalis in the MSP (4.6 and 2.8, respectively P = 0.002) and in stratum functionalis in the ESP (7 and 3.2, respectively P = 0.008)., Limitations, Reasons for Caution: The protein expression of vascular EC markers and ECM components was assessed using a semi-quantitative approach in both straight and spiral arterioles. In our hospital, HMB is determined by subjective criteria and levels of blood loss were not assessed., Wider Implications of the Findings: Variation in the protein expression pattern between the four EC markers highlights the importance of choice of EC marker for investigation of endometrial vessels. Differences in expression of the different EC markers may reflect developmental stage dependent expression of EC markers in endometrial vessels, and their altered expression in HMB may reflect dysregulated vascular development. This hypothesis is supported by altered expression of ECM proteins within endometrial vessel walls, as well as our previous data showing a dysregulation in VSMC contractile protein expression in the endometrium of women with HMB. Taken together, these data support the suggestion that HMB symptoms are associated with weaker vascular structures, particularly in the LSP of the menstrual cycle, which may lead to increased and extended blood flow during menstruation., Study Funding/competing Interest(s): This study was funded by Wellbeing of Women (RG1342) and Newcastle University. There are no competing interests to declare., Trial Registration Number: Not applicable.

Introduction: Adenomyosis is defined as the presence of endometrial glands and stroma within the myometrium. The true prevalence is unknown and has been reported to range from 1 to 70%. It has a significantly negative impact on women's quality of life, causing abnormal uterine bleeding, dysmenorrhea, and chronic pelvic pain. The definitive treatment for adenomyosis is hysterectomy, although it does not contemplate patients who wish to preserve their fertility. The aim of this paper is to discuss the latest evidence on the surgical techniques for the treatment of adenomyosis published in medical-scientific databases., Method: A comprehensive literature search for articles published from 1996 to 2017 related to surgery for adenomyosis was made in Pubmed, Medline, the Cochrane Library, and Google Scholar, in English, by the following MeSH terms: adenomyosis, surgery, pathogenesis, dysmenorrhea and infertility., Results: There is extensive evidence on several surgical approaches for the improvement of adenomyosis-related symptoms; however, there is no robust evidence that they are effective for infertility., Conclusion: The management of adenomyosis is quite complex and controversial. Complications after extensive uterine reconstruction, such as uterine rupture, should be considered and discussed with the patient. There are still limited data to support surgery effectiveness, especially for infertility, and further well-designed studies are required.

Objectives: The primary aim of this systematic review was to ascertain whether ultrasound signs suggestive of abnormally invasive placenta (AIP) are present in the first trimester of pregnancy. Secondary aims were to ascertain the strength of association and the predictive accuracy of such signs in detecting AIP in the first trimester., Methods: An electronic search of MEDLINE, EMBASE, CINAHL and Cochrane databases (2000-2016) was performed. Only studies reporting on first-trimester diagnosis of AIP that was subsequently confirmed in the third trimester either during operative delivery or by pathological examination were included. Meta-analysis of proportions, random-effects meta-analysis and hierarchical summary receiver-operating characteristics curve analysis were used to analyze the data., Results: Seven studies, involving 551 pregnancies at high risk of AIP, were included. At least one ultrasound sign suggestive of AIP was detected in 91.4% (95% CI, 85.8-95.7%) of cases with confirmed AIP. The most common ultrasound feature in the first trimester of pregnancy was low implantation of the gestational sac close to a previous uterine scar, which was observed in 82.4% (95% CI, 46.6-99.8%) of cases. Anechoic spaces within the placental mass (lacunae) were observed in 46.0% (95% CI, 10.9-83.7%) and a reduced myometrial thickness in 66.8% (95% CI, 45.2-85.2%) of cases affected by AIP. Pregnancies with a low implantation of the gestational sac had a significantly higher risk of AIP (odds ratio, 19.6 (95% CI, 6.7-57.3)), with a sensitivity and specificity of 44.4% (95% CI, 21.5-69.2%) and 93.4% (95% CI, 90.5-95.7%), respectively., Conclusions: Ultrasound signs of AIP can be present during the first trimester of pregnancy, even before 11 weeks' gestation. Low anterior implantation of the placenta/gestational sac close to or within the scar was the most commonly seen early ultrasound sign suggestive of AIP, although its individual predictive accuracy was not high. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Study Question: Does the use of a vascular contrast agent facilitate earlier detection of maternal flow to the placental intervillous space (IVS) in the first trimester of pregnancy?, Summary Answer: Microvascular filling of the IVS was demonstrated by contrast-enhanced ultrasound from 6 weeks of gestation onwards, earlier than previously believed., What Is Known Already: During placental establishment and remodeling of maternal spiral arteries, endovascular trophoblast cells invade and accumulate in the lumen of these vessels to form 'trophoblast plugs'. Prior evidence from morphological and Doppler ultrasound studies has been conflicting as to whether the spiral arteries are completely plugged, preventing maternal blood flow to the IVS until late in the first trimester., Study Design, Size, Duration: Uteroplacental flow was examined across the first trimester in human subjects given an intravenous infusion of lipid-shelled octofluoropropane microbubbles with ultrasound measurement of destruction and replenishment kinetics. We also performed a comprehensive histopathological correlation using two separately archived uteroplacental tissue collections to evaluate the degree of spiral artery plugging and evaluate remodeling of the upstream myometrial radial and arcurate arteries., Participants/materials, Setting, Methods: Pregnant women (n = 34) were recruited in the first trimester (range: 6+3 to 13+6 weeks gestation) for contrast-enhanced ultrasound studies with destruction-replenishment analysis of signal intensity for assessment of microvascular flux rate. Histological samples from archived in situ (Boyd Collection, n = 11) and fresh first, second, and third trimester decidual and post-hysterectomy uterine specimens (n = 16) were evaluated by immunohistochemistry (using markers of epithelial, endothelial and T-cells, as well as cell adhesion and proliferation) and ultrastructural analysis., Main Results and the Role of Chance: Contrast agent entry into the IVS was visualized as early as 6+3 weeks of gestation with some variability in microvascular flux rate noted in the 6-7+6 week samples. Spiral artery plug canalization was observed from 7 weeks with progressive disintegration thereafter. Of note, microvascular flux rate did not progressively increase until 13 weeks, which suggests that resistance to maternal flow in the early placenta may be mediated more proximally by myometrial radial arteries that begin remodeling at the end of the first trimester., Limitations Reasons for Caution: Gestational age was determined by crown-rump length measurements obtained by transvaginal ultrasound on the day of contrast-enhanced imaging studies, which may explain the variability in the earliest gestational age samples due to the margin of error in this type of measurement., Wider Implications of the Findings: Our comprehensive in situ histological analysis, in combination with the use of an in vivo imaging modality that has the sensitivity to permit visualization of microvascular filling, has allowed us to reveal new evidence in support of increasing blood flow to the IVS from 6 weeks of gestation. Histologic review suggested the mechanism may be blood flow through capillary-sized channels that form through the loosely cohesive 'plugs' by 7 weeks gestation. However, spiral artery remodeling on its own did not appear to explain why there is significantly more blood flow at 13 weeks gestation. Histologic studies suggest it may be related to radial artery remodeling, which begins at the end of the first trimester., Study Funding/competing Interest(s): This project was supported by the Oregon Health and Science University Knight Cardiovascular Institute, Center for Developmental Health and the Struble Foundation. There are no competing interests., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Study Question: Do platelets play any role in the development of adenomyosis?, Summary Answer: As in endometriosis, adenomyotic lesions show significantly increased platelet aggregation, increased expression of transforming growth factor (TGF)-β1, phosphorylated Smad3, markers of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), and smooth muscle metaplasia (SMM), in conjunction with increased fibrosis as compared with normal endometrium., What Is Known Already: Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis. SMM is universally seen in endometriosis and also in adenomyosis, and is correlated positively with the extent of fibrosis. However, there has been no published study on the role of platelets in fibrogenesis in adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which suggests the involvement of platelets and their possible roles in fibrogenesis., Study Design, Size, Duration: Cross-sectional studies of ectopic endometrial and control endometrial tissue samples from three sets of women with and without adenomyosis (n= 34 and 20, 12 and 10, and 8 and 8, respectively) were carried out from 2014 to 2015., Participants/materials, Setting, Methods: Immunohistochemistry analysis of ectopic endometrial tissues from women with (n= 34) and without (n= 20) adenomyosis with respect to biomarkers of EMT, FMT and highly differentiated smooth muscle cells as well as TGF-β1, phosphorylated Smad3, markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits. Masson trichrome staining, Van Gieson staining and Pico-Sirius staining were performed to evaluate and quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. In addition, CD42b-positive platelets in ectopic (n= 12) and control (n= 10) endometrium were counted by confocal microscopy and compared. The protein expression levels of TGF-β1 and phosphorylated Smad3 in both ectopic (n= 8) and control (n= 8) endometrium were measured by western blot analysis. Immunofluorescent staining of both platelets and hepatocyte growth factor (HGF) was also performed for adenomyotic tissue samples (n= 10)., Main Results and the Role of Chance: Adenomyotic lesions had a significantly higher extent of platelet aggregation and increased staining for TGF-β1 and phosphorylated Smad3 (both P-values <0.001 versus control). In addition, E-cadherin staining was decreased while vimentin staining in adenomyotic epithelial cells was increased, along with increased staining of proliferating cell nuclear antigen, vascular endothelial growth factor and CD31 (all P-values <0.001), markers of proliferation and angiogenesis. Staining for α-SMA, a marker for myofibroblast, desmin, smooth muscle myosin heavy chain and oxytocin receptor was significantly increased in adenomyotic lesions versus control, concomitant with increased staining of collagen I and lysyl oxidase (all P-values <0.001). Histochemistry analysis indicates that the extent of fibrosis is high in adenomyotic lesions (P < 0.001), and the extent appeared to correlate negatively with the microvessel density (P < 0.05). PR-B staining was significantly decreased in adenomyotic lesion as compared with control endometrium (P < 0.001). Platelets and HGF were co-localized mostly in the stromal component of adenomyotic lesions, near the glandular epithelium., Limitations, Reasons for Caution: The results are limited by the cross-sectional nature of the study and the use of histochemistry and immunohistochemistry analyses only, but nonetheless is a validation of our previous finding in mouse experiments., Wider Implications of the Findings: The data presented are consistent with the notion that platelet-induced activation of the TGF-β/Smad signaling pathway may be a driving force in EMT, FMT and SMM in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and, as such, platelets play critical roles in the development of adenomyosis by promoting proliferation, angiogenesis, increasing ECM deposits, and SMM, resulting in fibrosis. Platelets may also be involved in uterine hyperactivity and myometrial hyperinnervation. Our results provide one explanation as to why adenomyosis is a challenge for medical treatment, and shed new light onto the pathophysiology of adenomyosis., Study Funding/competing Interests: Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Uterine leiomyomata present major problem for females. Although they are benign tumors their frequency is associated with many symptoms like infertility, abdominal pain, menorrhagia. Authors based on their own morphological studies and review of the literature try to indicate main factors causing angiogenesis within leiomyomata and its influence on tumor growth. The strongest proangiogenic factor seems to be hypoxia, which stimulates up- and down-regulation of numerous genetically determined substances. Also mechanical pressure acting upon newly growing vessels is one of the factors which may determine formation of so called "vascular pseudocapsule" around the lesion.

Purpose: We aimed to compare polyvinyl alcohol (PVA) particles with calibrated superparamagnetic iron oxide (SPIO) nanoparticle-loaded chitosan microspheres in a rabbit model, specifically regarding the relative distribution of embolic agents within the uterus based on magnetic resonance imaging (MRI) and pathological evaluation., Methods: Twelve New Zealand white rabbits underwent uterine artery embolization using either standard PVA particles (45-150 µm or 350-500 µm) or calibrated SPIO-embedded chitosan microspheres (45-150 µm or 300-500 µm). MRI and histopathological findings were compared one week after embolization., Results: Calibrated SPIO-loaded chitosan microspheres 45-150 µm in size were detected on T2-weighted images. On histological analysis, calibrated SPIO-embedded chitosan microspheres were found in both myometrium and endometrium, whereas PVA particles were found only in the perimyometrium or extrauterine fat pads. A proportional relationship was noted between the calibrated SPIO-embedded chitosan microsphere size and the size of the occluded artery., Conclusion: Calibrated SPIO-embedded chitosan microspheres induced greater segmental arterial occlusion than PVA particles and showed great potential as a new embolic material. SPIO-embedded chitosan microspheres can be used to follow distribution of embolic particles through MRI studies.

Expression and function of the follicle-stimulating hormone receptor (FSHR) in females were long thought to be limited to the ovary. Here, however, we identify extragonadal FSHR in both the human female reproductive tract and the placenta, and test its physiological relevance in mice. We show that in nonpregnant women FSHR is present on: endothelial cells of blood vessels in the endometrium, myometrium, and cervix; endometrial glands of the proliferative and secretory endometrium; cervical glands and the cervical stroma; and (at low levels) stromal cells and muscle fibers of the myometrium. In pregnant women, placental FSHR was detected as early as 8-10 wk of gestation and continued through term. It was expressed on: endothelial cells in fetal portions of the placenta and the umbilical cord; epithelial cells of the amnion; decidualized cells surrounding the maternal arteries in the maternal decidua; and the stromal cells and muscle fibers of the myometrium, with particularly strong expression at term. These findings suggest that FSHR expression is upregulated during decidualization and upregulated in myometrium as a function of pregnancy. The presence of FSHR in the placental vasculature suggests a role in placental angiogenesis. Analysis of genetically modified mice in which Fshr is lacking in fetal portions of the placenta revealed adverse effects on fetoplacental development. Our data further demonstrate FSHB and CGA mRNAs in placenta and uterus, consistent with potential local sources of FSH. Collectively, our data suggest heretofore unappreciated roles of extragonadal FSHR in female reproductive physiology., (© 2014 by the Society for the Study of Reproduction, Inc.)

Obese women (body mass index ≥30 kg/m(2)) are at greater risk than normal weight women of pregnancy complications associated with maternal and infant morbidity, particularly the development of cardiovascular disease and metabolic disorders in later life; why this occurs is unknown. Nonpregnant, obese individuals exhibit systemic vascular endothelial dysfunction. We tested the hypothesis that obese pregnant women have altered myometrial arterial function compared to pregnant women of normal (18-24 kg/m(2)) and overweight (25-29 kg/m(2)) body mass index. Responses to vasoconstrictors, U46619 (thromboxane mimetic) and arginine vasopressin, and vasodilators, bradykinin and the nitric oxide donor sodium nitroprusside, were assessed by wire myography in myometrial arteries from normal weight (n = 18), overweight (n = 18), and obese (n = 20) women with uncomplicated pregnancies. Thromboxane-prostanoid receptor expression was assessed using immunostaining in myometrial arteries of normal weight and obese women. Vasoconstriction and vasodilatation were impaired in myometrial arteries from obese women with otherwise uncomplicated pregnancies. Disparate agonist responses suggest that vascular function in obese women is not globally dysregulated but may be specific to thromboxane and nitric oxide pathways. Because obesity rates are escalating, it is important to identify the mechanisms underlying impaired vascular function and establish why some obese women compensate for vascular dysfunction and some do not. Future studies are needed to determine whether central adiposity results in an altered endocrine milieu that may promote vascular dysfunction by altering the function of perivascular adipose tissue.

Failure to transform uteroplacental spiral arteries is thought to underpin disorders of pregnancy, including preeclampsia and fetal growth restriction (FGR). In this study, spiral artery remodeling and extravillous-cytotrophoblast were examined in placental bed biopsies from normal pregnancy (n = 25), preeclampsia (n = 22), and severe FGR (n = 10) and then compared with clinical parameters. Biopsies were immunostained to determine vessel wall integrity, extravillous-cytotrophoblast location/density, periarterial fibrinoid, and endothelium. Muscle disruption was reduced in myometrial spiral arteries in preeclampsia (P = 0.0001) and FGR (P = 0.0001) compared with controls. Myometrial vessels from cases with birth weight <5th percentile (P<0.001), abnormal uterine Doppler (P<0.01), abnormal umbilical artery Doppler (P<0.001), and preterm delivery (P<0.001) had less muscle destruction compared with >5th percentile. Fewer extravillous-cytotrophoblast surrounded both decidual and myometrial vessels in the normal group and preeclampsia group compared with the FGR group (P = 0.001). For myometrial vessels, the normal group contained more intramural extravillous-cytotrophoblast than in preeclampsia (P = 0.015). Decidual vessels in the FGR group had less fibrinoid deposition compared with controls (P = 0.013). For myometrial vessels, less fibrinoid was deposited in both the preeclampsia group (P = 0.0001) and the FGR group (P = 0.01) when compared with controls, and less fibrinoid was deposited in the preeclampsia group when compared with FGR group (P<0.001). Myometrial vessels obtained from birth weights <5th percentile had less periarterial fibrinoid than those with >5th percentile (P<0.02). A major defect in myometrial spiral artery remodeling occurs in preeclampsia and FGR that is linked to clinical parameters. Interstitial extravillous-cytotrophoblast is not reduced in preeclampsia but is increased in FGR.

Endothelial-dependent regulation of vascular tone occurs in part via protein kinase G1α-mediated changes in smooth muscle myofilament sensitivity to Ca(2+). Tissue-specific differences in PKG-dependent relaxation have been attributed to altered expression of myofilament-associated proteins that are substrates for PKG binding. These include the alternative splicing of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase to yield leucine zipper positive (LZ(+)) and negative (LZ(-)) isovariants, with the former being required for PKG-mediated relaxation, and/or altered expressions of telokin, vasodilator-stimulated phosphoprotein (VASP) or heat shock protein Hsp20. During human pregnancy the uterine and placental circulations remain distinct entities and, as such, their mechanisms of vascular tone regulation may differ. Indeed, the sensitivity of myometrial arteries to endothelial-dependent agonists has been suggested to be greater than that of placental arteries. We tested the hypothesis that this was related to tissue-specific changes in PKG-mediated myofilament Ca(2+)-desensitization and/or the expressions of PKG-interacting myofilament-associated proteins. Permeabilized human placental and myometrial arteries were constricted with maximal activating Ca(2+) (pCa 4.5), or sub-maximal Ca(2+) (pCa 6.7) and the thrombane mimetic U46619, and exposed to 8-Br-cGMP. In each case, relaxation was significantly greater in myometrial arteries (e.g. relaxation in pCa 4.5 to 8-Br-cGMP was 49 ± 9.7%, n = 7) than placental arteries (relaxation of 23 ± 6.6%, n = 6, P < 0.05). MYPT1 protein levels, or MYPT1 LZ(+)/LZ(-) mRNA ratios, were similar for both artery types. Of other proteins examined, only Hsp20 expression was significantly elevated in myometrial arteries than placental arteries. These results demonstrate that the reduced human placental artery relaxation to PKG stimulation lies partly at the level of myofilament (de)activation and may be related to a lower expression of Hsp20 than in myometrial arteries.

Study Question: What are the in vitro effects of estrogen receptor β (ERβ) activation on the function of endothelial cells (ECs) from different vascular beds: human endometrial ECs (HEECs; endometrium), uterine myometrial microvascular ECs (UtMVECs; myometrium) and human umbilical vein ECs (HUVECs)?, Summary Answer: Studies conducted in vitro demonstrate that the ERβ agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) has EC type-specific effects on patterns of gene expression and network formation. Identification of a key role for the transcription factor Sp1 in ERβ-dependent signaling in uterine ECs offers new insights into cell-specific molecular mechanisms of estrogen action in the human uterus., What Is Known Already: Estrogens, acting via ERs (ERα and ERβ), have important, body-wide impacts on the vasculature. The human uterus is an estrogen target organ, the endometrial lining of which exhibits physiological, cyclical angiogenesis. In fixed tissue sections, human endometrial ECs are immunopositive for ERβ., Study Design, Size, Duration: Cells were treated with a vehicle control or the ERβ agonist, DPN, for 2 h or 24 h (n = 5) followed by gene expression analysis. Functional assays were analyzed after a 16 h incubation with ligand (n = 5)., Participant/materials, Setting, Methods: Analysis of DPN-treated ECs using Taqman gene array cards focused on genes involved in angiogenesis and inflammation identified cell type-specific ERβ-dependent changes in gene expression, with validation using qPCR and immunohistochemistry. Molecular mechanisms involved in ERβ signaling were investigated using bioinformatics, reporter assays, immunoprecipitation, siRNA and a specific inhibitor blocking Sp1-binding sites. The endometrium and myometrium from women with regular menses were used to validate the protein expression of candidate genes., Main Results and the Role of Chance: HEECs and UtMVECs were ERβ+/ERα-. Treatment of ECs with DPN had opposite effects on network formation: a decrease in network formation in HEECs (P ≤ 0.001) but an increase in UtMVECs (P ≤ 0.05). Genomic analysis identified opposite changes in ERβ target gene expression with only three common transcripts (HEY1, ICAM1, CASP1) in all three ECs; a unique profile was observed for each. An important role for Sp1 was identified, consistent with the regulation of ERβ target genes via association with the transcription factor ('tethered' mechanism)., Limitations, Reasons for Caution: The study was mainly carried out in vitro using ECs of which one type was immortalized. Although the analysis of the protein expression of candidate genes was carried out using intact tissue samples from patients, investigations into in vivo angiogenesis were not carried out., Wider Implications of the Findings: These results have implications for our understanding of the mechanisms responsible for ERβ-dependent changes in EC gene expression in hormone-dependent disorders.

The pseudocapsule (PC) of the uterine leiomyoma (UL) is an anatomic entity that surrounds the myoma separating it from the myometrium (UM). Although a number of microarray experiments have identified differences in gene expression profile in the UL when compared with the UM, there is a lack of systematic studies on the PC. In this study, quantitative RT-PCR analysis was performed on 18 matched PC, UL and UM specimens and results showed that the PC displays a specific gene expression profile. The low expression level of insulin-like growth factor (IGF-2), a fibroid specific marker, that we found in the PC and the UM when compared with the UL, clearly indicates that the PC is in structural continuity with the UM. However, the significant increase in endoglin expression level in PC with respect to the UL and UM indicates that an active neoangiogenesis is present in PC. Conversely, other angiogenic factors such as von Willebrand factor (vWF) and vascular endothelial growth factor A (VEGF-A) seem to have little influence on the PC angiogenesis. Because the endoglin is preferentially expressed in proliferating endothelial cells, whereas the vWF and VEGF-A are preferentially expressed in preexisting endothelial cells, our idea is that the angiogenic activity in the PC is linked to wound healing. The angiogenic activity is also sustained by intermediate expression level of cystein-rich angiogenesis inducer 61, connective tissue growth factor and collagen 4α2 genes all involved in the neoangiogenesis, that we detected in the PC. Taken together our data demonstrate that the specific expression pattern observed in the PC could be the response of the uterine wall's smooth cells to the tension imposed by the tumor. As a consequence, a neovascular structure is generated involving regenerative processes. For these reasons, we suggest that the laparoscopic intracapsular myomectomy (LIM), a new surgical technique that preserves the PC during the UL removal, should always be preferred, to favor a faster and proper uterine healing.

A 71-year-old woman presents with acute onset abdominal pain with sepsis. Initial workup with an abdominal CT scanning revealed intraperitoneal air with an enlarged uterus and thickened small bowel loops. Haemodynamic instability with sepsis prompted urgent laparotomy. At laparotomy, spontaneous perforation of the uterus was identified. The cause was due to infarction of the myometrium. This occurred on a background of not having any previous instrumentation of the uterus.

Purpose: This study aimed to examine the role of local uterine contractions during pregnancy depicted as asymmetric thickening of the myometrium ultrasonographically., Methods: 419 pregnant women at 12-21 weeks of gestation who visited our outpatient department were studied. These subjects visited either for regular antenatal examinations or because of ill-defined subjective symptoms. Ultrasonographic examination was conducted to detect asymmetric thickening of the uterine myometrium. Blood flow in the region of myometrial thickening was studied by color Doppler imaging., Results: Among 419 subjects, 27.38 % (112/419) patients visited our outpatient department showed asymmetric thickening of myometrium. Since cervical changes or progression to labor occurred in none of the subjects, the reviewed symptoms were considered to be benign contractions. Many women with ill-defined symptoms showed asymmetric thickenings of the myometrium (73.75 % sensitivity and 84.32 % specificity). Myometrial thickening under the placenta tended to be associated with abundant blood flow (88.46 % sensitivity and 87.21 % specificity). This different pattern of the blood flow was considered to correlate to arcuate artery resistance but did not correlate to the severity of ill-defined symptoms. Among those patients having no clinical symptoms, 53 exhibited asymmetric thickening of the myometrium. This phenomenon might be the caution of ill-defined symptoms., Conclusion: Asymmetric thickening of the uterine myometrium during pregnancy represented the ill-defined symptoms. Different patterns of blood flow images at this local contraction did not correlate to the severity of these symptoms.

Aim: The main goal of this study was assessment of vascular structure of uterine leiomyomata localized between outer myometrium and endometrium., Materials and Methods: The study was carried out on thirty two human uteri collected upon autopsy. Vessels were injected with synthetic resin, next corroded and coated with gold, finally observed using scanning electron microscope. Next ten uteri were injected with acrylic emulsion and studies using immunohistochemical staining for von Willebrandt's factor., Results: Vascular structure of outer myometrial leiomyomata was quite similar to those observed in the middle of muscular layer of uterus, characterized by relatively dense 'vascular capsule', consisted of flattened vein, arterioles and capillaries., Conclusions: Structure of outer myometrial uterine leiomyomata was similar to those observed during growth within myometrium.

Myogenic tone (MT) is a primary modulator of blood flow in the resistance vasculature of the brain, kidney, skeletal muscle, and perhaps in other high-flow organs such as the pregnant uterus. MT is known to be regulated by endothelium-derived factors, including products of the nitric oxide synthase (NOS) and/or the cyclooxygenase (COX) pathways. We asked whether pregnancy influenced MT in myometrial arteries (MA), and if so, whether such an effect could be attributed to alterations in NOS and/or COX. MA (200-300 μm internal diameter, 2-3 mm length) were isolated from 10 nonpregnant and 12 pregnant women undergoing elective hysterectomy or cesarean section, respectively. In the absence of NOS and/or COX inhibition, pregnancy was associated with increased MT in endothelium-intact MA compared with MA from nonpregnant women (P < 0.01). The increase in MT was not due to increased Ca(2+) entry via voltage-dependent channels since both groups of MA exhibited similar levels of constriction when exposed to 50 mM KCl. NOS inhibition (N(ω)-nitro-L-arginine methyl ester, L-NAME) or combined NOS/COX inhibition (L-NAME/indomethacin) increased MT in MA from pregnant women (P = 0.001 and P = 0.042, respectively) but was without effect in arteries from nonpregnant women. Indomethacin alone was without effect on MT in MA from either nonpregnant or pregnant women. We concluded that MT increases in MA during human pregnancy and that this effect was partially opposed by enhanced NOS activity.

Background: The aim of this study was to visualise and describe the vasculature of the human uterine cervix., Material and Methods: The material for this study was obtained from women (age between 20 to 45 years) during autopsy. The material was collected not later than 24 h post-mortem. This study was performed using uteri from cadavers of menstruating nulliparas (33 uteri) and menstruating multiparas (27 uteri). Collected uteri were perfused via the afferent vessels with Mercox resin (for corrosion-casting and SEM assessment) or acrylic paint solution (light microscopy assessment). The research protocol was approved by the Jagiellonian University Ethics Committee (registry KBET/121/8/2007)., Results: In all cases bilateral cervical branches (1-4), originating from the uterine artery, were found. Both in the vaginal and supravaginal parts of the cervix, four distinct vascular zones were found. In the pericanalar zone ran small veins, responsible for draining the mucosal capillaries. Both in the muscular layer, as well as in the pericanalar zone, arterioles, and venules passed close to each other, often adjoining., Conclusions: This study does not confirm the existence of a single cervicovaginal artery, but shows that the vascular supply of the cervix comes from several vessels. It also introduces the idea of two systems, responsible for draining blood from the mucosal capillaries. Neither assessment in light microscopy nor in SEM revealed any differences between multiparas and nulliparas, regarding the vascular architecture of the cervix.

Emerging evidence suggests that early embryo implantation is a more active maternal process than hitherto appreciated, involving active encapsulation of the implanting blastocyst by maternal decidual cells and coordinated changes in the underlying inner myometrium, known as the junctional zone. These concepts raise the possibility that early ultrasound markers predictive of adverse pregnancy outcome could be identified. In this review we assess the role of ultrasound in predicting the likelihood of different pregnancy outcomes and highlight potential novel markers that could be tested., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Preeclampsia and fetal growth restriction are responsible for the majority of maternal and perinatal morbidity and mortality associated with complicated pregnancies. Although their etiologies are complex and multifactorial, both are associated with increased uterine artery resistance. Sildenafil citrate is able to rescue the dysfunction observed ex vivo in uterine arteries of women with preeclampsia. The ability of sildenafil citrate to increase uterine artery vasodilation, thereby decreasing uterine artery resistance and, hence, ameliorated preeclampsia and fetal growth restriction, was tested in a mouse model of preeclampsia, the catechol-O-methyl transferase knockout mouse (COMT(-/-)). COMT(-/-) and C57BL/6J mice were treated (0.2 mg/mL in drinking water, n=6-12) from gestational day 12.5 to 18.5. Measures of pup growth, including body weight, crown/rump length, and abdominal circumference, were reduced in COMT(-/-) mice; this was normalized after treatment with Sildenafil. COMT(-/-) mice also demonstrated abnormal umbilical Doppler waveforms, including reverse arterial blood flow velocity. This was normalized after treatment with Sildenafil. Abnormal uterine artery Doppler waveforms were not demonstrated in COMT(-/-) mice, although ex vivo responses of uterine arteries to phenylephrine were increased; moreover, treatment with Sildenafil did improve ex vivo sensitivity to an endothelium-dependent vasodilator. The data presented here demonstrate that Sildenafil can rescue pup growth and improve abnormal umbilical Doppler waveforms, providing support for a potential new therapeutic strategy targeting fetal growth restriction.

Aims: Alternative transcription and splicing of the allograft inflammatory factor-1 (AIF-1) gene results in the expression of two different proteins: AIF-1 and interferon responsive transcript-1 (IRT-1).  Here, we explore the impact of AIF-1 and IRT-1 on vascular smooth muscle cell (VSMC) activation and neointima formation, the mechanisms underlying their alternative splicing, and associations of AIF-1 and IRT-1 mRNA with parameters defining human atherosclerotic plaque phenotype., Methods and Results: Translation of AIF-1 and IRT-1 results in different products with contrasting cellular distribution and functions. Overexpression of AIF-1 stimulates migration and proliferation of human VSMCs, whereas IRT-1 exerts opposite effects. Adenoviral infection of angioplasty-injured rat carotid arteries with AdAIF-1 exacerbates intima hyperplasia, whereas infection with AdIRT-1 reduces neointima. Expression of these variants is modulated by changes in nuclear factor of activated T-cells (NFAT) activity.  Pharmacological inhibition of NFAT or targeting of NFATc3 with small interfering RNA (siRNA) lowers the AIF-1/IRT-1 ratio and favours an anti-proliferative outcome.  NFAT acts as a repressor on the IRT-1 transcriptional start site, which is also sensitive to interferon-γ stimulation. Expression of AIF-1 mRNA in human carotid plaques associates with less extracellular matrix and a more pro-inflammatory plaque and plasma profile, features that may predispose to plaque rupture. In contrast, expression of IRT-1 mRNA associates with a less aggressive phenotype and less VSMCs at the most stenotic region of the plaque., Conclusion: Inhibition of NFAT signalling, by shifting the AIF-1/IRT-1 ratio, may be an attractive target to regulate the VSMC response to injury and manipulate plaque stability in atherosclerosis.

Objective: To clarify, whether uterine endothelial proliferation could be regulated via an autocrine estrogen producing mechanism or direct actions of testosterone., Design: In vitro study., Setting: Tertiary care facility., Patient(s): Human myometrial tissue obtained from 40 women undergoing hysterectomy without further intrauterine pathology., Intervention(s): Cell culture, proliferation assay and CYP19 activity assay on human myometrial endothelial cells treated with testosterone, estradiol, letrozole, flutamide, PD98059, MG-132 alone or in combination., Main Outcome Measure(s): We analyzed whether aromatase is expressed in human myometrial microvascular endothelial cells (HMMECs) and whether it affects proliferation and converts androgens to estrogens. In addition, we aimed to define whether or not T could have a direct capability to affect HMMEC proliferation., Result(s): Using quantitative real-time PCR and Western analysis, primary passage four HMMECs were shown to express low levels of aromatase mRNA and protein, respectively. However, HMMECs were unable to convert radioactively labeled 3∗H-1β-androstenedione to estrogen. Pharmacologic doses of T (10(-6) and 10(-4) M) increased HMMEC proliferation, assessed through a bromodeoxyuridine ELISA. This effect of T on proliferation could not be blocked after pretreatment of cells with the aromatase inhibitor letrozole. In addition, HMMECs were found to express androgen receptors (ARs), and the AR antagonist flutamide abolished T-dependent proliferation. T was shown to increase AR protein levels, which was due to T-dependent receptor stabilization and not activation of gene transcription., Conclusion(s): We conclude that myometrial endothelial proliferation is not regulated through myometrial endothelial estrogen production. However, pharmacologic doses of T increase myometrial endothelial proliferation through a receptor-dependent and -stabilizing mechanism., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This ex vivo study focuses on the mechanisms of endothelium-dependent dilatation in the uterine circulation of normal pregnancy (n = 12) and in women with preeclampsia (n = 12). Arteries (internal diameter, ∼250 μm) isolated by myometrial biopsy from women undergoing planned cesarean delivery or delivery as a result of the deterioration of preeclampsia were studied using a wire myograph. Bradykinin-induced dilatation was assessed in the presence and/or absence of pharmacological inhibitors to determine the contribution of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), as well as that of EDHF-mediated pathways such as myoendothelial gap junctions (MEGJs) and products of arachidonic acid, H(2)O(2) and cytochrome P450 2C9 (CYP2C9). Transmission electron microscopy was used to visualize morphological prerequisites for MEGJs. In normal pregnancy, EDHF through MEGJs appeared to be a predominant mediator conferring endothelium-dependent relaxation in small myometrial arteries. In preeclampsia, bradykinin-induced relaxation was reduced via compromised EDHF-type responses, in which the contribution of MEGJs became negligible. The attenuated role of MEGJs to endothelium-dependent relaxation was partly compensated through the contribution of H(2)O(2) or other endothelium-derived relaxing factors. CYP2C9 products of arachidonic acid had no effect on EDHF-type relaxation in arteries of women with normal pregnancy or with preeclampsia. We suggest that EDHF-type responses via MEGJs are primarily targeted in small myometrial arteries in women with preeclampsia. This could significantly contribute to the impaired uteroplacental blood flow in this disorder.

Proliferation, differentiation, and apoptosis are three major processes by which the pregnant uterus maintains homeostasis to accommodate the growing fetus. We demonstrated previously that caspase activation in the pregnant rat myometrium at midgestation coincides with the transition from uterine hyperplasia to hypertrophy. We hypothesized that this transition was induced by stasis of myometrial blood flow (and subsequent hypoxia/ischaemia insult) resulting from acute myometrial stretch induced by a growing embryo. Therefore, we measured the expression of active caspase 3 and two hypoxia markers (transcription factor HIF1A and pimonidazole hydrochloride) in pregnant rat myometrium. To investigate the effect of gravidity we used unilaterally pregnant rats. Caspase 3 was activated only in the gravid horn of the unilaterally pregnant animals on Gestational Days 12-15. This activation was associated with high levels of HIF1A and pimonidazole immunostaining, which were limited to the circular myometrial layer of the gravid horn, indicative of hypoxia within this tissue. To isolate the effect of myometrial stretch applied by the growing fetus, we inserted an expandable polymer tube (intra-uterine expandable tube [IUET]) into the empty horn of Day 13 and Day 20 unilaterally pregnant rats. Tissue was collected 2, 14, and 24 h later. In the IUET-stretched empty horn, cleaved caspase 3 was activated at midgestation (Day 14), but not at late gestation (Day 21). We speculate that hypoxia resulting from mechanical stretch may activate caspase 3 within the pregnant myometrium only in the context of a specific endocrine environment.

While there is a growing realization that the origins of major obstetrical complications associated with defective deep placentation, such as pre-term labour, fetal growth restriction and pre-eclampsia, may lie in the very early pregnancy events, the underlying mechanisms are not understood. Impaired deep placentation is foremost a vascular pathology, characterized by a lack of endovascular trophoblast invasion and remodelling of a segment of the spiral arteries embedded within the inner myometrium of the uterus. Outside pregnancy, the inner myometrium represents a highly specialized, hormone-dependent structure, termed the junctional zone (JZ), which plays an integral part in the implantation process. The JZ changes with age and is disrupted in several reproductive disorders, such as endometriosis and adenomyosis, which in turn may account for the increased risk of adverse pregnancy outcome. Unlike the endometrium, the myometrial JZ is not readily accessible to biochemical or molecular studies, yet its structure and function can be assessed using imaging techniques, such as high-resolution ultrasound and magnetic resonance imaging. Thus, non-invasive assessment of the JZ prior to conception may turn out to be useful in identifying those women at risk of major obstetrical complications.

Cytochrome P-450 (CYP450) enzymes of the CYP2 and -4 family in humans metabolize arachidonic acid to generate bioactive epoxyeicosatrienenoic acids (EETs) and hydroxyeicosatetrenoic acids (HETEs). We report significantly higher levels of CYP 2J2 protein expression following the onset of labor (n = 6, P < 0.05), implying increased EET-generating capacity within the uterus. Myometrial relaxation to 8,9-EET and 5,6-EET was observed, with the latter being inhibited by preincubation with 1 muM paxilline and is supported by whole cell recordings showing a modest effect of 5,6-EET on myometrial outward-current density (n = 4, P < 0.05). Only 5,6-EET of the EETs tested affected vascular reactivity (n = 6). Both 12- and 20-HETE (n = 5-6) caused vasoconstriction of partially depolarized blood vessels, with glibenclamide (n = 5) enhancing the effect of 12-HETE alone. Our findings signify a role for CYP2C9/19, -2J2, and -4A11/22 in late pregnancy, possibly related to the synthesis of lipid metabolites and downstream effects on vascular remodeling in the term pregnant uterus. The presence of CYP4A11/22 and their resultant procontractile metabolites could argue either a role in the control and initiation of labor and/or modification of the vascular delivery system to influence blood flow to the laboring uterus. The differential effects of the EETs and HETEs in the pregnant human uterus identify the CYP pathway as a novel modulator of myometrial and vascular physiology during late pregnancy.

Objective: We aimed to compare the diagnostic performance of transvaginal sonography (TVS), magnetic resonance imaging (MRI), and intraoperative frozen section in the assessment of myometrial invasion and to evaluate intratumoral blood flow in any myometrial invasion with transvaginal Color Doppler ultrasonography (TV-CDU)., Methods: This prospective study included 64 women consecutively diagnosed with endometrial carcinoma. The subjects were evaluated by TVS, MRI, and TV-CDU by 2 radiologists with a special training in gynecology. Intraoperatively, a frozen section was obtained and processed for interpretation by a blinded pathologist. Sensitivity, specificity, negative, and positive predictive values were calculated for each imaging modality and frozen section with regard to assessment of myometrial invasion. The intratumoral blood flow was evaluated by TV-CDU., Results: Transvaginal sonography, MRI, and frozen section showed no statistical significant differences in overall diagnostic performance for the preoperative and intraoperative assessment of any myometrial invasion, although frozen section seemed to be slightly superior to the imaging techniques. The positive rate of intratumoral blood flow was higher in deep myometrial invasion, but statistical significance was not obtained. The mean value of resistance index was significantly lower in the cases with deep myometrial invasion., Conclusions: Transvaginal sonography with concomitant TV-UCD is low-cost, easily performed, and repeated technique for particularly deep myometrial invasion. Because of its high costs and time-consuming, MRI may be recommended in the cases with poor quality of TVS. Because depending solely on imaging methods could lead to insufficient treatment schedules, intraoperative frozen section should also be performed for myometrial assessment.

Objectives: Myometrial contractions are one of the most important aspects of effective labor. For cells within the myometrium to work efficiently they need to be well oxygenated and this requires an adequate blood supply. This study used quantitative three-dimensional (3D) power Doppler angiography to calculate the percentage change in myometrial blood flow during a relaxation-contraction-relaxation cycle of active labor., Methods: Transabdominal 3D power Doppler ultrasound imaging was used to acquire volumetric data during the first stage of spontaneous labor in 20 term, nulliparous women. 3D datasets were acquired during a single cycle of uterine relaxation, contraction and subsequent relaxation for each subject. The resultant datasets were analyzed independently by two investigators on two occasions using Virtual Organ Computer-aided AnaLysis to define a volume of interest within the myometrium; the power Doppler signal within this volume was quantified to provide 3D indices of vascularity: vascularization index (VI), flow index (FI) and vascularization flow index (VFI). The percentage change in these indices, during a uterine contraction, was calculated from the baseline value during the initial uterine relaxation phase (taken as a maximum of 100%)., Results: Myometrial blood flow fell significantly during the uterine contraction and returned during the subsequent relaxation phase of the cycle (P < 0.001 for VI and VFI, P = 0.002 for FI). From the initial baseline relaxation value, VI dropped to 43.9%, FI to 85.5% and VFI to 40.8% during uterine contraction, and returned to 86.7%, 98.1% and 89.1%, respectively, during the subsequent relaxation. The intraclass correlation coefficients in blood flow measurements of 0.982-0.999 between the two investigators were indicative of good interobserver reliability., Conclusions: This study confirms that myometrial perfusion, as measured by quantitative 3D power Doppler angiography, significantly falls during uterine contractions, returns during the subsequent relaxation phase, and can be quantified reliably from stored datasets. Further work is now required to establish clinical applicability for this non-invasive investigation., ((c) 2009 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To report a case of successful treatment of a heterotopic cervical pregnancy from IVF-embryo transfer and intracytoplasmic sperm injection (ICSI) that resulted in uterine varices at the cervical site., Design: Case report., Setting: Tertiary university clinical center., Patient(s): A 34-year-old with a history of infertility associated with oligospermia who developed a heterotopic cervical pregnancy diagnosed at 7 weeks gestation., Intervention(s): Transvaginal ultrasound (TVS)-guided aspiration of the cervical pregnancy; preoperative placement of bilateral hypogastric artery occlusion balloons; cesarean section., Main Outcome Measure(s): Successful delivery of intrauterine pregnancy; conservation of the uterus., Result(s): Successful termination of the cervical site pregnancy was achieved with TVS-guided aspiration. However, the pregnancy was then complicated by development of uterine varices at the cervical site noted on serial obstetric ultrasounds and magnetic resonance imaging (MRI). Successful management of the pregnancy required a multidisciplinary approach and preoperative placement of bilateral hypogastric artery occlusion balloons. A scheduled high fundal classic cesarean section at 37 weeks allowed for safe delivery of a healthy infant. Complete spontaneous resolution of the uterine varices was noted after the delivery., Conclusion(s): It is unclear whether residual ectopic tissue contributed to this later complication; however, it cannot be ignored that the locations of the aborted site and the prominence of dilated venous vasculature in this same location suggests a correlation. The interventions applied are reasonable conservative treatments of a cervical heterotopic pregnancy and a management strategy for uterine varices.

Endometrial tissue in the myometrium vessels space, whit no relation to menstrual period, is a rarely reported event. It is unknown if it is part of the natural history of ectopic localization of endometrial tissue or it is related to more or less aggressive behavior of endometriosis. This paper reports two cases: a 35- and 51-year-old women. The first one made suspect a clear cells adenocarcinoma undiagnosed before hysterectomy, because there were no endometrial glands in the myometrium vessels space, but only nest of stromal cells isolated, simulating thrombus of an invasive neoplasm. Since a wrong diagnosis affects the integral treatment of patients, differential diagnosis must be established in order to increase certainty.

The objectives of this study were to determine whether placental growth factor (PlGF) exerts a vasodilatory effect on rat uterine vessels (arcuate arteries and veins) and to examine regional differences in reactivity by comparing these responses to those of comparably sized mesenteric vessels. We also sought to examine and compare its effects on human uterine and subcutaneous vessels. All vessels were studied in vitro, under pressurized (rat) or isometric wire-mounted (human) conditions, and exposed to a range of PlGF concentrations. Inhibitors of nitric oxide and prostaglandin synthesis were included in an effort to understand the causal mechanism(s). In rat uterine arteries, the effects of receptor inhibition and activation using selective ligands for VEGFR-1 (PlGF) vs. VEGFR-2 (VEGF-E) were determined, and real-time RT-PCR was performed to evaluate the effect of pregnancy on relative abundance of VEGFR-1 and VEGFR-2 message in the vascular wall. PlGF was a potent vasodilator of all vessels studied, with greatest sensitivity observed in rat uterine arteries. Pregnancy significantly augmented dilator sensitivity to PlGF, and this effect was associated with selective upregulation of VEGFR-1 message in the pregnant state. The contribution of nitric oxide was appreciable in rat and human uterine arteries, with lesser effects in rat uterine veins and mesenteric arteries, and with no observable effect in human subcutaneous vessels. Based on these results, we conclude that PlGF is a potent vasodilator of several vessel types in both humans and rats. Its potency and mechanism vary with physiological state and vessel location and are mediated solely by the VEGFR-1 receptor subtype. Gestational changes in the uterine circulation suggest that this factor may play a role in modulating uterine vascular remodeling and blood flow during the pregnant state.

Maternal endothelial activation in pre-eclampsia is attributed to the release of unknown factors from a hypoperfused placenta. To further characterize these factors, we have used a serum-free placental villous explant culture model and investigated the effect of the liberated soluble factors produced on human endothelial cell cultures. Term placental villous explants from uncomplicated pregnancies were cultured for 4 days in 20, 6 or 1% O2 to mimic placental hyperoxia, normoxia and hypoxia. Medium collected from viable explants was applied to cultured human uterine microvascular endothelial cells. Medium conditioned by hypoxic explants caused a significant decrease in endothelial cell ATP levels and mitochondrial dehydrogenase activity, suggestive of a reduced metabolic rate. An additional reduction in mitochondrial membrane potential and increased endothelial cell death occurred as the oxygen concentration to which explants had been exposed decreased. Effects of the hypoxic explant medium were also seen ex vivo in a wire myography model of myometrial artery function, with increased vasoconstriction and attenuated vasodilation following exposure to hypoxic explant medium. These results suggest that hypoxia (1% O2) may stimulate the release of soluble factors from the placenta, which have an adverse effect on endothelial cell metabolism and mitochondrial integrity in vitro. These potentially pathogenic factors are now being characterized.

Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that has been implicated in cardiovascular disease. The objective of the present study was to determine the vasoactive effects and underlying mechanisms of S1P on adult human maternal arteries. The isometric tensions of the omental and myometrial arteries isolated from normal pregnant women at term were assessed in response to incremental doses of S1P in the presence or absence of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The putative involvement of Rho-associated kinases (ROCKs) in intact arteries and in those permeabilized with alpha-toxin, to study agonist-dependent calcium-sensitization, was assessed with the inhibitor Y27632. Real-time RT-PCR established the presence of mRNA encoding the S1P receptors (S1P(1) to (3)), previously known as endothelial differentiation gene receptors (EDG1, 3 and 5), in both artery types. S1P induced a dose-dependent increase in the isometric tension of all the arteries. Y27632 reduced constriction due to S1P in intact arteries and reduced S1P-induced sensitization of contraction to submaximal activating Ca(2+) in permeabilized arteries. L-NAME also modulated S1P vasoactive responses in a tissue-specific manner. Two subgroups of omental arteries were identified, one of which utilizes the NO pathway. In myometrial arteries, S1P evoked oscillatory constrictions, whereas pretreatment with L-NAME resulted in only tonic constrictions of unaltered peak magnitude. The prominent vasoactive actions of S1P in the maternal arteries of pregnant women are modulated by inhibitors of ROCKs and NO bioavailability. The subtle tissue-specific functional differences in the modulation of S1P actions by NO have important implications for vascular tone regulation by this bioactive circulatory metabolite during pregnancy.

Remodeling of the uterine spiral arteries during pregnancy transforms them from high to low resistance vessels that lack vasoconstrictive properties. This process is essential to meet the demand for increased blood flow imposed by the growing fetus. Loss of endothelial and smooth muscle cells (SMC) is evident in remodeled arteries but the mechanisms underlying this transformation remain unknown. This study investigated the hypothesis that fetal trophoblast invading from the placenta instigate remodeling by triggering cell death in vascular SMC. Specifically, a role for trophoblast-derived death inducing cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) was investigated. Expression of the activating TRAIL receptors R1 and R2 was detected by flow cytometry on human aortic SMC and by immunohistochemistry on spiral artery SMC. Recombinant human TRAIL induced human aortic SMC apoptosis, which was inhibited by antibodies against TRAIL-R1 or -R2. Perfusion of denuded spiral artery segments with recombinant human TRAIL also induced SMC apoptosis. Trophoblasts isolated from first trimester placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic SMC; apoptosis was significantly inhibited by a recombinant human TRAIL-R1:Fc construct. Trophoblast within the first trimester placental bed also expressed TRAIL. These data show that: 1) TRAIL causes SMC death; 2) trophoblast produce the apoptotic cytokine TRAIL; and 3) trophoblast induce SMC apoptosis via a TRAIL-dependent mechanism. We conclude that TRAIL produced by trophoblast causes apoptosis of SMC and thus may contribute to SMC loss during spiral artery remodeling in pregnancy.

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [(35)S]methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.