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Background: The mechanisms responsible for menstrual pain are poorly understood. However, dynamic, noninvasive pelvic imaging of menstrual pain sufferers could aid in identifying therapeutic targets and testing novel treatments., Objective: To study the mechanisms responsible for menstrual pain, we analyzed ultrasonographic and complementary functional magnetic resonance imaging parameters in dysmenorrhea sufferers and pain-free controls under multiple conditions., Study Design: We performed functional magnetic resonance imaging on participants with and those without dysmenorrhea during menses and outside menses. To clarify whether regional changes in oxygen availability and perfusion occur, functional magnetic resonance imaging R2∗ measurements of the endometrium and myometrium were obtained. R2∗ measurements are calculated nuclear magnetic resonance relaxation rates sensitive to the paramagnetic properties of oxygenated and deoxygenated hemoglobin. We also compared parameters before and after an analgesic dose of naproxen sodium. In addition, we performed similar measurements with Doppler ultrasonography to identify if changes in uterine arterial velocity occurred during menstrual cramping in real time. Mixed model statistics were performed to account for within-subject effects across conditions. Corrections for multiple comparisons were made with a false discovery rate adjustment., Results: During menstruation, a notable increase in R2∗ values, indicative of tissue ischemia, was observed in both the myometrium (beta ± standard error of the mean, 15.74±2.29 s -1 ; P=.001; q=.002) and the endometrium (26.37±9.33 s -1 ; P=.005; q=.008) of participants who experienced dysmenorrhea. A similar increase was noted in the myometrium (28.89±2.85 s -1 ; P=.001; q=.002) and endometrium (75.50±2.57 s -1 ; P=.001; q=.003) of pain-free controls. Post hoc analyses revealed that the R2∗ values during menstruation were significantly higher among the pain-free controls (myometrium, P=.008; endometrium, P=.043). Although naproxen sodium increased the endometrial R2∗ values among participants with dysmenorrhea (48.29±15.78 s -1 ; P=.005; q=.008), it decreased myometrial R2∗ values among pain-free controls. The Doppler findings were consistent with the functional magnetic resonance imaging (-8.62±3.25 s -1 ; P=.008; q=.011). The pulsatility index (-0.42±0.14; P=.004; q=.004) and resistance index (-0.042±0.012; P=.001; q=.001) decreased during menses when compared with the measurements outside of menses, and the effects were significantly reversed by naproxen sodium. Naproxen sodium had the opposite effect in pain-free controls. There were no significant real-time changes in the pulsatility index, resistance index, peak systolic velocity, or minimum diastolic velocity during episodes of symptomatic menstrual cramping., Conclusion: Functional magnetic resonance imaging and Doppler metrics suggest that participants with dysmenorrhea have better perfusion and oxygen availability than pain-free controls. Naproxen sodium's therapeutic mechanism is associated with relative reductions in uterine perfusion and oxygen availability. An opposite pharmacologic effect was observed in pain-free controls. During menstrual cramping, there is insufficient evidence of episodic impaired uterine perfusion. Thus, prostaglandins may have protective vasoconstrictive effects in pain-free controls and opposite effects in participants with dysmenorrhea., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The term placental bed was coined to describe the maternal-fetal interface (ie, the area in which the placenta attaches itself to the uterus). Appropriate vascularization of this area is of vital importance for the development of the fetus; this is why systematic investigations of this area have now been carried out. Initially, the challenge was the identification and classification of the various successive branching of uterine arteries in this area. These vessels have a unique importance because failure of their physiological transformation is considered to be the anatomical basis for reduced perfusion to the intervillous space in women with preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, abruptio placentae, and fetal death. To investigate in depth the pathophysiology of the placental bed, some 60 years ago, a large number of placental bed biopsies, as well as of cesarean hysterectomy specimens with placenta in situ, from both early and late normotensive and hypertensive pregnancies, were carefully dissected and analyzed. Thanks to the presence of a series of specific physiological changes, characterized by the invasion and substitution of the arterial intima by trophoblast, this material allowed the identification in the placental bed of normal pregnancies of the main vessels, the uteroplacental arteries. It was then discovered that preeclampsia is associated with defective or absent transformation of the myometrial segment of the uteroplacental arteries. In addition, in severe hypertensive disease, atherosclerotic lesions were also found in the defective myometrial segment. Finally, in the basal decidua, a unique vascular lesion, coined acute atherosis, was also identified This disorder of deep placentation, coined defective deep placentation, has been associated with the great obstetrical syndromes, grouping together preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. More recently, simplified techniques of tissue sampling have been also introduced: decidual suction allows to obtain a large number of decidual arteries, although their origin in the placental bed cannot be determined. Biopsies parallel to the surface of the basal plate have been more interesting, making possible to identify the vessels' region (central, paracentral, or peripheral) of origin in the placental bed and providing decidual material for immunohistochemical studies. Finally, histochemical and electron microscopy investigations have now clarified the pathology and pathogenetic mechanisms underlying the impairment of the physiological vascular changes., (Copyright © 2019. Published by Elsevier Inc.)

Study Objective: To show the tips and tricks of a simpler technique for temporary blocking of the uterine artery in laparoscopic resection of a diffuse adenomyosis lesion to make the procedure more efficient and reproducible., Design: This study is designed to be a step-by-step explanation of the technique using videos and pictures (Canadian Task Force classification III)., Setting: Changzhou Maternal and Child Health Hospital, Changzhou, China., Patients: Three patients (age 39-42 years, 41±1.73) were diagnosed with diffuse adenomyosis with severe secondary dysmenorrhea willing to reserve the uterus and a poor response to medical management. Gynecologic examination revealed that the uteri sizes were 9 to 14 weeks. Transvaginal ultrasonography revealed that the lesions were 4 to 7 cm in size., Interventions: Laparoscopic resection of the diffuse adenomyosis lesion was conducted after temporary blocking of the uterine artery with a rubber belt., Measurements and Main Results: The traditional methods for injecting diluted vasopressin in the myometrium around the affected area and a half-life period of 30 minutes were used. Many adenomyosis patients with severe dysmenorrhea and menometrorrhagia have a large lesion; thus, the operating time is longer. The maximum dose of vasopressin is 20 units daily, and hypertensive patients have a contraindication. We made an incision of the broad ligament of the avascular area near the uterine artery and pulled the rubber pressure pulse ligation tightly through to temporarily block the uterine artery without vasopressin completely through the laparoscopic resection of the diffuse adenomyosis lesion. Intraoperative blood loss was only 120 to 230 mL. In this video, we show a simpler technique for temporarily blocking the uterine artery in laparoscopic resection of diffuse adenomyosis with a stepwise expiation. A levonorgestrel-releasing intrauterine system (Mirena; Bayer, Leverkusen, Germany) was placed in the uterus from the vagina immediately after surgery. At the 3-25 month (10.67±12.42) follow-up, visual analog scale scores were obviously reduced, and the menstrual quantity and amenorrhea dramatically declined after the surgery. All patients had no recurrence and no Mirena loss as assessed by vaginal ultrasound and the visual analog scale [1]. Estrogen was maintained at the normal level after 3 months. This study was approved by the Institutional Review Board of the Changzhou Maternal and Child Health Hospital Affiliated to Nanjing Medical University., Conclusion: The incidence of adenomyosis is a newer trend that is being used in patients with a poor response to medical management of uterine lesions and large lesions in China. Using the rubber belt to temporarily block the uterine artery in laparoscopic resection of the diffuse adenomyosis lesion offers the possibility of the rubber belt being effective, safe, and reproducible. Minimally invasive surgery in expert hands is the preferred solution of an increasing number of patients after drug treatment failure., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: Low placental vascularization measured by three-dimensional (3-D) ultrasound with power Doppler can predict preeclampsia. We evaluated the reliability and reproducibility of the ultrasonic sphere biopsy (USSB) technique to evaluate placental and subplacental myometrium vascularization in the first trimester., Methods: We performed a secondary analysis of a case-control study nested in a prospective cohort of women with a singleton pregnancy undergoing ultrasound at 11 to 14 weeks' gestation. Women who developed preeclampsia (n = 20) and randomly selected controls (n = 60) were compared. Other controls (n = 60) were also randomly selected to evaluate intra- and inter-observer reproducibility. Using 3-D power Doppler, the vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured from the volume of the whole placenta and the subplacental myometrium and from their respective USSB. Pearson's correlation coefficients (cc) with their P-values were calculated., Results: We observed that USSB is reliable in estimating the vascularization of the whole placenta in the first trimester (cc of VI 0.83; of FI 0.62; and of VFI 0.78; P < 0.001 for all) but was not as reliable for estimating subplacental myometrium vascularization (cc of VI 0.71; of FI 0.35; and of VFI 0.73). Measurement of placental vascularization using USSB showed good to excellent intra- and inter-observer reproducibility (cc of VI 0.86 and 0.85, respectively; of FI 0.75 and 0.75, respectively; and of VFI 0.83 and 0.83, respectively; P < 0.001 for all). Finally, we observed that women who subsequently developed preeclampsia had lower placental USSB VI (2.1 vs 4.8, P = 0.02), FI (32.4 vs. 42.5, P = 0.002), and VFI (0.8 vs. 2.1, P = 0.01) than controls., Conclusion: First-trimester USSB of the placenta using 3-D power Doppler is a reliable and reproducible procedure for estimating placental vascularization and could be used to predict preeclampsia., (Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Arteriovenous malformation is a short circuit between an organ's arterial and venous circulation. Arteriovenous malformations are classified as congenital and acquired. In the uterus, they may appear after curettage, cesarean delivery, and myomectomy among others. Their clinical feature is usually vaginal bleeding, which may be severe, if curettage is performed in unrecognized cases. Sonographically on 2-dimensional grayscale ultrasound scanning, the pathologic evidence appears as irregular, anechoic, tortuous, tubular structures that show evidence of increased vascularity when color Doppler is applied. Most of the time they resolve spontaneously; however, if left untreated, they may require involved treatments such as uterine artery embolization or hysterectomy. In the past, uterine artery angiography was the gold standard for the diagnosis; however, ultrasound scanning has diagnosed successfully and helped in the clinical management. Recently, arteriovenous malformations have been referred to as enhanced myometrial vascularities., Objectives: The purpose of this study was to evaluate the role of transvaginal ultrasound scanning in the diagnosis and treatment of acquired enhanced myometrial vascularity/arteriovenous malformations to outline the natural history of conservatively followed vs treated lesions., Methods: This was a retrospective study to assess the presentation, treatment, and clinical pictures of patients with uterine Enhanced myometrial vascularity/arteriovenous malformations that were diagnosed with transvaginal ultrasound scanning. We reviewed both (1) ultrasound data (images, measured dimensions, and Doppler blood flow that were defined by its peak systolic velocity and (2) clinical data (age, reproductive status, clinical presentation, inciting event or procedure, surgical history, clinical course, time intervals that included detection to resolution or detection to treatment, and treatment rendered). The diagnostic criteria were "subjective" with a rich vascular network in the myometrium with the use of color Doppler images and "objective" with a high peak systolic velocity of ≥20 cm/sec in the vascular web. Statistical analysis was performed and coded with statistical software where necessary., Results: Twenty-seven patients met the diagnostic criteria of uterine enhanced myometrial vascularity/arteriovenous malformation. Mean age was 31.8 years (range, 18-42 years). Clinical diagnoses of the patients included 10 incomplete abortions, 6 missed abortions, 5 spontaneous complete abortions, 5 cesarean scar pregnancies, and 1 molar pregnancy. Eighty-nine percent of patients had bleeding (n = 24/27), although 1 patient was febrile, and 2 patients were asymptomatic. Recent surgical procedures were performed in 55.5% patients (15/27) that included curettage (n = 10), cesarean deliveries (n = 5), or both (n = 1); 4 patients had a remote history of uterine surgery that included myomectomy. Treatment was varied and included expectant treatment alone in 48% of the patients with serial ultrasound scans and serum human chorionic gonadotropin until resolution (n = 13/27 patients), uterine artery embolization (29.6%; 8/27 patients), methotrexate administration (22.2%; 6/27 patients), hysterectomy (7.4%; 2/27 patients), and curettage (3.7%; 1/27 patients). Three patients required a blood transfusion. Of the 9 patients whose condition required embolization, the conditions of 7 patients resolved after the procedure although 1 patient's condition required operative hysteroscopy and 1 patient's condition required hysterectomy for intractable bleeding. Average peak systolic velocity after embolization in the 9 patients was 85.2 cm/sec (range, 35-170 cm/sec); the average peak systolic velocity of the 16 patients with spontaneous resolution was 58.5 cm/sec (range, 23-90 cm/sec)., Conclusions: Acquired enhanced myometrial vascularity/arteriovenous malformations occurred after unsuccessful pregnancies or treatment procedures that included uterine curettage, cesarean delivery, or cesarean scar pregnancy. Triage of patients for expectant treatment vs intervention with uterine artery embolization based on their clinical status, which was supplemented by objective measurements of blood velocity measurement in the arteriovenous malformation, appears to be a good predictor of outcome. Ultrasound evaluation of patients with early pregnancy failure and persistent bleeding should be considered for evaluation of a possible enhanced myometrial vascularity/arteriovenous malformation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Endometriosis and adenomyosis are characterized by the presence of ectopic endometrium, but are also associated with functional and structural changes in the eutopic endometrium and inner myometrium. Alterations in the inner myometrium occurring in women with endometriosis and adenomyosis may be at the root of a defective remodelling of the myometrial spiral arteries from the onset of decidualization and result in vascular resistance and increased risk of defective deep placentation. The association of major obstetrical syndromes and different types of defective remodelling of the myometrial spiral arteries has been well documented. The possibility of a link between both endometriosis and adenomyosis and some major obstetric syndromes remains controversial because of at least two factors: first, changes of the inner myometrium are frequently present in women with endometriosis but the diagnosis requires high-resolution imaging such as magnetic resonance which is not routinely performed and second, patients with endometriosis are frequently subjected to prolonged hormone suppressive therapy. Indeed, there is evidence that pre-treatment with a Gonadotropin Releasing-Hormone analogue can improve the uterine microenvironment and implantation rate following IVF in infertile patients with endometriosis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Placenta creta is an increasingly prevalent cause of maternal morbidity/mortality. Decidua is at least focally defective and extravillous trophoblast (EVT) may be abnormal. The study aims to compare differences in migratory trophoblast and spiral artery remodeling between areas with and without decidua at the placental implantation site., Study Design: Sixteen (12 creta, 4 non-creta) caesarean hysterectomy specimens were studied immunohistochemically. Invasive EVT and multinucleate trophoblast giant cells (MTGC) were quantified; confluent EVT (>5 opposed EVTs) and spiral artery remodeling were assessed semi-quantitatively., Results: In 6 cases, placenta creta was focal. Compared to placenta creta with local decidua, cases without local decidua had increased interstitial EVT cells (×200 field) (SEM 45.6 [4.9] vs. 80.5 [3.9], p < 0.0001), fewer multinucleate trophoblast giant cells (expressed as a percentage of total EVT) (0.8 [0.3] vs. 31.5 [2.2]% p < 0.0001) and EVT was more confluent (p < 0.0001). In contrast, placenta creta cases with local decidua had a greater degree of spiral artery remodeling (mean remodeling score 1.65 [0.07] vs. 1.13 [0.05], p < 0.0001) associated with increased intramural trophoblast (p = 0.0008). The only difference between placenta creta with local decidua and normal placentation cases was an increased number of interstitial EVT cells in creta cases (45.6 [4.9] vs. 24.8 [3.2], p = 0.04)., Conclusions: Numbers of interstitial EVT are increased in placenta creta, more so in cases without local decidua. Despite this spiral artery modeling is reduced in placenta creta cases with no decidua. The results emphasize the crucial role of decidua in control of trophoblast invasion and spiral artery remodeling., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Calreticulin is a calcium binding, endoplasmic reticulum resident protein best known for its roles in intracellular calcium homeostasis and the quality control processes of the endoplasmic reticulum. There is evidence for a range of activities for calreticulin outside the endoplasmic reticulum, including in the cytosol, on the surface of different cells types and in the extracellular matrix. Recent evidence indicates that human pregnancy is a condition of elevated circulating calreticulin. Calreticulin was increased in the plasma of women throughout pregnancy compared to the non-pregnant state. Calreticulin was also further increased during the hypertensive disorder of human pregnancy, pre-eclampsia. To clarify the roles of circulating calreticulin in pregnancy and pre-eclampsia, the aim of this study was to determine the effects of exogenous calreticulin on two cell types that are relevant to normal human pregnancy and to pre-eclampsia. Human primary myometrial microvascular endothelial cells (UtMVEC-Myo) and the human trophoblast cell line, HTR8/SVneo, were cultured with exogenous calreticulin at concentrations (2 μg/ml and 5 μg/ml) comparable to that measured in maternal blood. The higher concentration of calreticulin significantly increased the migration of the UtMVEC-Myo cells, but significantly reduced the migration of the HTR8/SVneo cells. In the presence of only FGF, FBS and antibiotics calreticulin at 5 μg/ml significantly reduced the number of UtMVEC-Myo cells during in vitro culture for 120 h. These results demonstrate that exogenous calreticulin can alter both HTR8/SVneo and UtMVEC-Myo cell functions in vitro at a (patho-) physiologically relevant concentration. Increased calreticulin may also contribute to altered functions of both cell types during pre-eclampsia., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: To evaluate whether 3D placental and myometrial power Doppler blood perfusion in the first trimester can be used to detect risk pregnancies., Methods: 3D power Doppler vascularization index (VI) and flow index (FI) of the entire placenta and the neighbouring myometrium were separately measured in the first trimester in all women with singleton pregnancies during a period of three months. In addition we measured placental volume, placental quotient, PAPP-A, as well as uterine artery at 12 and 22 weeks (mean PI and mean notch) and compared those data with the pregnancy outcome., Results: Data from 383 women could be evaluated. 10 developed pre-eclampsia (PE). Both flow and vascularization were markedly lower in the placentas compared to the adjoining decidua and myometria. There was some correlation between placental vascularization Index (PVI) as well as deciduo-myometrial vascularization index (MVI) and placental volume, PAPP-A and number of pregnancies and a marked correlation between PVI and especially MVI to mean notch at 12 weeks and 22 weeks (PVI: -0.215, -0.274 MVI: -0.316,-0.322). PVI and MVI were significantly reduced in women with pregnancy problems and showed the greatest reduction in PE-pregnancies (p: 0.0018, 0.0004). Of all measured parameters MVI showed the best sensitivity for the detection of PE., Conclusion: The correlation between PVI and MVI in the first trimester and mean notch in the second shows that they provide valuable information at as early as 12 weeks which normally so far is only available at 22 weeks by uterine artery Doppler flow. As MVI measures the percentage of vessels in the deciduo-myometrial area it could also provide information on trophoblast invasion. This hypothesis is supported in particular by a marked decrease of the MVI in pregnancy problems especially in PE-pregnancies., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A good blood supply to the endometrium is usually considered as an essential requirement for implantation. Endometrial and subendometrial blood flow was evaluated on the days of human chorionic gonadotrophin (HCG) administration and embryo transfer and the percentage change in endometrial and subendometrial blood flow between these 2 days was assessed as a predictor of pregnancy during IVF treatment. A three-dimensional (3D) ultrasound examination with power Doppler was performed in 293 patients undergoing the first IVF cycle to determine endometrial thickness, endometrial volume, vascularization index, flow index and vascularization flow index of endometrial and subendometrial regions on the days of HCG and embryo transfer. Patients in non-pregnant and pregnant groups had comparable endometrial thickness, endometrial volume and 3D power Doppler flow indices of endometrial and subendometrial regions measured on either day. Percentage changes in endometrial and subendometrial 3D power Doppler flow indices were also similar. In conclusion, endometrial and subendometrial blood flow on the days of HCG and embryo transfer and the percentage change in endometrial and subendometrial blood flows between these 2 days were not predictive of pregnancy in IVF treatment.

Endometrial development is largely dependent on a good blood supply to the basal endometrium. This study evaluated the endometrial and subendometrial vascularity in patients with thin (

Objective: This study was undertaken to study vascular reactivity of small myometrial arteries in women with idiopathic menorrhagia., Study Design: Small myometrial arteries were isolated from 6 patients with idiopathic menorrhagia and 4 controls. The contractile responses to thromboxane mimetic (U46619) and endothelin-1 were assessed before and after incubation with N(w)-nitro-L arginine methyl ester alone or in combination with indomethacin (Indo). Endothelium-dependent dilation to bradykinin and basal tension were compared before and after incubation with N(w)-nitro-L arginine methyl ester alone, or with N(w)-nitro-L arginine methyl ester in combination with indomethacin., Results: Constriction to endothelin-1 was enhanced in idiopathic menorrhagia arteries (P < .05). Idiopathic menorrhagia arteries demonstrated enhanced basal tension after incubation with N(w)-nitro-L arginine methyl ester, which was further exaggerated by indomethacin. NOS inhibition had no effect on basal tension in controls, but basal tension was enhanced after inhibition of cyclooxygenase-derived products (P < .05). Bradykinin-mediated dilation was significantly increased in idiopathic menorrhagia (P < .05)., Conclusion: The presence of functional alterations in small myometrial arteries could contribute to idiopathic menorrhagia.

Agonist-induced tone oscillations (rhythmic contractions and relaxations) occur in vascular beds to allow acute regulation of volume flow and thus the delivery of oxygen and nutrients to the tissue. Mechanisms responsible for the control of human placental vasomotor tone and blood flow are poorly characterized. This study aimed to characterise thromboxane-induced tone oscillations in human placental and myometrial arteries. Chorionic plate and myometrial arteries obtained from biopsies at term were mounted for isometric tension measurement. Tone oscillations were observed in chorionic arteries only when exposed to sub-maximal (<1 microM) concentrations of U46619. Slow (mean+/-SEM) frequency (2.6+/-0.5 per hour), large amplitude (39+/-7% of peak contraction) tone oscillations were elicited by 0.03 microM U46619 (n=18). In the presence of the nitric oxide synthase (NOS) inhibitor l-NNA (100 microM) the amplitude was significantly reduced (40+/-13% to 18+/-8%, P<0.05, n=6), frequency was unaltered and the bradykinin-dependent vasodilator response was reduced (68+/-13% to 40+/-19%, P<0.05, n=6). Myometrial arteries exposed to 1 microM U46619 developed tone oscillations within 10 min, which increased in amplitude over 30min occurring at relatively constant frequency. The mean amplitude of oscillations at 30 min (31+/-7%, n=16) was similar to that in chorionic arteries but the occurrence more frequent (42.8+/-9.7 per hour, P<0.001). Inhibition of NOS did not alter tone oscillations in myometrial arteries. Tone oscillations in chorionic arteries from pre-eclamptic and growth restricted (FGR) pregnancies were reduced in amplitude whereas those in myometrial arteries had increased frequency. Inhibition of NOS further reduced oscillation amplitude in chorionic arteries from FGR pregnancies. The alterations may contribute to the vasculopathology of these conditions, or, may represent compensatory mechanisms to maintain a matching of materno-placental blood flow.

Objective: The objective of the study was to quantify markers of myometrial ischemia, necrosis, and inflammation in women undergoing uterine artery embolization (UAE)., Study Design: Women with symptomatic fibroids were randomized to treatment with UAE (n = 14) or abdominal myomectomy (n = 11). Peripheral venous blood samples were taken before and after the procedure, at 24 hours and 6 weeks. Creatine kinase (CK) and ischemia-modified albumin (IMA) were measured as markers of necrosis and ischemia. Inflammation was assessed by measurement of C-reactive protein (CRP)., Outcome Measures: Changes in the markers following UAE and myomectomy were measured., Results: Following UAE, no change was seen in CK or IMA, but CRP was raised only at 6 weeks. At 24 hours after myomectomy, there were significant rises in all 3 markers, with a return to normal by 6 weeks., Conclusion: No significant ischemia or necrosis occurs in the myometrium following UAE, whereas the delayed rise in CRP is likely to reflect necrosis in fibroids.

The ability of a blood vessel to develop tone is dependent upon morphological parameters of the smooth muscle cells (SMC), including density, relationship with the endothelium and subcellular distribution of myofilaments and intracellular organelles. Consequently, wall ultrastructure of isolated human placental chorionic plate arteries (n=12), fixed when pressurised to mimic their in vivo geometry, was examined qualitatively using electron microscopy, and compared with maternal arteries (omental, n=10, myometrial, n=6). Arteries from women with uncomplicated pregnancy were tested for contractile viability before fixing, with some vessels post-fixed in osmium-ferricyanide for sarcoplasmic reticulum (SR) identification. In contrast to maternal arteries, placental arteries had no internal elastic lamina but exhibited considerable extracellular matrix separating circularly orientated SMC. Human SMC contained tightly packed arrays of myofilaments running parallel to the plasma membrane, enveloping cellular organelles. Synthetic SMC, with few myofilaments and much rough SR, were observed in placental arteries only. SR in SMC from maternal arteries was located centrally, often encircling mitochondria, and also near the plasma membrane associated with caveolae. Positive SR staining was rarely observed in SMC of placental arteries. This study highlights ultrastructural differences between placental and maternal arteries that may underlie specialised mechanisms of regulating vascular tone in the placenta.

Objective: The purpose of this study was to assess the involvement of rho kinase (ROK) in agonist-dependent contraction of omental, myometrial, and placental arteries of pregnant women at term., Study Design: Wire myography was used to assess if contractions of intact or alpha-toxin-permeabilized arteries obtained from women at elective cesarean section were influenced by the ROK inhibitor Y-27632., Results: Western blotting indicated the presence of ROKalpha in each of the 3 tissue types. In intact human omental, myometrial, or placental arteries, Y-27632 dose-dependently reduced constrictions to the thromboxane-mimetic U46619. In permeabilized vessels, U46619 induced substantial Ca(2+)-sensitization of contraction that was inhibited by Y27632. The phosphatase inhibitor calyculin A induced a Ca(2+)sensitization of contraction similar to that of U46619 in permeabilized omental arteries that was unaffected by Y-27632, suggesting that ROK may signal via myosin phosphatase in these vessels., Conclusion: These results are the first report of the involvement of ROK in the receptor-coupled constriction of intact and permeabilized arteries from pregnant women.

The involvement of endovascular trophoblast in fibrinoid deposition, replacement of the endothelium and vascular smooth muscle breakdown is studied in spiral arteries of the mesometrial triangle from day 15 to day 21 of rat pregnancy, by examining arterial cross sections after staining for cytokeratin, PAS, CD31 and alpha-actin. From day 15 to day 18 of pregnancy, fibrinoid deposition underneath the endovascular trophoblast increases gradually, whereas the amount of endovascular trophoblast in invaded arteries remains constant. CD31 staining is significantly reduced in sub-ET (= underlying the endovascular trophoblast) as compared to extra-ET (= outside the endovascular trophoblast) and no-ET (= non-invaded arterial sections) at each time-point of pregnancy examined (P < 0.005 and P < 0.0005 at each day of pregnancy), whereas alpha-actin staining is reduced both in sub-ET and in extra-ET as compared to no-ET. During pregnancy, CD31 staining in sub-ET initially declines, but increases significantly on day 21 (P < 0.001 versus d20) suggesting re-endothelialization of the vascular wall. In conclusion, changes in spiral arteries of pregnant rats reveal striking similarities with physiological changes seen in human pregnancy, thus emphasizing the usefulness of this species as an experimental model for studying normal and complicated pregnancies in humans.

Objective: Preeclampsia is a common and serious complication of pregnancy, characterized by maternal hypertension and proteinuria, placental insufficiency, and fetal growth restriction. The purpose of this study was to investigate whether intracellular Ca 2+ ([Ca 2+ ] i ) and contractile responses of vascular smooth muscle to vasoactive agents are altered in preeclampsia compared with normal pregnancy and the nonpregnant state., Study Design: Subcutaneous and myometrial resistance arteries from women who had preeclampsia, normal pregnancy, and nonpregnant women were obtained at the time of cesarean section or hysterectomy. Arteries were mounted on an isometric myograph and loaded with the Ca 2+ indicator, fura-2AM, to permit simultaneous measurement of force and [Ca 2+ ] i . Reponses to endothelium-dependent relaxants (acetylcholine and substance P) and vasoconstrictors (depolarizing potassium solution, phenylephrine, and angiotensin II) were examined., Results: The fall in [Ca 2+ ] i and relaxation in response to acetylcholine was significantly inhibited in both myometrial and subcutaneous arteries from preeclamptic women compared with arteries from nonpregnant or normal pregnant women. However, responses to substance P did not differ between the 3 groups. There were no significant differences in [Ca 2+ ] i or force responses to high potassium, phenylephrine, or angiotensin II in myometrial and subcutaneous resistance vessels in women with preeclampsia compared with normal pregnant women. However, force, but not [Ca 2+ ] i responses to angiotensin II, in subcutaneous vessels from normal pregnant and preeclamptic women were reduced compared with subcutaneous arteries from nonpregnant women, indicating that pregnancy is associated with a reduction in Ca 2+ sensitization in this tissue. A similar effect was not seen in myometrial arteries., Conclusion: Endothelial function is altered in preeclampsia, with loss of effect of acetylcholine, but not substance P. Vasoconstrictor reactivity is not increased in preeclampsia compared with uncomplicated normal pregnancy, and this is unlikely to be an explanation for the increased peripheral vascular resistance seen in preeclampsia.

Objective: This study was undertaken to test for structural differences between myometrial radial arteries isolated from women having normal pregnancies and pregnancies complicated by preeclampsia and intrauterine growth restriction., Study Design: Pressure myography was used to study myometrial radial arteries obtained at cesarean section. With the use of a transilluminating system, lumen diameter, wall thickness, wall/lumen ratio, distensibility and stress-strain relationship were studied through a range of pressures. Arteries were then fixed in glutaraldehyde, embedded in resin, cross-sectioned, and studied in greater detail by light and electron microscopy., Results: Pressure myography showed that arteries from women with preeclampsia had a reduced lumen diameter, thicker wall, and greater wall/lumen ratio compared with vessels isolated from women with normal pregnancy. Light microscopy indicated an identical media content remodeled around a smaller lumen. Electron microscopy indicated enlarged extracellular spaces in the media but no change in myocyte profile size or number. There was no clear evidence of structural changes in myometrial radial arteries isolated from women with intrauterine growth restriction compared with normal pregnancy. No differences in vessel distensibility or stress-strain relationships were detected in complicated pregnancies., Conclusion: The changes observed in myometrial radial arteries isolated from women with preeclampsia are due to inward eutrophic remodeling. Alterations in these vessels may contribute to increased uterine vascular resistance in preeclampsia.

Objective: Parathyroid hormone-related protein (PTHrP) has been reported to relax different vessels. We investigated the influence of both endothelium and gestation on the relaxation of uterine arteries (UA), which supply blood to myometrium and placenta., Methods: Small uterine and mesenteric arteries (MA) with (E+) and without endothelium (E-) from day 20 pregnant (P) and nonpregnant (NP) rats were mounted in a myograph, precontracted with phenylephrine (PE) in a physiologic salt solution. Relaxations to PTHrP, acetylcholine, and forskolin were performed and expressed as a percentage of the PE-induced contraction. Blockade of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) was also studied with Nomega-nitro-L-arginine methyl ester (L-NAME) and with charybdotoxin + apamin, respectively., Results: Gestation significantly increases maximal vasodilating effect of acetylcholine in UA (68% vs 52%, P < .05) and sensitivity to acetylcholine in small mesenteric vessels (P < .05). PTHrP relaxes uterine (maximal relaxation P: 32%, NP: 46%), as well as small MA (P: 68%, NP: 89%), but the maximal relaxation is significantly greater in NP than in P rats (P: 32%, NP: 46%, P < .01) in both vascular beds. In addition, in the UA of P rats, PTHrP only produces relaxation if functional endothelium is present; nevertheless in the absence of endothelium, forskolin still elicits relaxation (65%, P < .01). L-NAME significantly impairs relaxation of E+ UA (P < .05), and so does the association of charybdotoxin + apamin (P < .05). Thus, NO and EDHF contribute largely to this vasorelaxant effect., Conclusion: PTHrP induces a relaxation on UA that is strongly endothelium-dependent during gestation, in contrast to what happens simultaneously in MA.

Objective: This study compared myoendometrial versus placental radial uterine arteries from late-pregnant rats to evaluate differences in passive mechanical properties and arterial wall hyperplasia., Study Design: Myoendometrial and placental radial uterine arteries were dissected from late-pregnant (day 17-19) Sprague-Dawley rats (n = 21) for determination of the lumen diameter and passive distensibility. Arterial wall hyperplasia was evaluated by bromodeoxyuridine incorporation and histologic determination of mitotic indices of endothelial, smooth muscle, and adventitial cells. Nonpregnant radial uterine and mesenteric arteries were used as control cells., Results: Both placental and myoendometrial uterine arteries were significantly larger than nonpregnant uterine arteries by 40% and 28%, respectively (P < .05). The lumen diameter of placental arteries was significantly (16%) larger than adjacent myoendometrial arteries (P < .05). In addition to the larger luminal diameter, placental arteries were significantly more distensible than myoendometrial arteries at all pressures that were studied, which demonstrates differential remodeling. Comparison of mitotic indices revealed that placental arteries had significantly increased cell division rates of both endothelial and smooth muscle significantly compared to myoendometrial arteries. Both types of arteries from pregnant animals had increased cell division rates compared with vessels from nonpregnant animals. The mitotic index of endothelial and smooth muscle cells for placental and myoendometrial arteries from late-pregnant and nonpregnant animals was 15.08% +/- 2.05% and 6.57% +/- 1.37%, 8.73% +/- 1.23%, and 3.04% +/- 0.48% (P < .05 vs placental), and 0.29% +/- 0.29% and 0.23% +/- 0.23% (P < .05 vs placental endothelial), respectively. Adventitial cell division was 10- to 15-fold higher in late-pregnant versus nonpregnant animals., Conclusion: These data demonstrate differential growth and remodeling of uterine arteries that supply the placenta versus the myoendometrium, which likely is facilitated by enhanced arterial wall hyperplasia in placental arteries.

Objective: The relative role of the two estrogen receptors, ERalpha and ERbeta, in mediating angiogenic responses in adult human endothelium is unknown. The aim of this study was to determine whether novel ERalpha-selective agonists, propyl pyrazole triol (PPT) and the tetrahydrochrysene (R,R-THC), up-regulate the expression of vascular endothelial growth factor receptor-2 (VEGFR-2), and promote VEGF-stimulated endothelial cell proliferation in primary cultures of adult female microvascular endothelial cells co-expressing endogenous ERalpha and ERbeta., Methods: Confluent primary cultures of microvascular endothelial cells isolated from human myometrium were incubated with 17beta-estradiol (1 and 10 nM), PPT (10 nM to 3 microM), or R,R-THC (10 nM to 3 microM) for 18 hours and VEGFR-2 expression measured by biotin-VEGF165 binding and flow cytometry. Endothelial cell proliferation was assessed in microvascular endothelial cells after incubation with 17beta-estradiol (10 nM), PPT (100 nM), and R,R-THC (100 nM) for 6 days using a tetrazolium-based bioassay., Results: Both PPT and R,R-THC increased VEGFR-2 expression on myometrial microvascular endothelial cells in a dose-dependent manner, reaching a maximum at 1 microM. Approximately 40% of myometrial microvascular endothelial cell isolates only express ERbeta and do not express ERalpha, and in these neither PPT, R,R-THC, nor 17beta-estradiol increased VEGF binding. PPT- or R,R-THC-stimulated increase in VEGF binding was significantly different between ERalpha+ and ERalpha- microvascular endothelial cell samples (P < .001 and P < .05, respectively). PPT, R,R-THC, and 17beta-estradiol significantly augmented VEGF-stimulated microvascular endothelial cell proliferation in ERalpha+ (P < .05), but not in ERalpha- samples., Conclusions: This angiogenic effect of 17beta-estradiol on adult female microvascular endothelial cells is mediated by ERalpha, rather than ERbeta.

Objective: In preeclampsia, endothelium-dependent function is markedly aberrant. Myometrial resistance arteries from women with preeclampsia show a minimal, wholly nitric oxide-mediated, bradykinin-induced relaxation. Our aim was to test that phosphodiesterase 5 (PDE5) inhibition could improve endothelium-dependent function in preeclampsia. Study design Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (N=22) or women with preeclampsia (N=24) were mounted on wire or pressure myographs. Vessels were constricted (arginine vasopressin or U46619) and relaxed (bradykinin) before and after incubation with a PDE5 inhibitor, UK-343664., Results: Endothelium-dependent vasodilatation was decreased in vessels from women with preeclampsia. 100 nmol/L UK-343664 did not affect normal pregnant but significantly improved relaxation of the vessels from women with preeclampsia., Conclusion: A PDE5 inhibitor enhances endothelial function of myometrial vessels from women with preeclampsia, such that the behavior of these arteries approximates to those from normal women. These agents offer a potential therapeutic strategy for the management of preeclampsia.

Objective: To determine the expression and intracellular localization of protein phosphatases 2A (PP2A) and 2B (PP2B), protein kinase A (PKA), and A-kinase anchoring protein (AKAP79), and expression of PKA (RII subunit) binding to AKAP79 in human postmenopausal and pregnant myometrium and to correlate their expressions to blood levels of estradiol, progesterone, and oxytocin., Methods: Myometrial samples were taken from postmenopausal hysterectomy specimens (group 1, n = 5), from pregnant nonlaboring women (group 2, n = 7) and pregnant laboring women (group 3, n = 5) at cesarean. Western immunoblotting, immunohistochemical, and RII overlay assays were performed. Blood samples were assayed for estradiol, progesterone, and oxytocin levels., Results: There were no significant differences in expression of PP2A, PKA, AKAP79, or PKA(RII) binding to AKAP79 between the three groups. Expression of PP2B was significantly greater in the nonlabor group (group 2) compared with groups 1 and 3. Protein phosphatase 2B, PKA, and AKAP79 expressions were localized in myometrial cytoplasm, but PP2A was localized in blood vessel endothelium. There was no significant correlation between the protein expression and the hormone level in the three groups., Conclusion: Human postmenopausal and pregnant (nonlabor and labor) myometrium expressed PP2A, PP2B, PKA, AKAP79, and PKA (RII)-AKAP79 binding. Levels of PP2A, PKA, and AKAP79 expression did not appear to be determinants of human myometrial contractility at parturition. Expression of PP2B may play a role in uterine quiescence. No association was found between protein expression and hormone level.

Objectives: Preeclampsia (PE) is a multisystem disease unique to human pregnancy. Abnormal placentation results in placental hypoperfusion leading to the secretion of a factor(s) by the placenta. Our aim was to investigate whether neurokinin B (NKB) is the circulating factor associated with PE., Study Design: Vascular effects of NKB were assessed in blood vessels dissected from myometrial and omental biopsy specimens obtained at caesarean section from normal pregnant women (n = 26) or in mesenteric blood vessels obtained from nonpregnant female Wistar rats (n = 4)., Results: Incubation with NKB did not alter endothelial-dependent relaxation of omental or myometrial arteries. NKB produced a dose-dependent relaxation in preconstricted omental arteries and veins. NKB did not affect vasoactive responsiveness of rat mesenteric arteries., Conclusion: We conclude from these observations that NKB is not the circulating factor associated with increased vascular resistance in PE.

Objective: This study was performed to establish whether microparticles from plasma of women with preeclampsia cause endothelial dysfunction, as described for isolated myometrial arteries in preeclampsia., Study Design: Myometrial arteries were isolated from biopsy specimens obtained at cesarean delivery from healthy pregnant women (n = 22) and mounted in a wire myograph. Bradykinin concentration-response curves were obtained before and after 1-hour incubation or after overnight incubation with one of the following preparations of plasma from individual women with preeclampsia (n = 16): Whole plasma, microparticle-free plasma, isolated microparticles resuspended in physiologic saline solution or physiologic saline solution. Overnight incubation was also performed with microparticles isolated from healthy pregnant women (n = 6). One-hour incubation was performed with 2% or 10% solution and overnight incubation with 5% solution., Results: No effect of preeclamptic plasma, with or without microparticles, on bradykinin-mediated relaxation was observed. Overnight, but not 1-hour, incubation with preeclamptic microparticles caused abolishment of bradykinin-mediated relaxation in contrast to healthy pregnant microparticles (P <.005)., Conclusion: Preeclamptic microparticles, but not healthy pregnant microparticles cause endothelial dysfunction in isolated myometrial arteries from healthy pregnant women after overnight incubation, whereas other preeclamptic plasma constituents protect the endothelium from this effect.

Objective: The purpose of this study was to evaluate whether a 3-hour incubation with 17beta-estradiol will enhance blood flow- and bradykinin-mediated dilatation and alter pressure-induced basal tone in myometrial resistance arteries from women with preeclampsia and to evaluate the role of nitric oxide in the responses that were observed., Study Design: Blood flow- and bradykinin-mediated dilatation and responses to intraluminal pressure of 60 and 80 mm Hg were compared before and after 3 hours of incubation with 17beta-estradiol (10(-8) mol/L) in isolated myometrial arteries with the pressure myography technique. In separate experiments, the role of nitric oxide on 17beta-estradiol-induced responses was evaluated in the presence of the nitric oxide synthase inhibitor (10(-4) mol/L). Endothelial morphologic condition was evaluated by scanning electron microscopy., Results: Incubation with 17beta-estradiol significantly improved blood flow-mediated dilatation compared with initial blood flow-mediated response in arteries from women with preeclampsia. This effect was nitric oxide mediated, because the nitric oxide synthase inhibitor abolished the response. Arteries from women with preeclampsia demonstrated impaired bradykinin-mediated dilatation compared with that obtained in arteries from normal pregnant women. The 17beta-estradiol had no effect on bradykinin-mediated dilatation in arteries from women with preeclampsia. The enhanced pressure-induced tone at 80 mm Hg compared with the tone that developed at 60 mm Hg in arteries from women with preeclampsia was reduced after incubation with 17beta-estradiol. This reduction was also nitric oxide mediated. Morphologic signs of endothelial dysfunction were evident in arteries from women with preeclampsia., Conclusion: The 17beta-estradiol improved impaired blood flow-mediated dilatation and reduced basal tone through a nitric oxide-mediated pathway in isolated myometrial arteries from women with preeclampsia.

Deep placentation in the human requires physiologic transformation of the spiral arteries into uteroplacental vessels. This process involves the inner myometrial segment (junctional zone) of the spiral arteries and is effected by trophoblast invasion of the vessel wall, resulting in complete loss of the arterial structure and deposition of fibrinoid and fibrous tissues. Absent or inadequate physiologic changes in the junctional zone spiral arteries limits placental blood flow in pregnancies complicated by preeclampsia and fetal growth restriction. The cause of defective deep placentation is still unknown, although it is often attributed to impaired trophoblast function and migration. However, trophoblast invasion is preceded by decidual remodeling of maternal tissues, a process that is initiated in the endometrium but extends into the junctional zone. This review examines the mechanisms that control decidualization and subsequent trophoblast invasion in normal and abnormal pregnancies. The possibility that disruption of the decidual process in the secretory phase of the menstrual cycle triggers a cascade of events resulting in failed deep placentation is explored.

Objective: The endothelium-dependent behavior of myometrial resistance vessels from women with preeclampsia differs dramatically from that of healthy pregnant women. Similar functional changes may be induced in vessels from healthy pregnant women by incubation with plasma from women with preeclampsia., Study Design: Myometrial arterioles, obtained from healthy pregnant women at elective cesarean section, were incubated with plasma from women with preeclampsia or plasma from healthy pregnant women. Myographic techniques were used to study the endothelium-dependent relaxation to bradykinin. The effects of subjecting plasma from women with preeclampsia to heat treatment, charcoal stripping, protein extraction and digestion, and column fractionation on the inducible changes in endothelial function were likewise investigated., Results: Incubation with plasma from women with preeclampsia resulted in a significant reduction in the vessel's endothelium-dependent relaxation, a change that was reversible. This effect was reduced by heat treating and charcoal stripping, maintained within a plasma protein concentrate, and completely removed by protease digestion. The vasoactive component(s) of the plasma had a molecular weight greater than 100 kd., Conclusions: Plasma of women with preeclampsia alters the endothelium-dependent relaxation of myometrial vessels. Our findings suggest that such alterations are induced by a high-molecular-weight protein/glycoprotein, with possible contributions from a hydrophobic, lipophilic factor.

Objective: It has previously been observed that a circulating factor or factors may be responsible for the changes in vessel behavior that are postulated to underlie the pathogenesis of preeclampsia. We wished to ascertain whether such changes in endothelial function are dependent on the vascular bed under investigation., Study Design: Myometrial and infracolic omental vessels resistance vessels were obtained at cesarean delivery or hysterectomy. After incubation with either plasma from women with preeclampsia or plasma from normotensive pregnant women, myographic techniques were used to assess the endothelium-dependent relaxations of these vessels., Results: Incubation of myometrial vessels from normotensive pregnant women with plasma from women with preeclampsia resulted in a significant reduction in endothelium-dependent relaxation, an effect that was independent of the parity of the patients from whom the vessels had been taken. Incubation of omental vessels from normotensive pregnant women and myometrial vessels from nonpregnant women with plasma from women with preeclampsia had no effect on the endothelium-dependent relaxation observed., Conclusions: This study demonstrates that the inducible changes in resistance vessel behavior are dependent on the tissue bed under investigation and on the pregnancy status of the patient.

In the last years, several single-bottle dental adhesives have been developed. They are supposed to chemically adhere to dentin, and a liner to protect pulp is not thought to be necessary. In the case of direct pulp capping, hemorrhage control is an important step in success, but little is known about the effect of these new bonding agents on pulpal bleeding. The aim of this study was to evaluate the effect of a new one-step single-bottle adhesive on the smooth muscle contraction of rat uterine muscle and carotid arteries. Efficacy of the bonding agent was compared with that of epinephrine (control), and the contraction forces induced were recorded using a force displacement transducer. Statistical analysis of data revealed that the bonding material produced epinephrine-like concentration-dependent contractions of the smooth muscle, suggesting that one-step bonding agents may act as candidates for hemorrhage control without the use of an additional agent in direct pulp capping procedures.

Objective: We sought to compare flow-mediated dilatation and myogenic and norepinephrine-induced tone in myometrial resistance arteries from women with preeclampsia and healthy pregnant women and to evaluate the role that nitric oxide may play in these responses., Study Design: Arteries (approximately 200 microm, at 50 mm Hg) were dissected from myometrial biopsy specimens from women undergoing emergency cesarean delivery because of preeclampsia (n = 6) and from healthy control subjects undergoing planned cesarean delivery (n = 9). Responses to intraluminal flow, pressure, and a constrictor agonist (norepinephrine, 10(-6) mol/L) were studied in the absence and presence of the nitric oxide synthase inhibitor N omeganitro-L -arginine (10(-4) mol/L). Myogenic and norepinephrine-induced tone were calculated after the determination of artery diameter in the absence of extracellular calcium and in the presence of papaverine (10(-4) mol/L)., Results: An increase in intraluminal flow led to dilatation of isolated myometrial arteries from healthy gravid women, whereas flow-mediated dilatation was absent in arteries from gravid patients with preeclampsia (increase in diameter at maximum flow rate of 204 microL/min, 28% +/- 5% in healthy gravid patients vs -15% +/- 6% in gravid women with preeclampsia; analysis of variance, P <.05). Addition of N omega-nitro-L -arginine had no significant effect on flow-mediated responses in arteries from women with preeclampsia, whereas flow-mediated dilatation was abolished after addition of N omega-nitro-L -arginine in arteries from healthy gravid women (increase in diameter at a maximum flow rate of 204 microL/min, 28% +/- 5% control vs -9% +/- 5% N omega-nitro-L -arginine; analysis of variance, P <.05). Arteries from women with preeclampsia developed pressure-induced myogenic and norepinephrine-induced tone, similar to that obtained in arteries from healthy gravid women. In arteries from gravid women with preeclampsia, inhibition of nitric oxide synthase enhanced myogenic-induced tone (25% +/- 4% control vs 35% +/- 5% N omega-nitro-L -arginine; P <.05) and norepinephrine-induced tone (36% +/- 4% control vs 46% +/- 6% N omega-nitro-L -arginine; P <.05), as in arteries from healthy gravid women., Conclusions: Nitric oxide may participate in modulation of pressure- and norepinephrine-induced tone even in preeclampsia, but the shear stress-mediated release of nitric oxide is absent. Failure of shear stress-mediated dilation in myometrial arteries from gravid women with preeclampsia might contribute to the impaired uteroplacental blood flow in this disease.

Objective: We evaluated the role of endothelium-derived nitric oxide and endothelin 1 in the modulation of myogenic tone, norepinephrine-induced tone, and flow-mediated responses in resistance arteries from pregnant women at term., Study Design: Arteries (approximately 200 microm at 50 mm Hg; n = 27) were dissected from myometrial biopsies obtained from women undergoing elective cesarean delivery at term and mounted in a pressure arteriograph. Responses to intraluminal flow, pressure, and norepinephrine were studied in the absence and presence of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine and the endothelin-converting enzyme inhibitor phosphoramidon., Results: Pressure-induced (80 mm Hg) myogenic tone was significantly enhanced after incubation with Nomega-nitro-L-arginine (33% +/- 8% vs 24% +/- 4%; P <.05), whereas phosphoramidon significantly reduced myogenic tone (24% +/- 5% vs 33% +/- 5%; P <.05). A combination of Nomega-nitro-L -arginine and phosphoramidon did not affect myogenic tone. Norepinephrine-induced tone was significantly enhanced after nitric oxide synthase inhibition (49% +/- 6% vs 41% +/- 5%; P <.05) but was not affected by phosphoramidon. Flow-mediated dilatation was increased in the presence of phosphoramidon compared with flow-induced dilatation in physiologic salt solution (maximum dilatation, 57% +/- 12% vs 30% +/- 5%; analysis of variance, P <.05), and all flow-induced dilatation was abolished by Nomega-nitro-L -arginine., Conclusions: Nitric oxide and endothelin 1 may play a significant role in modulation of myogenic tone and flow-mediated responses in the resistance vasculature of the uterine circulation in normal pregnancy.

Objective: We determined whether local regulation by vasoactive agents differs in the myometrial and omental vascular beds in the pregnant sheep. Specifically, we hypothesized that there would be blunting of in vitro responses to constrictor agonists, enhancement of sensitivity to dilator agonists, or both in myometrial compared with omental resistance arteries., Study Design: We compared in vitro responsiveness of small resistance intramyometrial and omental arteries from near-term pregnant ewes to the vasoconstrictor agents norepinephrine, U46619 (a thromboxane sympathomimetic), and potassium and the vasodilator agents acetylcholine and bradykinin., Results: The vascular sensitivity and the maximum response of intramyometrial small arteries to U46619 was attenuated compared with that of omental arteries. There were no significant differences between the intramyometrial and omental arteries in response to norepinephrine, potassium, acetylcholine, or bradykinin., Conclusions: These results support regional heterogeneity of regulation of function in different maternal vascular beds during pregnancy. The relative insensitivity of the myometrial arteries to the thromboxane mimetic indicates the existence of decreased constrictor function that may facilitate preservation of uterine blood flow in vivo.

Objectives: To determine the degree of endothelium-dependent relaxation in myometrial and omental resistance arteries from normal pregnancies and pregnancies complicated with preeclampsia or fetal growth restriction (FGR) (compromised pregnancy group), and to correlate the results with the endothelial surface expression of cell adhesion molecules (CAMs) in the same vessels., Methods: Parallel wire myography was used to assess the relaxation of omentum or myometrial vessels obtained from nonpregnant women (n = 3), women with normal pregnancies (n = 11), and women with pregnancies complicated by preeclampsia or fetal growth restriction (n = 10). These resistance vessels were constricted with incremental concentrations of vasopressin (10(-10) mol/L to 3.3 x 10(-8) mol/L) prior to the addition of incremental concentrations of bradykinin (10(-10) mol/L to 3.3 x 10(-6) mol/L). Immunohistochemistry was used to assess the endothelial expression of the CAMs E-selectin, ICAM-1, VCAM-1, and PECAM., Results: A significant reduction in endothelium-dependent relaxation of myometrial vessels was found in the compromised pregnancy group when compared with both the normotensive pregnant group and the nonpregnant group. This reduction was not noted with omental vessels. All vessels in the nonpregnant group, normal pregnant group, and compromised pregnancy group expressed PECAM and ICAM-1 on the endothelium. There was no difference in intensity of immunostaining between the groups. None of the vessels in any of the groups expressed VCAM-1 or E-selectin., Conclusions: We found no evidence that impaired relaxation responses to bradykinin are linked to altered expression of CAMs in preeclampsia and FGR. These results suggest that increased CAM expression occurs in a vascular bed separate from those investigated in the present study. Possible sites for this would be in the microcirculation of organs such as the kidney.

Objectives: The study investigated whether an inducible alteration in endothelium-dependent relaxation in myometrial vessels could be correlated with plasma lipid composition., Study Design: Myometrial resistance vessels were obtained from 10 women with normal pregnancy undergoing elective cesarean delivery. Paired vessels were incubated with plasma samples from patients with preeclampsia or from women with normal pregnancy and mounted on a wire myograph. After contraction with vasopressin, the degree of relaxation in response to bradykinin was observed. Plasma samples were assayed for cholesterol, triglycerides, apolipoprotein A1, and apolipoprotein B., Results: A significant reduction in endothelium-dependent relaxation with respect to control values was observed in vessels incubated in plasma samples from patients with preeclampsia (P =.0001). Although no significant difference was noted between the lipid profiles of the 2 subgroups, a significant correlation was found between the vessel relaxation and the plasma content of apolipoprotein A1 (R2 = 0.36, P = .025)., Conclusion: Plasma samples from women with pregnancies complicated by preeclampsia are capable of altering endothelium-dependent myometrial vessel relaxation. A significant relationship between the apolipoprotein A1 concentration and endothelial behavior supports the suggestion that aberrant lipid metabolism may be involved in the endothelial dysfunction characteristic of preeclampsia.

Pregnancy-induced structural changes in spiral arteries seem to be a prerequisite for successful fetal outcome in humans. It is unknown whether these changes also occur in other preplacental vessels (radial and arcuate arteries) in normal pregnancies. Since the radial and arcuate arteries need to dilate in order to accommodate the increase in placental blood flow during pregnancy, it is expected that they are also invaded by trophoblast and respond with structural changes. The objective of the present study was to evaluate the extent of trophoblast invasion in the guinea-pig preplacental vasculature and its effect on the vascular structure of mesometrial, myometrial and arcade arteries. Under general anaesthesia the vascular system of non- (n = 4), mid- (n = 4) and late- (n = 8) pregnant guinea-pigs was fixed by immersion or perfusion. Cross-sections of immersion-fixed mesometrial and arcade arteries were stained with toluidine blue. Cross-sections of perfusion-fixed mesometrial, myometrial and arcade arteries were stained with haematoxylin-eosin, Elastica van Gieson staining and antibodies against alpha-smooth-muscle-actin (ASMA), cytokeratin and factor VIII, to detect vascular smooth muscle, trophoblastic, and endothelial cells, respectively. In addition, the external and internal vascular circumference of sections from perfusion-fixed tissue was determined. All cross-sections were evaluated by light microscopy. In the course of pregnancy, progressive endothelial swelling, disappearance of the elastic lamina interna and disarrangement of the tunica media were observed in the myometrial and throughout the mesometrial arteries up to the junction with the arcade arteries. These changes coincided the migration of keratin-positive staining giant cells. It is concluded that in normal guinea-pig pregnancy, structural changes occur in the entire mesometrial artery and at least a part of the myometrial artery, although such changes were not seen in the arcade artery.

Objective: Our purpose was to evaluate flow-induced responses, myogenic tone, and norepinephrine-induced constriction in myometrial resistance arteries from normal term pregnant women and the role that nitric oxide and prostanoids may play in these responses., Study Design: Arteries (approximately 200 microns, n = 14, at 40 mm Hg) were dissected from myometrial biopsy specimens from women undergoing cesarean section and then were mounted in a pressure arteriograph. Responses to intraluminal flow, pressure, and a constrictor agonist (norepinephrine 10(-6) mol/L) were studied in the absence and presence of N omega-nitro-L-arginine methyl ester (n = 7) or indomethacin (n = 5). Myogenic and norepinephrine-induced tone were calculated after the determination of artery diameter in the absence of extracellular calcium., Results: Arteries developed myogenic tone (80 mm Hg) that was not modulated by nitric oxide or prostanoid release, whereas norepinephrine-induced tone was significantly enhanced by the nitric oxide inhibitor. An increase in intraluminal flow led to dilatation in physiologic salt solution and indomethacin, but to constriction in the presence of N omega-nitro-L-arginine methyl ester (percent increase in diameter at flow rate of 184.6 microliters/min, 24% +/- 8% in physiologic salt solution and 20% +/- 4% in the presence of indomethacin versus -27% +/- 12% in N omega-nitro-L-arginine methyl ester alone and -21% +/- 10% in indomethacin and N omega-nitro-L-arginine methyl ester, respectively, analysis of variance, p < 0.05)., Conclusions: Flow-induced shear stress is a physiologic modulator of vascular tone in myometrial arteries from pregnant women. Nitric oxide, but not prostanoids, mediates this response and also blunts norepinephrine constriction. Nitric oxide may play a fundamental role in the maintenance of adequate blood supply to the fetus during human pregnancy.

Objective: This study compared late-pregnant radial uterine arteries that supplied the placenta versus the myoendometrium to evaluate differences in active and passive mechanical properties., Study Design: Pressurized segments of placental versus myoendometrial radial uterine arteries from late-pregnant (day 28 to 30) New Zealand White rabbits (n = 12) were compared in vitro for differences in luminal diameter, wall thickness, distensibility, and intrinsic tone as a function of transmural pressure., Results: Both types of arteries responded to increased transmural pressure with active vasoconstriction; however, the amount of tone present in myoendometrial arteries was significantly greater than in placental arteries (percent tone at 75 mm Hg = 39% +/- 3% for myoendometrial versus 31% +/- 2% for placental arteries, p < 0.01). Measurements of unpressurized, fully relaxed arteries revealed that placental arteries were 38% larger in diameter and had thicker walls than myoendometrial arteries did. However, myoendometrial arteries were significantly more distensible at transmural pressures >5 mm Hg., Conclusions: The increased size and diminished tone of placental compared with adjacent myoendometrial arteries would favor increased blood flow to the placenta; differences in size and passive mechanical properties suggest that a localized factor(s) originating from the fetus or placenta contributes to the gestational enlargement of those arteries that perfuse the placenta.

The process of placentation in the macaque has been extensively studied and found to resemble closely that observed in the human. In this model, histopathologically, intervillous flow is anticipated from week 3 post-conception. We set out to document the nature and onset of intervillous flow in the macaque in vivo using colour Doppler imaging (CDI), colour Doppler energy (CDE) and pulsed-wave Doppler (PWD). Pregnant females were assessed between 15-50 days gestation (term = 165 days) with an Acuson 128/XP10 high-resolution ultrasound scanner, using a 7-MHz linear array probe. The placenta, subjacent decidua and myometrium were assessed using CDI and CDE. Specific regions of flow were interrogated using PWD; the resulting flow velocity waveforms were stored and quantified using conventional Doppler indices. B-mode sonography was able to demonstrate the well-defined placental-decidual interface observed in this species; CDI and CDE clearly visualized the uteroplacental vasculature. Spiral arteries were followed to their point of discharge into the intervillous space, and PWD at these sites obtained a characteristic flow velocity waveform. The indices obtained confirmed a flow of low resistance and pulsatility throughout the gestation studied. Flow within the intervillous space was noted from day 20 of gestation.

Objective: Our purpose was to compare myometrial and omental resistance arteries from term pregnant women with respect to myogenic behavior in the presence or absence of a nitric oxide synthase inhibitor and to compare distensibility and acetylcholine-mediated dilatation in these vessels., Study Design: Intramyometrial (n = 17) and omental (n = 14) resistance arteries from term normal pregnant women were studied in a pressurized arteriograph system. Myogenic tone was evaluated during increments in intraluminal pressure from 20 to 120 mm Hg with and without inhibition of nitric oxide synthase. Endothelium-dependent relaxation was assessed by evaluating the response to acetylcholine (10(-6) mol/L) in arteries pressurized at 70 mm Hg., Results: Myogenic tone was greater at all pressure steps in the myometrial than in the omental arteries (p < 0.05). Inhibition of nitric oxide synthase with N(omega)-nitro-L-arginine had no influence on myogenic tone in either group. Relaxation to acetylcholine was greater in myometrial (18% +/- 4%) compared with omental vessels (7% +/- 2%, p < 0.05). The passive distensibility (Ca++-free solution and in the presence of papaverine) of arteries from the myometrium and the omentum was similar., Conclusion: Normal pregnancy is associated with different mechanical properties of resistance vessels from the two vascular beds studied. Basal nitric oxide release does not modify myogenic tone, at least under no-flow conditions. Acetylcholine-induced relaxation is greater in myometrial than in omental arteries.

Objective: Our purpose was to elucidate the mechanism of direct (nongenomic) action of antiestrogens on spontaneous and agonist-induced contractions of the human myometrium and uterine arteries., Study Design: Myometrial strips and pieces of uterine arteries were obtained from nonpregnant premenopausal women undergoing hysterectomy. Spontaneous activity of myometrium and responses of myometrium and artery to K(+)-depolarization and vasopressin were recorded under isometric conditions. Quantification of the responses was done by planimetry., Results: The 50% inhibitory concentration values for tamoxifen, clomiphene, and cyclofenil in the case of myometrial spontaneous activity were 2.8, 43, and 331 nmol/L, respectively. Vasopressin-induced contractions in both the myometrium and arteries were potently inhibited by tamoxifen, and the 50% inhibitory concentration for the myometrium (1.4 nmol/L) was significantly lower (p < 0.05) than that for the arteries (11 nmol/L). Although tamoxifen caused no inhibition of responses induced by high potassium chloride (80 mmol/L), responses induced by low potassium chloride (20 mmol/L) were inhibited by 40% to 50% in both the myometrium and arteries. Glibenclamide reversed the inhibition by tamoxifen of spontaneous myometrial activity., Conclusions: Tamoxifen is a highly potent inhibitor of the contractile activity of the human nonpregnant myometrium and uterine arteries. It is suggested that tamoxifen could have strong potential in the treatment of dysmenorrhea.

Objectives: The study aimed to compare endothelium-dependent relaxation in the resistance arteries of the uterine vascular bed by use of a systemic comparison and to investigate the role of the endothelium in adaptation to pregnancy in these vascular beds., Study Design: Myometrial and omental resistance arteries were collected from 22 normotensive pregnant women and 27 nonpregnant women of reproductive age. On a wire myograph and preconstricted with vasopressin, the arteries were relaxed with the endothelium-dependent vasodilator bradykinin., Results: The omental arteries showed a consistently greater endothelium-dependent relaxation than the myometrial arteries, both in the nonpregnant state (p < 0.0001) and in pregnancy (p = 0.008); pregnancy did not significantly alter this relaxation in arteries from either the myometrial (p = 0.2075) or omental (p = 0.372) vascular beds., Conclusions: The endothelium-dependent relaxation to bradykinin is less in myometrial resistance arteries than in omental resistance arteries. There appears to be no intrinsic difference between vessels from nonpregnant and pregnant women in endothelium-dependent response to bradykinin.

Objective: Our purpose was to study local angiotensin-converting enzyme activity and the mechanical effects of angiotensin I and II in human uteroplacental arteries., Study Design: Angiotensin-converting enzyme activity was measured by a simple radioimmunoassay with tritiated benzoyl-glycyl-glycyl-glycine as substrate in isolated human intramyometrial arteries from nonpregnant (n = 8) and term pregnant women (n = 8) and placental (n = 8) stem villous arteries. Moreover, in these vessels the mechanical effects of angiotensin I and II were investigated in organ bath experiments. Endothelium-intact and endothelium-denuded arteries were used, and the integrity of the endothelium was examined by histologic studies., Results: The activity of angiotensin-converting enzyme ranked the intramyometrial arteries from pregnant women >> intramyometrial arteries from nonpregnant women > fetal stem villous arteries. Angiotensin-converting enzyme activity was unaffected by removal of the endothelium. Angiotensin II 10(-5) mol/L produced contractile responses in the intramyometrial arteries without significant differences between arteries from nonpregnant and pregnant women. In fetal stem villous arteries the effects of angiotensin II 10(-5) mol/L were less pronounced. As for angiotensin II, the contractile responses to angiotensin I 10(-5) mol/L showed marked development of tachyphylaxis. In the endothelium-denuded preparations the contractile responses to angiotensin I 10(-5) mol/L were significantly enhanced in intramyometrial arteries from nonpregnant women but remained unchanged in intramyometrial arteries from pregnant women and in fetal stem villous arteries. In all preparations pretreatment with captopril or perindopril (10(-5) mol/L) markedly reduced angiotensin-converting enzyme activity, whereas no effects were observed on the contractile responses to angiotensin I. Saralasin 10(-5) mol/L completely abolished the contractile responses to angiotensin I and II., Conclusion: Local angiotensin-converting enzyme activity in human intramyometrial arteries seems to be markedly increased during pregnancy and shows marked differences between maternal and fetal uteroplacental arteries. High concentrations of angiotensin I may imply direct effects on the angiotensin II receptor independent of the local angiotensin-converting enzyme activity.

The mechanisms that mediate changes in uterine activity from a quiescent state during pregnancy to active labor at parturition are unknown. Nitric oxide (NO), a potent mediator of smooth muscle relaxation, and its presence in the uterus is the subject of this report. Nitric oxide synthase (NOS) activity was demonstrated in nerves, blood vessels and decidua of gravid rat uterus by the NADPH-diaphorase staining method. Uterine tissue fixed during labor demonstrated markedly less NOS. Quantitation of NOS activity in subcellular fractions of pregnant and laboring uterus revealed its presence in both the cytosolic and the membranous compartments of uterine homogenates. In both cellular subfractions the enzyme activity decreased significantly from pregnancy to term. We conclude NOS is present in multiple structures within the uterus. Its presence in two cellular compartments suggests more than one form of NOS may be present in the uterus. Reduction in NOS activity at parturition suggests NO may contribute to the maintenance of uterine contractile quiescence during gestation.

Objective: We hypothesized that arcuate arteries supplying placental and nonplacental myometrial portions would respond with different degrees of change in their resistance during Braxton Hicks contractions., Study Design: We examined 20 healthy pregnant women between 18 and 24 weeks' gestation with pulsed-wave and color-flow Doppler during focal Braxton Hicks contractions identified by real-time ultrasonography by means of the characteristic thickening of the myometrium. Systolic/diastolic ratio was used as an expression of resistance. Statistical analysis was performed by Wilcoxon signed-ranks and Mann-Whitney test., Results: When the contractions are localized in the subplacental myometrium, the resistance of the arcuate artery did not differ during and after the contraction. In contrast, when the contraction involved only nonplacental myometrium, the resistance during the contraction was significantly higher and in some patients there was complete absence of flow during the diastolic phase. During subplacental myometrial contractions, the main uterine artery resistance was not affected. When the contraction involved the nonplacental myometrium, the resistance of the main uterine artery increased with more pronounced changes when the contraction involved the lateral myometrial wall ipsilateral to the uterine artery under examination., Conclusion: We speculate that the differences in the degree of resistance change are the result of different degrees of contractility exhibited by the subplacental and nonplacental myometrium. We conclude that the intact human myometrium manifests functional asymmetry and our Doppler findings confirm previous in vitro studies.