Uterine Radial Artery Research Articles

Synergistic regulation of uterine radial artery adaptation to pregnancy by paracrine and hemodynamic factors.

Fetal growth throughout pregnancy relies on delivery of an increasing volume of maternal blood to the placenta. To facilitate this, the uterine vascular network adapts structurally and functionally, resulting in wider blood vessels with decreased flow-mediated reactivity. Impaired remodeling of the rate-limiting uterine radial arteries has been associated with fetal growth restriction. However, the mechanisms underlying normal or pathological radial artery remodeling are poorly understood. Here, we used pressure myography to determine the roles of hemodynamic (resistance, flow rate, shear stress) and paracrine [β-estradiol, progesterone, placental growth factor (PlGF), vascular endothelial growth factor] factors on rat radial artery reactivity. We show that β-estradiol, progesterone, and PlGF attenuate flow-mediated constriction of radial arteries from nonpregnant rats, allowing them to withstand higher flow rates in a similar manner to pregnant vessels. This effect was partly mediated by nitric oxide (NO) production. To better understand how the combination of paracrine factors and shear stress may impact human radial artery remodeling in the first half of gestation, computational models of uterine hemodynamics, incorporating physiological parameters for trophoblast plugging and spiral artery remodeling, were used to predict shear stress in the upstream radial arteries across the first half of pregnancy. Human microvascular endothelial cells subjected to these predicted shear stresses demonstrated higher NO production when paracrine factors were added. This suggests that synergistic effects of paracrine and hemodynamic factors induce uterine vascular remodeling and that alterations in this balance could impair radial artery adaptation, limiting blood flow to the placenta and negatively impacting fetal growth.NEW & NOTEWORTHY Placenta-specific paracrine factors β-estradiol, progesterone, and placental growth factor attenuate flow-mediated constriction of the rate-limiting uterine radial arteries, enabling higher flow rates in pregnancy. These paracrine factors induce their actions in part via nitric oxide mediated mechanisms. A synergistic combination of paracrine factors and shear stress is likely necessary to produce sufficient levels of nitric oxide during early human pregnancy to trigger adequate uterine vascular adaptation.

Successful Pregnancy and Delivery at Term Following Intravenous Immunoglobulin Therapy with Heparin for Unexplained Recurrent Pregnancy Loss Suspected of Immunological Abnormalities: A Case Report and Brief Literature Review

About 60% of cases of recurrent pregnancy loss have unexplained etiology. Immunotherapy for unexplained recurrent pregnancy loss is still unestablished. A 36-year-old woman, not obese, had a stillbirth at 22 gestational weeks and a spontaneous abortion at 8 weeks. She had been examined for recurrent pregnancy loss at previous clinics with no significant findings. When she visited our clinic, a hematologic test showed a Th1/Th2 ratio imbalance. Ultrasonography, hysteroscopy, and semen analysis showed no abnormalities. She successfully conceived by embryo transfer in hormone replacement therapy cycle. However, she had a miscarriage at 19 weeks. The baby had no deformities, but a chromosomal test was not performed, according to the parents' will. The placenta pathologically suggested hemoperfusion problems. Her and her husband's chromosomal tests showed normal karyotypes. Other examinations revealed a repeated Th1/Th2 ratio imbalance and a high resistance index of uterine radial artery blood flow. She was administered low-dose aspirin, intravenous immunoglobulin, and unfractionated heparin after the second embryo was transferred. Her baby was healthily born by cesarean section at 40 weeks. Intravenous immunoglobulin therapy can be a choice for recurrent miscarriage without risk factors because it has clinically beneficial influences on the patient's immunological aberration.

G-Protein-Coupled Estrogen Receptor Expression in Rat Uterine Artery Is Increased by Pregnancy and Induces Dilation in a Ca2+ and ERK1/2 Dependent Manner.

Increasing levels of estrogens across gestation are partly responsible for the physiological adaptations of the maternal vasculature to pregnancy. The G protein-coupled estrogen receptor (GPER) mediates acute vasorelaxing effects in the uterine vasculature, which may contribute to the regulation of uteroplacental blood flow. The aim of this study was to investigate whether GPER expression and vasorelaxation may occur following pregnancy. Elucidation of the functional signalling involved was also investigated. Radial uterine and third-order mesenteric arteries were isolated from non-pregnant (NP) and pregnant rats (P). GPER mRNA levels were determined and—concentration–response curve to the GPER-specific agonist, G1 (10−10–10−6 M), was assessed in arteries pre-constricted with phenylephrine. In uterine arteries, GPER mRNA expression was significantly increased and vasorelaxation to G1 was significantly enhanced in P compared with NP rats. Meanwhile, in mesenteric arteries, there was a similar order of magnitude in NP and P rats. Inhibition of L-type calcium channels and extracellular signal-regulated kinases 1/2 significantly reduced vasorelaxation triggered by G1 in uterine arteries. Increased GPER expression and GPER-mediated vasorelaxation are associated with the advancement of gestation in uterine arteries. The modulation of GPER is exclusive to uterine arteries, thus suggesting a physiological contribution of GPER toward the regulation of uteroplacental blood flow during pregnancy.

Pregnancy-specific uterine vascular reactivity: a data-driven computational model of shear-dependent, myogenic, and mechanical radial artery features.

`The entire maternal circulation adapts to pregnancy, and this adaption is particularly extensive in the uterine circulation where the major vessels double in size to facilitate an approximately 15-fold increase in blood supply to this organ over the course of pregnancy. Several factors may play a role in both the remodeling and biomechanical function of the uterine vasculature including the paracrine microenvironment, passive properties of the vessel wall, and active components of vascular function (incorporating the myogenic response and response to shear stress induced by intravascular blood flow). However, the interplay between these factors and how this plays out in an organ-specific manner to induce the extent of remodeling observed in the uterus is not well understood. Here we present an integrated assessment of the uterine radial arteries, likely rate limiters to the flow of oxygenated maternal blood to the placental surface, via computational modeling and pressure myography. We show that uterine radial arteries behave differently to other systemic vessels (higher compliance and shear-mediated constriction) and that their properties change with the adaptation to pregnancy (higher myogenic tone, higher compliance, and ability to tolerate higher flow rates before constricting). Together, this provides a useful tool to improve our understanding of the role of uterine vascular adaptation in normal and abnormal pregnancies and highlights the need for vascular bed-specific investigations of vascular function in health and disease.NEW & NOTEWORTHY To our knowledge, this is the first data-driven computational model of autoregulation of uterine radial arteries, likely rate limiters of maternal blood flow to the placenta. The study demonstrates that uterine radial arteries behave differently from systemic vessels (higher compliance, shear-mediated constriction) and change in pregnancy (higher myogenic tone, higher compliance, tolerance of higher flow rates). This pregnancy-specific mathematical model of vascular reactivity allows interrogation of the functional significance of incomplete vascular adaption in pathology.

Maternal Nanomaterial Inhalation Exposure: Critical Gestational Period in the Uterine Microcirculation is Angiotensin II Dependent.

Maternal inhalation exposure to engineered nanomaterials (ENM) has been associated with microvascular dysfunction and adverse cardiovascular responses. Pregnancy requires coordinated vascular adaptation and growththat are imperative for survival. Key events in pregnancy hallmark distinct periods of gestation such as implantation, spiral artery remodeling, placentation, and trophoblast invasion. Angiotensin II (Ang II) is a critical vasoactive mediator responsible for adaptations and is implicated in the pathology of preeclampsia. If perturbations occur during gestation, such as those caused by ENM inhalation exposure, then maternal-fetal health consequences may occur. Our study aimed to identify the period of gestation in which maternal microvascular functional and fetal health are most vulnerable. Additionally, we wanted to determine if Ang II sensitivity and receptor density is altered due to exposure. Dams were exposed to ENM aerosols (nano-titanium dioxide) during three gestational windows: early (EE, gestational day (GD) 2-6), mid (ME, GD 8-12) or late (LE, GD 15-19). Within the EE group dry pup mass decreased by 16.3% and uterine radial artery wall to lumen ratio (WLR) increased by 25.9%. Uterine radial artery response to Ang II sensitivity increased by 40.5% in the EE group. Ang II receptor density was altered in the EE and LE group with decreased levels of AT2R. We conclude that early gestational maternal inhalation exposures resulted in altered vascular anatomy and physiology. Exposure during this time-period results in altered vascular reactivity and changes to uterine radial artery WLR, leading to decreased perfusion to the fetus and resulting in lower pup mass.

Ageing impairs restoration of endometrial blood flow impedance after laparoscopic myomectomy in infertile women with uterine fibroids

The aim of this study was to evaluate temporal changes in endometrial blood flow after laparoscopic myomectomy (LM). Nineteen infertile women with uterine fibroids who underwent LM were included. The uterine radial artery resistance index (RA-RI) and recovery index were measured before and at 1 week and 3 months after LM. The median RA-RI at 1 week but not 3 months after LM was significantly higher than before. The median recovery indexes at 1 week and 3 months after LM were 14.3% and 1.3%, respectively. Although there was no significant correlation between the patient’s age and recovery index at 1 week (r = 0.28, p = .24) after LM, a moderately significant correlation was observed at 3 months (r = 0.54, p = .002). In conclusion, the endometrial blood flow after LM changed over time, and recovery of blood flow was negatively correlated with patient age. IMPACT STATEMENT What is already known on this subject? Uterine blood flow is important for wound healing after myomectomy, but no studies have evaluated endometrial blood flow after myomectomy. What do the results of this study add? The endometrial blood flow impedance of RA-RI increased after LM and returned to before surgery at 3 months postoperatively. RA-RI recovery index negatively correlated with patient age. What are the implications of these findings for clinical practice and/or further research? The changes in endometrial blood flow impedance after myomectomy suggest that endometrial blood flow may be involved in wound healing at the enucleation site. The impairment of endometrial blood flow recovery after myomectomy due to increased age may provide a rationale for individualised wound healing after myomectomy. The measurement of endometrial blood flow may be useful in personalising the assessment of the waiting period for pregnancy after myomectomy.

Relationship between temporal changes of endometrial blood flow impedance during natural and hormone replacement cycles and prediction of pregnancy during vitrified-warmed embryo transfer.

This study aimed to examine the relationship between the temporal changes in endometrial blood flow impedance during natural and hormone replacement therapy (HRT) cycles and clinical outcomes of vitrified-warmed embryo transfer (ET). This retrospective observational cohort study included 60 women, 28 with natural, and 32 with HRT cycles, who underwent vitrified-warmed ET. Uterine radial artery resistance index (RA-RI) was measured during the natural and HRT cycles at the following time points: early follicular phase, day of the human chorionic gonadotropin injection during a natural cycle or day of progesterone administration during an HRT cycle, and day of ET. The clinical pregnancy rates of the natural and HRT cycles were 32.1% and 34.4%, respectively. The RA-RI at the early follicular phase was significantly lower in the pregnant group than in the nonpregnant group with natural but not HRT cycles (p = 0.04). The odds ratio for pregnancy was 0.70 (95% confidence interval [CI], 0.52-0.95) when the RA-RI value at the early follicular phase was increased by 0.01 in the natural cycle. With the natural cycle, the area under the receiver-operating characteristic curves for the RA-RI at the early follicular phase with a threshold of 0.68 was 0.75 (95% CI, 0.57-0.93), and the positive and negative predictive values were 0.53 (95% CI, 0.37-0.59) and 0.92 (0.74-0.99), respectively. RA-RI at the early follicular phase might be an effective and useful tool for deciding between natural or HRT cycles for vitrified-warmed ET.

ULTRASOUND PARAMETERS AND THE STATE OF UTERINE HEMODYNAMICS IN WOMEN WITH MENSTRUAL DYSFUNCTION IN PUBERTY

The study of hemodynamic features of the pelvic organs in women is of great clinical importance, since it allows assessing the degree of recovery of endometrial regeneration after menstruation, the possibility of implantating a fertilized egg and placental development. Women who have had menstrual dysfunction in puberty, the determination of qualitative and quantitative parameters of uterine hemodynamics can be useful while choosing treatment tactics, evaluating its effectiveness, and will also provide significant assistance in predicting the prospects for their reproductive health. The purpose of the study. To examine the hemodynamics of uterus and assess the ability of endometrium to implant in women with menstrual dysfunction in puberty with the help of ultrasound and dopplerometry.Materials and methods. To achieve the set goals, 120 women of reproductive age from 19 to 32 years old were examined. By the nature of the disorders, the main group of women (n = 90) with menstrual dysfunction in puberty were divided into 3 subgroups (n = 30): the first group - women with primary oligomenorrhea, the second one - with late menarche, the third one - with pubertal bleeding. The control group consisted of women (n = 30) with the correct rhythm of menstruation in puberty. Results. On the basis of a comparative analysis of the echographic parameters of the size of the uterus in women with menstrual dysfunctions in puberty (main group) and women with the correct rhythm of menstruation (control group), it was found that, on the average stage of endometrial secretion, the volume of the uterus is 1, 2 times smaller in women of the main group (p˂0.05) due to the width of the body of the uterus (p˂0.001). The ratio between the length of the body and cervix in the examined groups did not differ significantly. The thickness of the anterior wall of the uterus is less than the control values in women with late menarche (p˂0.05) and pubertal bleeding (p˂0.01), which was a predictor of the absence of combined uterine pathology. Echographic examination of the thickness of the endometrium at a late stage of the proliferation phase in the examined women did not reveal significant differences with the control group. In the middle stage of the secretion phase, the thickness of the endometrium was less in women, who had menstrual dysfunction in puberty - 9.50 ± 0.27 mm versus 11.38 ± 0.48 mm in the group with the correct menstruation rhythm (p <0.001), but remained within the reference values. Dopplerometry of uterine arteries was performed to assess the functional activity and the possibility of sectorial transformation of the endometrium, which did not reveal significant differences in women of the main and control groups. Conclusions. An analysis of the ratio between the body length and the cervix of the uterus proves the absence of signs of genital infantilism in patients with menstrual dysfunctions in puberty. Doppler studies of hemodynamics in the arteries of uterus in this group of women in different phases of the menstrual cycle indicate an adequate blood supply to the uterus. Although the inferior phase of proliferation of endometrial thickness in its middle stages remained insufficient secretion (9,52 ± 0,42 mm; p <0.01), however, the normal blood flow in the radial and basal uterine arteries contributed to the successful implantation of the blastocyst.

RELATIONSHIP BETWEEN TEMPORAL CHANGES OF ENDOMETRIAL BLOOD FLOW IMPEDANCE IN A NATURAL AND HORMONE REPLACEMENT CYCLE AND PREDICTION OF PREGNANCY DURING VITRIFIED-WARMED EMBRYO TRANSFER

Frozen-thawed embryo transfer (ET) is performed in a natural or hormone replacement therapy (HRT) cycle for endometrial preparations. However, how to determine which endometrial preparation method is suitable for the individual is unknown.This study was to examine the relationship between the temporal changes in endometrial blood flow impedance during natural and HRT cycles and clinical outcomes in vitrified-warmed ET. A single-center retrospective observational cohort study. This study was approved by the institutional review board of the Fukushima Medical University. This study included a total of 60 women, 28 with natural and 32 with HRT cycles, who underwent vitrified-warmed ET. Uterine radial artery resistance index (RA-RI) was measured during the natural and HRT cycles at the early follicular phase, days of the human chorionic gonadotropin trigger during a natural cycle or start of progesterone administration during the HRT cycle, and the day of ET. The association between the RA-RI at the different measurement point and the pregnancy were examined in the natural and HRT cycles by univariate analysis and multivariate logistic analysis. Receiver-operating characteristic analysis was used to determine the cut-off value of the RI with respect to pregnancy in natural and HRT cycles. The area under the curves (AUC) and their 95% confidence intervals (CI) were calculated. The clinical pregnancy rates of the natural and HRT cycles were 32.1% and 34.4%, respectively. In the univariate analysis, the RA-RI at the early follicular phase was significantly lower in the pregnant group than that in the non-pregnant group in the natural but not HRT cycle (P=0.04). In the multivariate logistic analysis, the RA-RI at the early follicular phase was an independent predictive factor for pregnancy in the natural but not HRT cycle (P=0.02). The odds ratio for pregnancy was 0.7 (95% CI, 0.52–0.95) when the levels of RA-RI at the early follicular phase was increased by 0.01 in the natural cycle. With the natural cycle, the area under the receiver-operating characteristic curves for the RA-RI at the early follicular phase with a threshold of 0.68 was 0.75 (95% CI, 0.57–0.93). The positive predictive and negative predictive values were 0.53 (95% CI, 0.37–0.59) and 0.92 (0.74–0.99), respectively. With the natural cycle, the RA-RI at the early follicular phase was associated with pregnancy, and this might have a potential in predicting pregnancy in vitrified-warmed ET cycles. Our findings suggest that RA-RI at the early follicular phase might be an effective and useful tool in choosing natural or HRT cycles for vitrified-warmed ET. This provides a clue to the individualization of the choice of an endometrial preparation method during the frozen-thawed ET.

Enhanced Vascular Smooth Muscle Calcium Sensitivity and Loss of Endothelial Vasodilator Influence Contribute to Myogenic Tone Development in Rat Radial Uterine Arteries during Gestation

Uterine artery myogenic tone (MT) develops during pregnancy in hemochorial placentates such as rats and humans. The physiological reason for its appearance is not clear, and we reasoned that it may be a late pregnancy (LP) event in preparation for controlling hemorrhage during parturition. We also hypothesized that gestational increases in RhoA-induced vascular smooth muscle (VSM) calcium sensitivity are contributory and occur under the tonic influence of nitric oxide (NO). Second-order pre-placental radial arteries from early-pregnant (day 12, n = 5), mid-pregnant (day 16, n = 5) and LP (day 20, n = 20) rats were used in combination with arteriography, VSM calcium measurements, pharmacological RHO/Rho-associated protein kinase (ROCK) and nitric oxide synthase (NOS) inhibition, and Western blotting. A subgroup of LP animals (LP + LN; n = 5) treated with L-NAME from gestational days 10 to 20 were used to determine the effects of NOS inhibition on MT and RhoA expression. MT was evident throughout pregnancy, but its expression in pressurized vessels was masked by endothelial NO-induced vasodilation during early gestation. RhoA protein expression was upregulated in LP and attenuated by in vivo NOS inhibition (as was MT). In vitro RHO/ROCK inhibition decreased MT in a concentration-dependent manner without reducing VSM calcium. In summary, pressure-dependent uterine artery tone increases with gestational age due to a combination of RhoA-mediated increases in VSM calcium sensitivity and a loss of endothelial NO influence.

Uterine Radial Artery Resistance Index Predicts Reproductive Outcome in Women with Recurrent Pregnancy Losses and Thrombophilia.

Uterine radial artery resistance index (URa-RI) by Doppler ultrasound may reflect the changes in the uteroplacental circulation and be associated with adverse events in early pregnancy. Recurrent pregnancy losses (RPL) are associated with thrombophilia, and anticoagulation treatment with low molecular weight heparin improves pregnancy outcome in women with RPL and thrombophilia. A retrospective cohort study was conducted in 139 pregnant women with 3 or more RPL and thrombophilia. The relationship between pregnancy outcome and dynamic changes of URa-RI was analyzed in 116 women who delivered a liveborn infant and 23 who miscarried the index pregnancy. Patients were on preconception low molecular weight heparin, low-dose aspirin (81mg per day), and prednisone treatment. URa-RI was measured during periovulation time, at the time of positive pregnancy test, and then repeated every two weeks until 32-week gestation or the time of miscarriage. The URa-RI at 8-week gestation was significantly higher in women who miscarried the index pregnancy than those who delivered alive born infant (0.51±0.08 vs. 0.42±0.03, P<0.001). Receiver operating characteristic curve analysis demonstrated that URa-RI of 8 wk gestation effectively distinguished women who miscarried from those who had a live birth with an area under the curve of 82.6% (95% CI 69.01-97.17). After adjusting for covariates including age, BMI, and number of miscarriages, multiple logistic regression models showed that each 0.1 unit increase of URa-RI of 8 wk gestation was associated with 18.70-point increase in the risk of miscarriage (OR19.70, 95%CI 4.26-91.1, P<0.001), and women with an URa-RI≥0.45 had an OR of 49.48 (95% CI 8.01-307.95; P<0.001) for miscarriage compared to those who had URa-RI<0.45. In women with RPL and inherited thrombophilia, increased URa-RI at 8-week gestation was associated with spontaneous abortion independent of other risk factors while they were on anticoagulation treatment.

Resistance of uterine radial artery blood flow was correlated with peripheral blood NK cell fraction and improved with low molecular weight heparin therapy in women with unexplained recurrent pregnancy loss

Female reproductive mucosa must allow allogenic sperm survival whereas at the same time, avoid pathogen infection. To preserve sperm from neutrophil attack, neutrophils disappear from the vagina during the ovulatory phase (high estradiol); although the mechanisms that regulate neutrophil influx to the vagina during insemination remain controversial.We investigated the sex hormone regulation of the neutrophil migration through the cervix during insemination and revealed that ovulatory estradiol dose fades the CXCL1 epithelial expression in the ectocervix and fornix; hence, retarding neutrophil migration and retaining them in the epithelium. These mechanisms spare sperm from neutrophil attack to preserve reproduction, but might compromise immunity. However, luteal progesterone dose promotes the CXCL1 gradient expression to restore neutrophil migration, to eliminate sperm and prevent sperm associated pathogen dissemination. Surprisingly, these mechanisms are hormone dependent and independent of the insemination. Thus, sex hormones orchestrate tolerance and immunity in the vaginal lumen by regulating neutrophil transepithelial migration in the fornix and ectocervix.

Trophoblast plugs: impact on utero-placental haemodynamics and spiral artery remodelling.

How does trophoblast plugging impact utero-placental haemodynamics? Physiological trophoblast plug structures are dense enough to restrict flow of oxygenated blood to the intervillous space (IVS) in the first trimester, and result in a shear stress environment upstream of the plugs that promotes spiral artery remodelling. Trophoblast plugging of the uterine spiral arteries is thought to be the dominant factor restricting the flow of oxygenated maternal blood to the placenta in the first trimester of pregnancy. However, the extent of plugging, the timing of plug break up, and the impact of plug structure on pregnancy outcomes is debated. A computational model of the uterine radial and spiral arteries, incorporating arteriovenous anastomoses was developed. The model was parameterized with our own histological data and previous literature descriptions of the dimensions of the spiral arteries, and the structural properties (porosity) of trophoblast plugs. Structural data were acquired from the literature, and supplemented by images of the spiral arteries acquired by standard thin-section 2D immunohistochemistry, and whole mount immunohistochemistry imaged in 3D by micro-CT. Computational models were solved using Matlab software, via custom written scripts. We confirm that physiological lengths (>0.1 mm) and porosities (0.2-0.6) of trophoblast plugs are sufficient to restrict the flow of oxygenated maternal blood flow to the placental surface. Trophoblast plugs also have important haemodynamic consequences upstream in the spiral arteries by generating shear stress conditions of <2 dyne/cm2 that promote trophoblast-induced spiral artery remodelling. Structural changes in plugs as they dislodge are likely to result in rapid increases in blood flow to the IVS, and it is likely at this stage of gestation that the major source of resistance in the utero-placental circulation transitions from the spiral arteries to the radial arteries, which then act as a the 'rate-limiting' step to IVS flow. Structural descriptions of the spiral arteries, radial arteries and trophoblast plugs largely rely on 2D histological sections, or historical measurements. Increased focus on quantitatively assessing the 3D structure of the uterine arteries using more modern imaging technologies in the future will strengthen model predictions. Our work suggests that trophoblast plugs play a previously under-appreciated role in regulating spiral artery remodelling in the first trimester of human pregnancy. This creates the possibility that inadequate trophoblast plugging in the first trimester may contribute to the inadequate artery remodelling observed in pregnancy pathologies such as pre-eclampsia. The incorporation of arteriovenous anastomoses in our model highlights the important influence that shunted blood can play in utero-placental haemodynamics, and together with the emerging role of radial arteries in regulating blood flow to the placenta, the influence of arteriovenous anastomoses on radial artery haemodynamics in normal and pathological pregnancies warrants further investigation. This research was supported by a Royal Society of New Zealand Marsden Fund award (13-UOA-032). A.R.C. is supported by a Royal Society of New Zealand Rutherford Discovery Fellowship (14-UOA-019). R.S. was supported by a Gravida (National Centre for Growth and Development) postgraduate scholarship. The authors have no conflicts of interest. N/A.

P3: Uterine radial artery blood flow resistance at 8‐week gestation indicates pregnancy loss in recurrent pregnancy loss women with inherited thrombophilia

P3: Uterine radial artery blood flow resistance at 8‐week gestation indicates pregnancy loss in recurrent pregnancy loss women with inherited thrombophilia

Activated NO pathway in uterine arteries during pregnancy in an IUGR rat model.

Insufficient development of the uteroplacental circulation may contribute to the development of intrauterine growth restriction (IUGR). We developed a rat model of IUGR by administering a low-Na+ diet. This diet reduces maternal blood volume expansion and uteroplacental perfusion. We hypothesized that an impaired endothelial function in radial arteries decreases vasorelaxation and lowers placental perfusion in this IUGR model. The objective was to assess radial uterine artery responses to vasoactive agents in the IUGR model versus controls. The vasoactive agents included phenylephrine and carbachol, use of a pressurized artery myograph, in the absence or presence of inhibitors of nitric oxide (NO) synthase [ N-nitro-l-arginine methyl ester (l-NAME)], cyclooxygenase (Ibuprofen), and endothelium-dependent hyperpolarization {apamin/1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole}, allowing better characterization of the mechanism implicated in endothelium-dependent relaxation. The results show that 1) the diameter of uterine radial arteries was significantly decreased in the IUGR group; 2) sensitivity to phenylephrine was reduced in IUGR arteries, which could be returned to control group values by inhibition of NO production; 3) the relaxation response to carbachol was increased in IUGR rats, principally mediated by endothelium-dependent hyperpolarization in both groups; 4) NO synthase inhibition by l-NAME decreased the maximum relaxation to carbachol only in the IUGR group; and 5) relaxation response to NO donors is increased in IUGR compared with control radial arteries. Contrary to the hypothesis, results in the IUGR model indicate that the NO pathway is activated in radial uterine arteries, most likely in compensation for the reduction in blood uteroplacental perfusion. NEW & NOTEWORTHY In contrast to genetic or surgical models of intrauterine growth restriction, the diet-induced model of reduced maternal volume expansion shows the nitric oxide pathway to be activated in the uterine artery, possibly from increased shear stress and/or placental factors.

Serial Evaluation of Endometrial Blood Flow for Prediction of Pregnancy Outcomes in Patients Who Underwent Controlled Ovarian Hyperstimulation and In Vitro Fertilization and Embryo Transfer.

To investigate endometrial blood flow during the menstrual cycle in patients undergoing controlled ovarian hyperstimulation (COH), in vitro fertilization (IVF), and embryo transfer (ET) and prediction of pregnancy outcomes based on these characteristics. Endometrial blood flow was measured in 35 patients undergoing COH and IVF-ET (nonpregnant [n = 15] and pregnant [n = 20]) by measuring the resistive index (RI) of the uterine radial artery using 2-dimensional Doppler ultrasonography. Measurements were obtained in 4 different phases of the menstrual cycle day: early follicular, midfollicular, preovulatory, and midluteal. The uterine radial artery RI during the early follicular phase was significantly lower in the pregnant group than in the nonpregnant group (mean ± SD, 0.61 ± 0.01 versus 0.66 ± 0.01; P = .029). There was no significant difference between groups during the midfollicular, preovulatory, and midluteal phases (mean ± SD, 0.60 ± 0.02 versus 0.60 ± 0.01; P = .84; 0.61 ± 0.09 versus 0.57 ± 0.01; P = .12; 0.54 ± 0.01 versus 0.57 ± 0.02; P = .32, respectively). There was a significant difference in endometrial blood flow between the pregnant and nonpregnant groups during each phase (P = .016). The difference in the changes of the uterine radial artery RI from the preovulatory to midluteal phase between the pregnant and non pregnant groups was significant (-0.002 ± 0.03 versus 0.07 ± 0.02; P = .038). Increased endometrial blood flow during the midluteal phase, compared to the preovulatory phase, may correlate with successful COH and IVF-ET. Additionally, sufficient blood flow at initiation of COH may affect COH and IVF-ET results.

TRPV3 expression and vasodilator function in isolated uterine radial arteries from non-pregnant and pregnant rats

This study investigated the expression and function of transient receptor potential vanilloid type-3 ion channels (TRPV3) in uterine radial arteries isolated from non-pregnant and twenty-day pregnant rats. Immunohistochemistry (IHC) suggested TRPV3 is primarily localized to the smooth muscle in arteries from both non-pregnant and pregnant rats. IHC using C′ targeted antibody, and qPCR of TRPV3 mRNA, suggested pregnancy increased arterial TRPV3 expression. The TRPV3 activator carvacrol caused endothelium-independent dilation of phenylephrine-constricted radial arteries, with no difference between vessels from non-pregnant and pregnant animals. Carvacrol-induced dilation was reduced by the TRPV3-blockers isopentenyl pyrophosphate and ruthenium red, but not by the TRPA1 or TRPV4 inhibitors HC-030031 or HC-067047, respectively. In radial arteries from non-pregnant rats only, inhibition of NOS and sGC, or PKG, enhanced carvacrol-mediated vasodilation. Carvacrol-induced dilation of arteries from both non-pregnant and pregnant rats was prevented by the IKCa blocker TRAM-34. TRPV3 caused an endothelium-independent, IKCa-mediated dilation of the uterine radial artery. NO-PKG-mediated modulation of TRPV3 activity is lost in pregnancy, but this did not alter the response to carvacrol.

Placental Underperfusion in a Rat Model of Intrauterine Growth Restriction Induced by a Reduced Plasma Volume Expansion.

Lower maternal plasma volume expansion was found in idiopathic intrauterine growth restriction (IUGR) but the link remains to be elucidated. An animal model of IUGR was developed by giving a low-sodium diet to rats over the last week of gestation. This treatment prevents full expansion of maternal circulating volume and the increase in uterine artery diameter, leading to reduced placental weight compared to normal gestation. We aimed to verify whether this is associated with reduced remodeling of uteroplacental circulation and placental hypoxia. Dams were divided into two groups: IUGR group and normal-fed controls. Blood velocity waveforms in the main uterine artery were obtained by Doppler sonography on days 14, 18 and 21 of pregnancy. On day 22 (term = 23 days), rats were sacrificed and placentas and uterine radial arteries were collected. Diameter and myogenic response of uterine arteries supplying placentas were determined while expression of hypoxia-modulated genes (HIF-1α, VEGFA and VEGFR2), apoptotic enzyme (Caspase -3 and -9) and glycogen cells clusters were measured in control and IUGR term-placentas. In the IUGR group, impaired blood velocity in the main uterine artery along with increased resistance index was observed without alteration in umbilical artery blood velocity. Radial uterine artery diameter was reduced while myogenic response was increased. IUGR placentas displayed increased expression of hypoxia markers without change in the caspases and increased glycogen cells in the junctional zone. The present data suggest that reduced placental and fetal growth in our IUGR model may be mediated, in part, through reduced maternal uteroplacental blood flow and increased placental hypoxia.

Resistance of Uterine Radial Artery Blood Flow was Correlated with Peripheral Blood NK Cell Fraction and Improved with Low Molecular Weight Heparin Therapy in Women with Unexplained Recurrent Pregnancy Loss

To investigate whether peripheral blood natural killer (pbNK) cell levels are associated with uterine blood flow, and low molecular weight heparin (LMWH) treatment is effective to improve uterine blood flow in women with decreased uterine blood flow and unexplained recurrent pregnancy loss (RPL). This was a prospective controlled study. Study population included 33 pregnant women (between 5 and 7 weeks gestation) with ≥ 2 RPL and controls were 47 healthy pregnant women. pbNK cell fractions (CD3(-)/56(+)/16(+)) of peripheral blood mononuclear cells were measured by flow cytometry. Uterine color-pulsed Doppler ultrasound was performed to evaluate uterine radial artery resistance index (URa-RI). In RPL women with elevated URa-RI (≥ 0.5), LMWH (ranges 40-60 mg/day) was administered subcutaneously daily and URa-RI was reassessed 1 week later. Pregnancy outcome was analyzed at 12 weeks gestation. URa-RI was significantly higher in pregnant women with RPL than controls (0.60 ± 0.14 versus 0.54 ± 0.12, P = 0.039). In pregnant women with RPL, pbNK cell fractions displayed a positive correlation with URa-RI (Pearson's r = 0.429, P = 0.013). URa-RI was significantly decreased 1 week after LMWH treatment as compared to that of pretreatment (pretreatment RI: 0.65 ± 0.11 versus post-treatment RI: 0.56 ± 0.13, P = 0.011). Pregnancy outcome of RPL women with LMWH treatment was not different from that of pregnant controls (73.3% versus 85.0%, P = NS). Increased pbNK cells are associated with decreased uterine radial artery blood flow. LMWH treatment effectively decreases URa-RI with improved pregnancy outcome in women with RPLs and elevated URa-RI. A larger scale study is needed to verify these findings.

Inflammatory immune responses and uterine radial artery blood flow in pregnant women with recurrent pregnancy losses: comparison of delivery and abortion groups

Inflammatory immune response and its role in angiogenesis are important determinants of a successful pregnancy. Ultrasonographic evaluation of blood flow using Doppler technique may reflect progress of angiogenesis at maternal fetal junction. In this study, we aim to investigate the relationship of the uterine radial artery resistance index (U-RI) and immune inflammatory markers in RPL patients during pregnancy, who were under preconception anti-coagulant, prednisone and/or intravenous immunoglobulin (IVIg) treatment.