Increase In Uterine Blood Flow Research Articles

ICI 182,780 Attenuates Selective Upregulation of Uterine Artery Cystathionine β-Synthase Expression in Rat Pregnancy.

Endogenous hydrogen sulfide (H2S) produced by cystathionine β-synthase (CBS) and cystathionine-γ lyase (CSE) has emerged as a novel uterine vasodilator contributing to pregnancy-associated increases in uterine blood flow, which safeguard pregnancy health. Uterine artery (UA) H2S production is stimulated via exogenous estrogen replacement and is associated with elevated endogenous estrogens during pregnancy through the selective upregulation of CBS without altering CSE. However, how endogenous estrogens regulate uterine artery CBS expression in pregnancy is unknown. This study was conducted to test a hypothesis that endogenous estrogens selectively stimulate UA CBS expression via specific estrogen receptors (ER). Treatment with E2β (0.01 to 100 nM) stimulated CBS but not CSE mRNA in organ cultures of fresh UA rings from both NP and P (gestational day 20, GD20) rats, with greater responses to all doses of E2β tested in P vs. NP UA. ER antagonist ICI 182,780 (ICI, 1 µM) completely attenuated E2β-stimulated CBS mRNA in both NP and P rat UA. Subcutaneous injection with ICI 182,780 (0.3 mg/rat) of GD19 P rats for 24 h significantly inhibited UA CBS but not mRNA expression, consistent with reduced endothelial and smooth muscle cell CBS (but not CSE) protein. ICI did not alter mesenteric and renal artery CBS and CSE mRNA. In addition, ICI decreased endothelial nitric oxide synthase mRNA in UA but not in mesenteric or renal arteries. Thus, pregnancy-augmented UA CBS/H2S production is mediated by the actions of endogenous estrogens via specific ER in pregnant rats.

Assessment of Hematological Parameters and Uterine Hemodynamic Indices in Bitches with Pyometra

Background: Pyometra is defined as chronic purulent inflammation of the uterus that causes changes in hematological and biochemical parameters. The disease is characterized with bacterial infection and pus accumulation in the uterus. Transabdominal B-mode ultrasonography provides easy and certain diagnosis of this disease. The hemodynamic changes in pyometra are evaluated by Doppler ultrasonography. The aim of the study is to determine the changes in hematological parameters and Doppler indices in bitches with pyometra, diestrus healthy bitches and evaluate the relationship between hematological parameters and hemodynamic indices within the both groups.Materials, Methods & Results: A total number of 27 bitches were enrolled in the study. The healthy diestrus bitches (group H; n = 7) aged 6.2 ± 1.14 years, weighted 14.57 ± 3.75 kg. The bitches with pyometra (group PYO; n = 20) aged 9.1 ± 0.62 years and weighted 17.65 ± 2.60 kg. Before all bitches had ovariohisterectomy, hematological analyses were performed. Transabdominal ultrasonography (USG) was performed with a 6.6 MHz convex transducer. The widest cross-sectional uterine diameter (UD), wall thickness of uterine horns (UWT) and presence of luminal content were evaluated. Diameter of the uterine artery (DUA) was measured on a mapped color image using the USG software program. The examination was carried out with pulsed-wave Doppler USG to characterize the waveform of the uterine artery (UA). Anechogenic areas in uterine lumen, increase in UD and UWT were observed in group PYO. All cases in group PYO had luminal content in both uterine horns ranging from 1.2 to 5.6 cm. The DUAs were measured in group H and in group PYO as 1.75 ± 0.03 mm, 1.94 ± 0.08 mm; respectively (P < 0.05). The PI and RI values of group PYO were lower than group H (P < 0.001). Hematological analysis results showed that RBC, HGB, HCT levels in group PYO were lower than group H (P < 0.001). However, WBC, NEU, LYM, MONO levels in group PYO were higher than group H. Hemodynamic indices were positively correlated with RBC, HGB, HCT, whereas they were inversely correlated with NEU, WBC, UD and UWT. Also, PI value was negatively correlated with MONO.Discussion: Cystic endometrial hyperplasia (CEH) is a predisposing factor for development of the pyometra in bitches. Besides, naturally occurring CEH and pyometra can arise independently from each other. The enlarged uterine body exhibits the development of intense exudative processes due to the higher proliferative stimulation in uterine infections. Uterine infections were associated with increase in uterine blood flow. Elevated uterine blood flow, vasodilatation and angiogenesis arise during inflammatory response. The inflammatory process leads to a diminution in hemodynamic indices of uterine arteries. Total blood count parameters are affected from the presence of pyometra. Elevated levels of leukocytes in bitches with pyometra are associated with worsening prognosis. Erythrocyte diapedesis into the lumen of the uterus, toxic depression of erythropoiesis in the bone marrow can cause anemia. In conclusion, hematological parameters were strongly correlated with hemodynamic indices in this study. Reduced RBC, HGB and HCT levels, decreased PI and RI values and elevated levels of UD, UWT, DUA were observed in group PYO. To our knowledge, this was the first study that observed the increase in DUA during pyometra in bitches.

Doppler ultrasound for prediction of IUCD-induced heavy menstrual bleeding: a prospective cohort study

BackgroundPrevious studies reported changes in the local vasoactive substance production within the endometrium with a subsequent increase in vascularity as a possible mechanism of intrauterine contraceptive device (IUCD)-induced heavy menstrual bleeding. This research investigates the role of power Doppler velocimetries of the uterine arteries, endometrium, and sub-endometrium vascularization as a predictor of IUCD-induced heavy menstrual bleeding.ResultsEndometrium flow index (FI) and vascularization flow index (VFI) significantly increased in both groups: women with heavy menstrual bleeding (group A) and women without heavy menstrual bleeding (group B), with significantly higher increase in group A. Endometrium VFI ≥ 0.18 had the highest significant diagnostic characteristics in the prediction of heavy menstrual bleeding, followed by sub-endometrium VI ≥ 3.75.ConclusionThe results of this study suggest an increase in uterine blood flow in women with IUCD-induced menorrhagia. Endometrial and sub-endometrial Doppler vascular indices can be used for the prediction of IUCD-induced heavy menstrual bleeding.

Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy.

Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal–fetal exchanges of respiratory gases and to provide sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remain incompletely understood, but this is associated with elevated estrogens, which stimulate specific estrogen receptor (ER)-dependent vasodilator production in the uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. The activation of these three ERs by estrogens enhances the endothelial production of nitric oxide (NO), which has been shown to play a key role in uterine vasodilation during pregnancy. However, the local blockade of NO biosynthesis only partially attenuates estrogen-induced and pregnancy-associated uterine vasodilation, suggesting that mechanisms other than NO exist to mediate uterine vasodilation. In this review, we summarize the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a “new” UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.

Phase-1 clinical study of tadalafil administered for selective fetal growth restriction in twin pregnancy

Background Selective fetal growth restriction (sFGR) is a condition of twin pregnancy in which the development of one fetus is restricted, despite normal growth of the other fetus. A method of intrauterine therapy for sFGR does not currently exist. The only treatment for sFGR is to terminate the pregnancy before the FGR worsens. In twin pregnancies, maternal and intrauterine environments are common in both fetuses, thus a placental factor is considered the cause of FGR in fetuses. Tadalafil is a phosphodiesterase (PDE)-5 inhibitor that induces an increase in uterine blood flow by dilatation of blood vessels in cases of FGR with placental dysfunction, which improves FGR. Purpose The aim of this study was to investigate the safety and maximum tolerated dose (MTD) of tadalafil administered for twin pregnancy (diamniotic-monochorionic twin or diamniotic-dichorionic twin). Methods In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) for twin pregnancy received tadalafil (20 or 40 mg/d) as a single dose by oral administration from the day they were diagnosed with sFGR, defined as estimated fetal weight (EFW) < 3% tiles, that is, −1.8 SD the mean EFW for gestational age (GA) to unacceptable toxicity or the day of delivery. This study evaluated the safety of maternally administered tadalafil for sFGR, examining maternal, fetal, and neonatal adverse events. Maternal adverse events were graded on the basis of the Common Terminology Criteria for Adverse Events v4.0. Results Six women with sFGR who were pregnant with twins were treated with tadalafil. There were no severe adverse events in either cohort, although the most common (≥3 patients) drug-related adverse events were headache and heart failure. The MTD of tadalafil among Japanese patients was 40 mg. Conclusions Tadalafil has a manageable safety profile up to an MTD of 40 mg/d.

Pregnancy upregulates angiotensin type 2 receptor expression and increases blood flow in uterine arteries of rats.

Normal pregnancy is associated with decreased uterine vascular contraction and increased blood flow even though angiotensin II (AngII) levels are increased. AngII not only activates the angiotensin type 1 receptor (AT1R) to mediate vasoconstriction but also angiotensin type 2 receptor (AT2R) to cause vasodilation. We hypothesized that upregulation of AT2R expression and function accounts for increased uterine artery blood flow during pregnancy. Virgin, pregnant (at different days of gestation) and post-partum Sprague-Dawley rats were used to determine uterine artery hemodynamics using micro ultrasound and plasma angiotensin II levels by ELISA. Isolated uterine arteries were examined for AT1R and AT2R expression and isometric contraction/relaxation. Plasma AngII levels were steady up to mid-pregnancy, increased as pregnancy advanced, reaching a peak in late pregnancy, and then restored to pre-pregnant levels after delivery. The pattern of increase in AngII levels mirrored a parallel increase in uterine blood flow. AT1R expression did not change, but AT2R expression increased during pregnancy correlating with uterine blood flow increase. Treatment with the AT2R antagonist PD123319 reduced uterine arterial blood flow. Vasoconstriction to angiotensin II was blunted in pregnant rats. Treatment with PD123319 caused greater enhancement of AngII contraction in pregnant than virgin rats. Ex vivo exposure of estradiol to uterine arterial rings dose dependently upregulated AT2R expression, that was inhibited by estrogen receptor antagonist. These results demonstrate that elevated AngII levels during gestation induce an increase in uterine blood flow via heightened AT2R-mediated signaling. Estrogens appear to directly upregulate uterine vascular AT2R independent of any endogenous factors.

Pregnancy Enhances Calcium Spark Activity Independent of Altitude in Ovine Uterine Arterial Myocytes

During pregnancy, uterine artery blood flow increases in order to accommodate the growing fetus. However, the molecular mechanisms by which this change in uterine blood flow occurs remains to be elucidated. The BKCa channel, which is activated in response to ryanodine receptor (RyR) generated increases in intracellular Ca2+ known as Ca2+ sparks, helps regulate uterine artery blood flow. BKCa channel activation leads to vascular smooth muscle relaxation, thus decreasing uterine artery vascular tone and increasing uterine blood flow during pregnancy. Further to this, long term hypoxia due to high altitude exposure diminishes pregnancy – related increases in uterine blood flow. Based on these relationships we hypothesized that both pregnancy and membrane depolarization would increase Ca2+ spark activity, whereas ryanodine and long term hypoxia would inhibit Ca2+ spark activity. Uterine arteries were isolated from near‐term pregnant (n=6) and non‐pregnant sheep (n=6) in normoxia, as well as near‐term pregnant (n=6) and non‐pregnant sheep (n=6) exposed to hypoxic conditions at White Mountain (elevation 3,801 m) for 100 plus days. Isolated uterine arteries were subjected to three distinct ex vivo treatments: (1) control (saline), (2) 30mM potassium (30K), which causes membrane depolarization, and (3) 30K with ryanodine (10 μM), an RyR antagonist. Indeed, Ca2+ spark activity was increased in pregnant uterine arteries as compared to non‐pregnant uterine arteries, whereas hypoxia reduced spark frequency in all the aforementioned groups. Treatment with 30K increased Ca2+ spark activity in all groups. In comparison, 30K + ryanodine treatment decreased Ca2+ spark activity. Pregnancy increased the full width of sparks. However, pregnancy or hypoxia caused only minor changes in the amplitude and temporal aspects of sparks. These findings support the claim that membrane depolarization, due to 30K treatment, causes an increase in Ca2+ spark activity whereas ryanodine inhibits release of Ca2+ from the sarcoplasmic reticulum and thus decreases Ca2+ sparks. Taken together, these findings support the notion that the ryanodine receptors and BKCa channels work in conjunction with each other. This study provides further insight into the mechanisms that regulate uterine artery vascular tone and blood flow, and thus may prove useful in designing treatments for pregnancy complications that arise from increased uterine vascular tone, such as intrauterine growth restriction.Support or Funding InformationThis work is supported by The National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development grant number HD083132, by the National Science Foundation under Grant No. MRI 0923559, and the Loma Linda University School of Medicine. VW was a Walter E Macpherson Medical Student Summer Research Fellow.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Description of a method for inducing fetal growth restriction in the spiny mouse.

Intrauterine or fetal growth restriction (IUGR) is a major complication of pregnancy and leads to significant perinatal morbidities and mortality. Typically, induction of IUGR in animals involves the complete occlusion or ablation of vessels to the uterus or placenta, acutely impairing blood flow and fetal growth, usually with high fetal loss. We aimed to produce a model of reduced fetal growth in the spiny mouse with minimal fetal loss. At 27 days gestational age (term is 38-39 days), a piece of silastic tubing was placed around the left uterine artery to prevent the further increase of uterine blood flow with advancing gestation to induce IUGR (occluded). Controls were generated from sham surgeries without placement of the tubing. Dams were humanely euthanized at 37 days gestational age and all fetuses and placentas were weighed and collected. Of the 17 dams that underwent surgery, 15 carried their pregnancies to 37 days gestational age and 95% of fetuses survived to this time. The difference in fetal body weight between occluded and control was ~21% for fetuses in the left uterus side: there were no differences for fetuses in the right uterus side. Offspring from the occluded group had significantly lower brain, liver, lung, kidney and carcass weights compared with shams. Preventing the gestation-related increase of uterine blood flow induced significant growth restriction in the fetal spiny mouse, with minimal fetal loss. This technique could be readily adapted for other small animal.

Effect of Low-Dose Aspirin on Midluteal Phase Uterine Artery Blood Flow in Patients With Recurrent Pregnancy Loss.

The purpose of this study was to evaluate differences in uterine artery blood flow parameters and pregnancy outcomes, if any. An investigation was conducted to determine the effects of low-dose aspirin on uterine artery blood flow indices in patients with recurrent pregnancy loss. This observational study included 353 Chinese women with a history of recurrent pregnancy loss and 85 women without a history of recurrent pregnancy loss (control group) from Ren Ji Hospital. All patients were scanned transvaginally with transvaginal Doppler sonography 6 to 8 days after ovulation to measure the pulsatility index (PI), resistive index (RI), and systolic-to-diastolic ratio (S/D) of the left and right main uterine arteries. Low-dose aspirin at a dose of 50 mg/d was administered orally in patients with recurrent pregnancy loss for 2 months, and the blood flow indices were measured subsequently. The Student t test was used for analysis of the results, P < .05 was considered significant. The mean PI and S/D of the uterine arteries in the recurrent pregnancy loss group were significantly higher than in the control group. Although not statistically significant, the RI was higher in the recurrent pregnancy loss group than the control group. Moreover, the PI and S/D increased as the number of pregnancy losses increased. Significant enhancements of the PI and S/D were observed in patients with 4 or more consecutive abortions. After low-dose aspirin supplementation, patients with recurrent pregnancy loss showed a highly significant reduction in the PI and S/D. Uterine blood flow decreased during the luteal phase in patients with recurrent pregnancy loss. Low-dose aspirin induced a reversible increase in uterine blood flow and may be of therapeutic value.

A randomized controlled study of the efficacy of 4 weeks of supplementation with ω-3 polyunsaturated fatty acids in cases of unexplained oligohydramnios

To investigate the effect of ω-3 fatty acids on amniotic fluid volume and uterine artery blood flow after 4 weeks of treatment. A randomized clinical trial was conducted on 140 participants with unexplained oligohydramnios at Woman's Health Hospital, Assiut University, Egypt. Participants were randomly assigned to ω-3 plus capsules or placebo. Categorical variables were analyzed by means of the χ2 test, whereas continuous variables were analyzed by means of the independent-sample T-test between the two groups. One hundred and forty women were recruited. There was significant improvement in the amniotic fluid index (AFI) in the ω-3 plus group in comparison with the placebo group (P=0.001). Moreover, there were significant decreases in the systolic/diastolic ratio (P=0.01), resistance index (P=0.041) and pulsatility index (P=0.002) of the uterine arteries in the ω-3 plus group when comparing baseline values with those after 4 weeks. The results suggest that ω-3 fatty acids may have a role in the increase in AFI in cases of unexplained oligohydramnios. This effect may be secondary to the increase in uterine blood flow.

Effects of age, parity, and pregnancy abnormalities on foal birth weight and uterine blood flow in the mare

Color Doppler sonography has become routine for the evaluation of high-risk pregnancies in human medicine. Previous studies documenting uterine blood flow parameters in the pregnant mare have found a decrease in peripheral blood flow resistance in the first pregnancy weeks and an increase in uterine blood flow, especially in the last trimester of pregnancy. However, these studies involved only a small number of mares. No naturally occurring pregnancy abnormalities occurred that would allow blood flow changes to be retrospectively examined and analyzed. The objective of the present study was to monitor the diameter of the uterine artery, uterine blood flow, and the combined thickness of the uterus and placenta (CTUP) throughout gestation in a large number of pregnant mares of different age and parity. In the present study, 51 warmblood mares were examined by ultrasonography on Days 16 and 30, at monthly intervals until Day 300, and then every 10 days from Day 300 until parturition. After localization of the uterine artery ipsilateral and contralateral to the conceptus, the diameter of each artery, the uterine blood flow (pulsatility index [PI], blood flow volume [BFV], and the presence of early diastolic notch), and the CTUP were measured and correlated to placental and foal birth weight after delivery. Furthermore, the effect of age (3–7 years [n = 16], 8–11 years [n = 17], 12–16 years [n = 18]) and parity (0–2 foals [n = 22], 3–4 foals [n = 15], 5–8 foals [n = 14]) on these parameters were analyzed. The diameter of the uterine artery increased more than threefold in the ipsilateral artery (0.40 ± 0.07–1.33 ± 0.08 cm) and 2.7-fold in the contralateral artery (0.39 ± 0.07–1.07 ± 0.08 cm [P < 0.0001]). The early diastolic notch disappeared in the pulse waves in 98% of the ipsilateral arteries and 85.7% in the contralateral arteries on Day 150 when placentation is complete. Blood flow volume increased 50-fold in the ipsilateral artery during pregnancy and increased dramatically in the last trimester. The median foal weight was 52.6 kg. Mares with heavier foals (>52.6 kg) had a 1.38-fold higher BFV in the last 2 months (P < 0.05) compared with lighter foals. Pulsatility index decreased 2-fold until completion of placentation at around Day 150 and continued to decline until Day 240 where it then stayed constant and at a low level until delivery. Age predominantly influenced PI, whereas the diameter of the uterine arteries, which is correlated to BFV (r ipsilateral = 0.919, P < 0.0001 and r contralateral = 0.909, P < 0.000), was strongly affected by parity. Four mares spontaneously aborted (Days 200, 208, 213, and 246) and four mares spontaneously developed placentitis that was diagnosed by the presence of an increased CTUP and/or placental pathology after delivery. Although not statistically relevant, the aborting mares showed a slightly increased total BFV, but no differences in PI were seen compared with mares without abnormalities of pregnancy. Mares that developed placentitis had a late (Days 150–210) disappearance of the early diastolic notch and an increased PI in the first half of pregnancy. In conclusion, the study documented differences in uterine artery diameter and blood flow in a large number of pregnant mares. Furthermore, this is the first known report to document uteroplacental blood flow changes associated with naturally occurring placentitis and abortion in mares.

Regulation of uterine blood flow. II. Functions of estrogen and estrogen receptor α/β in genomic and non-genomic actions of the uterine endothelium

Pregnancy is marked by changes and cardiovascular adaptations that are important for the maintenance and growth of the placenta and fetus. During this period, the uterine vascular adaptations manifest changes that can be classified as short or long term and they related to adaptations for vasodilation, angiogenic or remodeling. Estrogen and the classical estrogen receptors (ERs), ER-α and ER-β, have been shown to be partially responsible for facilitating this dramatic increase in uterine blood flow needed during pregnancy. This literature review discusses the basis for structural diversity and functional selectivity of ERs by estrogen, the role of ERs on the genomic and non-genomic effects in endothelial cells of uterine arteries (UAEC). These themes integrate scientific knowledge about the molecular regulation of UAEC to maintain the physiological increase in uteroplacental perfusion observed during normal pregnancy.

Gap junction regulation of vascular tone: implications of modulatory intercellular communication during gestation.

In the vasculature, gap junctions (GJ) play a multifaceted role by serving as direct conduits for cell-cell intercellular communication via the facilitated diffusion of signaling molecules. GJs are essential for the control of gene expression and coordinated vascular development in addition to vascular function. The coupling of endothelial cells to each other, as well as with vascular smooth muscle cells via GJs, plays a relevant role in the control of vasomotor tone, tissue perfusion and arterial blood pressure. The regulation of cell-signaling is paramount to cardiovascular adaptations of pregnancy. Pregnancy requires highly developed cell-to-cell coupling, which is affected partly through the formation of intercellular GJs by Cx43, a gap junction protein, within adjacent cell membranes to help facilitate the increase of uterine blood flow (UBF) in order to ensure adequate perfusion for nutrient and oxygen delivery to the placenta and thus the fetus. One mode of communication that plays a critical role in regulating Cx43 is the release of endothelial-derived vasodilators such as prostacyclin (PGI2) and nitric oxide (NO) and their respective signaling mechanisms involving second messengers (cAMP and cGMP, respectively) that are likely to be important in maintaining UBF. Therefore, the assertion we present in this review is that GJs play an integral if not a central role in maintaining UBF by controlling rises in vasodilators (PGI2 and NO) via cyclic nucleotides. In this review, we discuss: (1) GJ structure and regulation; (2) second messenger regulation of GJ phosphorylation and formation; (3) pregnancy-induced changes in cell-signaling; and (4) the role of uterine arterial endothelial GJs during gestation. These topics integrate the current knowledge of this scientific field with interpretations and hypotheses regarding the vascular effects that are mediated by GJs and their relationship with vasodilatory vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion and blood flow observed during normal pregnancy.

Local Effects of Pregnancy on Connexin Proteins That Mediate Ca 2+ -Associated Uterine Endothelial NO Synthesis

Uterine artery adaptations during gestation facilitate increases in uterine blood flow and fetal growth. local expression and distribution of uterine artery connexins play roles in mediating in vivo gestational eNOS activation and NO production. We established an ovine model restricting pregnancy to a single uterine horn and measured uterine blood flow, uterine artery shear stress, connexins 37/43, and P(635)eNOS protein levels in uterine artery and systemic artery (omental and renal) endothelium and connexins in vascular smooth muscle. Uterine blood flow and shear stress were locally (unilaterally) and substantially elevated by gestation. During pregnancy, uterine artery endothelial gap junction proteins connexins 37/43 were locally regulated in the gravid horn and elevated 10.3- and 25.6-fold; uterine artery endothelial P(635)eNOS and total eNOS were elevated 3.3- and 2.9-fold; whereas uterine artery vascular smooth muscle connexins 37/43 were locally elevated 12.5- and 5.9-fold, respectively. Less pronounced changes were observed in systemic vasculature except for significant pregnancy-associated increases in omental artery vascular smooth muscle connexin 43 and omental artery endothelial P(635)eNOS and total eNOS. Gap junction blockade using connexin 43, but not connexin 37-specific Gap peptides, abrogated uterine artery endothelial ATP-induced Ca(2+)-mediated NO production. Thus, uterine artery endothelial connexin 43, but not connexin 37, regulates Ca(2+)-mediated NO production required for the vasodilation to accommodate increases in uterine blood flow and shear stress during healthy pregnancies.

Potassium Channels and Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia

During a normal course of pregnancy, uterine vascular tone is significantly decreased resulting in a striking increase in uterine blood flow, which is essential for fetal development and fetal growth. Chronic hypoxia during gestation may adversely affect the normal adaptation of uterine vascular tone and increase the risk of preeclampsia and fetal intrauterine growth restriction. In this review, we present evidence that the regulation of K+ channels is an important mechanism in the adaptation of uterine vascular tone to pregnancy and hypoxia. There are four types of K+ channels identified in arterial smooth muscle cells: 1) voltage-dependent K(+) (Kv) channels, 2) Ca2+-activated K(+) (KCa) channels, 3) inward rectifier K(+) (KIR) channels, and 4) ATP-sensitive K(+) (KATP) channels. Pregnancy differentially augments the expression and activity of K(+) channels via downregulation of protein kinase C signaling in uterine and other vascular beds, leading to decreased uterine vascular tone and increased uterine blood flow. Sex steroid hormones play an important role in the pregnancy- mediated alteration of K+ channels in the uterine vasculature. In addition, chronic hypoxia alters uterine vascular K(+) channels expression and activities via modulation of steroid hormones/receptors-mediated signaling, resulting in increased uterine vascular tone during pregnancy.

Editorial (Thematic Issue: Uteroplacental Circulation and Fetal Vascular Development and Function)

The striking increase of uterine blood flow in pregnancy is essential both for optimal growth and survival of the fetus, as well as for cardiovascular well-being of the mother. Maladaptation of the uteroplacental circulation during pregnancy is associated with high incidence of clinical complications including preeclampsia and fetal intrauterine growth restriction. Thus, a comprehensive understanding of regulatory mechanisms of uteroplacental vascular adaptation in pregnancy has long been sought, but has not been achieved. Interactions between the mother and fetus via the placenta during gestation are sophisticated and complex, which determine the optimal growth and health of the fetus. Pregnancy complications and fetal growth restriction occur when things go wrong in the uteroplacental circulation. One of the most provocative recent findings in modern medicine is that uteroplacental insufficiency and perinatal stress not only significantly increase maternal and infant mortality and morbidity rates, but also have long-term adverse effects on adult health, predisposing to cardiovascular and metabolic diseases later in life. Multiple factors may be involved in determining maternal/fetal health and developmental programming of health and disease but the function of uteroplacental circulation is the center of all. This hot-topic issue provides broad and up-to-date information and recent advancement of our knowledge in physiology and pathophysiology of the uteroplacental circulation and the development of fetal cerebral, coronary and pulmonary vasculatures. Each Chapter is written by leading experts in the field, providing the highest academic level for readers including basic, clinical, and translational scientists, pediatricians, maternal-fetal medicine specialists, and physiologists.

112 INFLUENCE OF LOW-VOLUME UTERINE FLUSHING ON UTERINE VASCULAR PERFUSION AND ENDOMETRIAL THICKNESS DURING EARLY DIOESTRUS IN BEEF CATTLE

The relevance of the uterine secretions during early embryonic development is due to its role as the only source of nutrients for embryo prior to implantation. Probing of the uterine secretions during early pregnancy without compromising gestation would be an important tool for the identification of fertility markers. Manipulations of the uterus could lead to a local increase in blood flow, which could result from the physical stimulation or tissue damage and inflammation. This study aimed to evaluate the effects of low-volume flushing of the uterine horn contralateral to the ovulation on uterine vascular perfusion and endometrial thickness 6 days after artificial insemination (AI). Transrectal B-mode and color Doppler ultrasonography (MyLab30 Vet Gold; Esaote Healthcare) were used to compare changes on endometrial thickness and uterine vascular perfusion, respectively. Examinations were carried out on 15 Nelore cows just prior to the flushing procedure (0 h), 6 and 24 h later. Cows were inseminated after oestrus detection and uterine flushings were performed 6 d after AI. The uterine horn, contralateral to the corpus luteum, was flushed with 20 mL of PBS using a Foley catheter. After massage of the uterine horn, flushing was collected in a syringe by suction. Vascular perfusion was estimated by scoring the extent of colored areas within the endometrium and mesometrium. Vascular perfusion scores indicated nil (1), minimal (2), intermediate (3), and maximal (4) vascular perfusion. Endometrial thickness was measured by taking the maximum diameter and its perpendicular diameter; these values were summed and then divided by four. Data that were not normally distributed were transformed to natural logarithms or ranks. For each variable, the main effect of side (flushed and nonflushed horns), hour, and their interaction were analyzed using the PROC MIXED procedure from the SAS software. The least significant difference method was used for the comparison of means among hours. An hour effect was detected for endometrial and mesometrial scores of vascular perfusion (Table 1), representing an increased vascular perfusion about 6 h after the flushing procedure and a return to basal perfusion at 24 h. Results indicate that the unilateral flushing procedure increases vascular perfusion on both uterine horns. For endometrial thickness, no effect of side, hour, or their interaction was detected. In conclusion, unilateral low-volume uterine flushing results in a transitory increase in uterine blood flow about 6 h post-flushing. Further studies are needed to evaluate other inflammatory characteristics and the potential effect on pregnancy rate in response to the uterine flushing procedure performed during early pregnancy. Table 1.Scores of endometrial and mesometrial vascular perfusion and endometrial thickness of both uterine horns at the time of uterine flushing (0 h), 6 and 24 h post-flushing (mean ± standard error of the mean)

Re: Effect of letrozole on uterine artery Doppler flow indices prior to first‐trimester termination of pregnancy: a randomized controlled trial. V. C. Y. Lee, T. W. Y. Yeung, O. S. Tang, E. H. Y. Ng, W. S. B. Yeung and P. C. Ho. Ultrasound Obstet Gynecol 2012; 40: 392–397.

I was excited when I read of the discovery of H. pylori (an infectious cause of gastric ulcers?), because it was known that bacteria could not survive in the high-acid environment of the stomach. I was excited when I was first presented with a lecture showing human papillomavirus as an infectious cause of cervical cancer, because cancer and infection were known to be two completely separate causes of pathology. So much for how much we know. These events turned my ideas upside down. Similarly, I was happily surprised when I read the results of this trial by Vivian Lee et al. It is often the surprises that can lead to real advances in medicine (did that area of mold on the agar plate really eliminate those bacterial colonies?). Lee et al. report the effect of letrozole, an aromatase inhibitor that inhibits the peripheral conversion of androgens to estrogens, on the Doppler blood flow indices of the uterine artery in early pregnancy, comparing these to placebo through the mechanism of a randomized trial. They demonstrated that pregnancies exposed to letrozole had a significant decrease in uterine artery resistance (RI) and pulsatility (PI) indices, concluding that blood flow in the uterine artery is increased in response to letrozole. This is a moderately surprising finding, given an inherent bias in most physicians towards the belief that estrogen in mammals is responsible for the marked increase in uterine blood flow in early pregnancy. The results are important mostly in terms of our disease knowledge or knowledge about the hormonal support of early pregnancies. This article reports findings that I believe are important to help eliminate biases in our understanding of how pregnancy-related hormones affect the early developing pregnancy and specifically the uterine vasculature. Our bias is that, in humans, estradiol increases blood flow and thus helps to support a pregnancy, and that a decrease in estradiol would lead to a marked reduction in blood flow, but the available data are few. There are two conclusions to be drawn from the data of Lee et al. presented in the current issue of the Journal. One is that there are other placentally derived growth factors that sustain uterine blood flow when an insult to uterine blood flow (such as letrozole) emerges1. However, it is, of course, the transformation of the uterine and spiral arteries by destruction of the smooth muscle in early pregnancy that allows the decreased resistance and increased blood flow throughout pregnancy, so the second conclusion is that estrogen plays a completely different role; indeed, there is some evidence available to suggest that estrogen actually limits the extent to which the uterine arteries are transformed by regulating expression of vascular endothelial growth factor and integrins2. If estrogen limits this process, then decreasing estrogen by the use of letrozole in early pregnancy should give us precisely the results seen in the current study. The limitations of this study are related to the narrow aims, which follow from the study design. Broad or general statements or conclusions about the clinical use of letrozole are not possible or are not wise at this stage in our knowledge. The strength of this study lies in the randomized design. Having a properly randomized and blinded placebo study demonstrates clearly that there are differences between normal ongoing first-trimester pregnancies (receiving placebo) and those exposed to letrozole. In addition, the surprising findings open doors for future investigations. The results of the trial by Lee et al., although perhaps not as dramatic a change in the world of medicine as the other examples I have mentioned above, confirm that reconsideration of the mechanisms of early pregnancy support through the action of estrogens is warranted. Let's get to work on these new studies! D. Skupski*, * Department of Obstetrics and Gynecology, New York Hospital Queens, 56-45 Main Street, Room M-372, Flushing, NY 11355, USA

Serum amyloid A concentration in mares with experimentally induced ascending placentitis

among repeated measures within the same mare. A linear regression model was used to assess the correlation between the daily mean relative VP and RI. A relative increase in VP was detected at D3 (29%; P 1⁄4 0.028), D4 (31%; P 1⁄4 0.027) and D5 (32%; P 1⁄4 0.026). A mean decrease of 24% in RI and PI in relation to D0were detected at D5 (P1⁄4 0.018 for both contrasts). A strong negative correlation was detected between relative VP and RI (R2 1⁄4 0.79; P < 0.01). Results of previous studies indicate an increase in uterine blood flow during the beginning of diestrus when evaluations of large vessels during the estrous cycle [1] and of small uterine vessels of inseminated mares [2] were performed. Nonetheless, it was questionable whether the increased uterine perfusion at D5 was a result of entry of the embryo into the uterus or if it was part of a uterine preparation for a possible entrance. The present study suggests that an increase in uterine local VP during the beginning of diestrus occurs in non-bred mares, which indicates that this is a natural alteration of the estrous cycle that coincides with the entry of the embryo into the uterus. More studies are still needed to confirm and to add more information to these findings.

Physiological Remodelling of the Maternal Uterine Circulation during Pregnancy

Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodelling of the entire maternal uterine vasculature. The main focus of this MiniReview is to provide information on upstream (pre-placental) maternal uterine vascular remodelling that facilitates gestational increases in uterine blood flow. Consideration of the three-dimensional pattern of remodelling (circumferential enlargement versus axial elongation), changes in vessel biomechanical properties, and underlying mechanisms [shear stress, nitric oxide, vascular endothelial growth factor (VEGF)/placental growth factor (PlGF), the renin-angiotensin system] and pathways (local versus systemic; venoarterial exchange) are provided using the rat as the principal animal model, although findings from other species are incorporated wherever possible to provide a comparative perspective. The process of maternal gestational uterine vascular remodelling involves a number of cellular processes and mechanisms, including trophoblast invasion, hyperplasia and hypertrophy, and changes in extracellular matrix composition. In addition, changes in cellular function, e.g. the secretory and contractile properties of smooth muscle and an up-regulation of endothelial vasodilatory influences may contribute to uteroplacental blood flow increases through changes in tone as well as in structure. Future studies aimed at better understanding the inter-relationship between changes in vessel structure (remodelling) and function (reactivity) would likely generate new mechanistic insights into the fascinating process of maternal gestational uterine vascular adaptation and provide a more physiological perspective of the underlying cellular processes involved in its regulation.