Cortisol-mediated regulation of uterine artery contractility: effect of chronic hypoxia

We previously demonstrated that cortisol regulated alpha(1)-adrenoceptor-mediated contractions differentially in nonpregnant and pregnant uterine arteries. Given that chronic hypoxia during pregnancy has profound effects on maternal uterine artery reactivity, the present study investigated the effects of chronic hypoxia on cortisol-mediated regulation of uterine artery contractions. Pregnant (day 30) and nonpregnant ewes were divided between normoxic control and chronically hypoxic [maintained at high altitude (3,820 m), arterial Po(2): 60 mmHg for 110 days] groups. Uterine arteries were isolated and contractions measured. In hypoxic animals, cortisol (10 ng/ml for 24 h) increased norepinephrine-induced contractions in pregnant, but not in nonpregnant, uterine arteries. The 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone did not change cortisol effects in nonpregnant uterine arteries, but abolished it in pregnant uterine arteries by increasing norepinephrine pD(2) (-log EC(50)) in control tissues. The dissociation constant of norepinephrine-alpha(1)-adrenoceptors was not changed by cortisol in nonpregnant, but decreased in pregnant uterine arteries. There were no differences in the density of glucocorticoid receptors between normoxic and hypoxic tissues. Cortisol inhibited the norepinephrine-induced increase in Ca(2+) concentrations in nonpregnant arteries, but potentiated it in pregnant arteries. In addition, cortisol attenuated phorbol 12,13-dibutyrate-induced contractions in normoxic nonpregnant and pregnant uterine arteries, but had no effect on the contractions in hypoxic arteries. The results suggest that cortisol differentially regulates alpha(1)-adrenoceptor- and PKC-mediated contractions in uterine arteries. Chronic hypoxia suppresses uterine artery sensitivity to cortisol, which may play an important role in the adaptation of uterine vascular tone and blood flow in response to chronic stress of hypoxia during pregnancy.     

Calcium homeostasis and contraction of the uterine artery: effect of pregnancy and chronic hypoxia

The present study tested the hypothesis that chronic hypoxia alters pregnancy-mediated adaptation of Ca2+ homeostasis and contractility in the uterine artery. Uterine arteries were isolated from nonpregnant and near-term pregnant ewes of normoxic control or high-altitude (3820 m) hypoxic (oxygen pressure in the blood [PaO2], 60 mm Hg) treatment for 110 days. Contractions and intracellular-free Ca2+ concentration ([Ca2+]i) were measured simultaneously in the same tissue. In normoxic animals, pregnancy increased norepinephrine (NE), but not 5-hydroxy-thymide (5-HT) or KCl, contractile sensitivity in the uterine artery. Chronic hypoxia significantly attenuated NE-induced contractions in the pregnant, but not nonpregnant, uterine arteries. Similarly, 5-HT-mediated contractions of nonpregnant arteries were not changed. In the pregnant uterine artery, chronic hypoxia significantly increased NE-mediated Ca2+ mobilization, but decreased the Ca2+ sensitivity. In addition, hypoxia increased the calcium ionophore A23187-induced relaxation in pregnant, but not nonpregnant, uterine arteries. However, the A23187-mediated reduction of [Ca2+]i was significantly impaired in hypoxic arteries. In contrast, hypoxia significantly increased the slope of the [Ca2+]i-tension relationship of A23187-induced reductions in [Ca2+]i and tension in the pregnant uterine artery. The results suggest that the contractility of nonpregnant uterine artery is insensitive to moderate chronic hypoxia, but the adaptation of sympathetic tone that normally occurs in the uterine artery during pregnancy is inhibited by chronic hypoxia. In addition, changes in Ca2+ sensitivity of myofilaments play a predominant role in the adaptation of uterine artery contractility to pregnancy and chronic hypoxia.     

Inhibitory effect of GnRH on isolated rat uterine muscle contractility

The effect of GnRH upon uterine contractions of both non-pregnant and pregnant rats was examined in vitro. In the non-pregnant rat uterus, GnRH inhibited in a concentration-and-time dependent manner the contractions induced by acetylcholine and oxytocin, but not those caused by bradykinin and angiotensin II. GnRH also inhibited the rhythmic contractions induced by oxytocin in uterine strips from late pregnant rats. These findings show that GnRH has a direct inhibitory effect on the rat uterine contractions, suggesting that GnRH-like substances may exert modulatory influences upon rat uterine contractility.     

The peptidergic innervation of the guinea pig uterine artery in pregnancy

The influence of pregnancy on the density and pattern of the peptidergic innervation of the guinea pig uterine artery was studied. Whole mount stretch preparations of the uterine artery from estrus and late pregnant guinea pigs were processed for the immunohistochemical demonstration of neuropeptide Y (NPY)-, vasoactive intestinal polypeptide (VIP)-, calcitonin gene-related peptide (CGRP)- and substance P (SP)- immunoreactive nerve fibres. In late pregnancy the density of NPY- and CGRP- containing nerve fibres was remarkably decreased, while that of VIP- and SP- immunoreactive nerves showed a moderate reduction. The meaning and the possible physiological relevance of the decreased density of peptide-immunoreactive nerves in the uterine artery in late pregnancy are discussed.     

Adaptation of uterine artery thick- and thin-filament regulatory pathways to pregnancy

Little is known about the adaptation of uterine artery smooth muscle contractile mechanisms to pregnancy. The present study tested the hypothesis that pregnancy differentially regulates thick- and thin-filament regulatory pathways in uterine arteries. Isometric tension, intracellular free Ca(2+) concentration, and phosphorylation of 20-kDa myosin light chain (MLC(20)) were measured simultaneously in uterine arteries isolated from nonpregnant and near-term (140 days gestation) pregnant sheep. Phenylephrine-mediated intracellular free Ca(2+) concentration, MLC(20) phosphorylation, and contraction tension were significantly increased in uterine arteries of pregnant compared with nonpregnant animals. In contrast, phenylephrine-mediated Ca(2+) sensitivity of MLC(20) phosphorylation was decreased in the uterine arteries of pregnant sheep. Simultaneous measurement of phenylephrine-stimulated tension and MLC(20) phosphorylation in the same tissue indicated a decrease in MLC(20) phosphorylation-independent contractions in the uterine arteries of pregnant sheep. In addition, activation of PKC produced significantly lower sustained contractions in uterine arteries of pregnant compared with nonpregnant animals in the absence of changes in MLC(20) phosphorylation levels in either vessels. In uterine arteries of nonpregnant sheep, the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase inhibitor PD-098059 significantly increased phenylephrine-mediated, MLC(20) phosphorylation-independent contractions. The results suggest that in uterine arteries, pregnancy upregulates alpha(1)-adrenoceptor-mediated Ca(2+) mobilization and MLC(20) phosphorylation. In contrast, pregnancy downregulates the Ca(2+) sensitivity of myofilaments, which is mediated by both thick- and thin-filament pathways.     

Mechanisms of uterine contractility in laying hens

The physiological basis of uterine contractility in laying hens is not well understood, but a better understanding is important for understanding the mechanisms governing egg laying. The characteristics of uterine contractility arising spontaneously or by prostaglandin F_2α (PGF_2α) stimulation were therefore examined and the underlying mechanisms investigated. Uterine strips were isolated from laying hens 4 h before oviposition and force measured. These strips remained healthy in vitro and produced regular spontaneous contractions. The contractions were phasic and could be recorded for several hours. Exposure to nifedipine, the specific L-type Ca channel blocker, led to the abolition of force. The contraction amplitude and frequency were significantly increased when Bay K8644, an agonist of L-type Ca channels, was applied or when the concentration of extracellular Ca was elevated. Spontaneous contractions were also significantly inhibited by wortmannin, the specific inhibitor of myosin light chain kinase (MLCK). When 1 μM PGF_2α was applied to spontaneously contracting uterus, it significantly increased their amplitude and frequency of the contractions. As with spontaneous contractions, PGF_2α-induced force production was abolished by nifedipine and wortmannin. In the absence of extracellular Ca, a small but tonic force was generated upon application of PGF_2α which was not affected by wortmannin. Thus, extracellular Ca entry and MLCK phosphorylation are essential for uterine force production occurring spontaneously or by PGF_2α stimulation. Our data supports the conclusion that the pathway dependent on extracellular Ca entry and MLCK phosphorylation predominates during PGF_2α stimulation but suggests some involvement of an alternative force-producing pathway, presumably Ca-sensitization.     

Suppression of trophoblast uterine spiral artery remodeling by estrogen during baboon pregnancy: impact on uterine and fetal blood flow dynamics

The present study was conducted to determine the impact of suppressing trophoblast remodeling of the uterine spiral arteries by prematurely elevating estrogen levels in the first trimester of baboon pregnancy on uterine and umbilical blood flow dynamics. Uteroplacental blood flow was assessed by Doppler ultrasonography after acute administration of saline (basal state) and serotonin on days 60, 100, and 160 of gestation (term: 184 days) to baboons in which uterine spiral artery remodeling had been suppressed by the administration of estradiol on days 25-59 of gestation. Maternal blood pressure in the basal state was increased (P < 0.01), and uterine artery diastolic notching and the umbilical artery pulsatility index and systolic-to-diastolic ratio, reflecting downstream flow impedance, were increased (P < 0.01) after serotonin administration on day 160, but not earlier, in baboons treated with estradiol in early gestation. These changes in uteroplacental flow dynamics in serotonin-infused, estradiol-treated animals were accompanied by a decrease (P < 0.05) in uterine and umbilical artery volume flow and fetal bradycardia. The results of this study show that suppression of uterine artery remodeling by advancing the rise in estrogen from the second trimester to the first trimester disrupted uteroplacental blood flow dynamics and fetal homeostasis after vasochallenge late in primate pregnancy.     

Role of the calcium store in uterine contractility

This article assesses the nature of the sarcoplasmic reticulum (SR) in uterine smooth muscle. Modern imagining techniques have revealed new information about the location and density of Ca storage and release. Release mechanisms, including IP(3) and Ca itself, via ryanodine receptors (RyR), as well as possible roles for cyclic ADP ribose, and the contribution of the SR to relaxation are detailed. The role of the SR Ca-ATPase in both decay of the Ca transient and maintaining Ca homeostasis is reviewed. Recent data on the role of local Ca signals from the SR in contributing to membrane excitability and contractility are discussed, along with interactions with ion channels in lipid microdomains.     

Effects of adipokines and obesity on uterine contractility

Obesity is a major public health problem. The prevalence of obesity has significantly increased in developed countries, particularly in France with an overall increase of 76% over the last 15 years. In pregnant women, obesity is associated with alterations in the quality of labor, such as delayed onset of labor, a higher rate of prolonged pregnancies, prolonged labor, and higher oxytocin requirements. There is also an increased prevalence of Cesarean sections, particularly during the active phase of labor, and perinatal complications (postpartum hemorrhage).It seems that some of these functional changes and their consequences can be attributed to a disruption of hormonal balance encountered in obese women and involving adipokines (apelin, ghrelin, visfatin, leptin), but also to the interactions between adipose tissue and the “oxytocin (OT) – oxytocin receptor (OTR)”.In this review, we detailed mechanisms to understand the impact of specific metabolic alterations in obesity on uterine contractility.Better knowledge of the impact of obesity on labor and delivery pathophysiology should strengthen the prevention of obesity in women of childbearing age and provide a suitable and effective management. The beneficial effect of weight loss and exercise in non-pregnant women on the correction of metabolic disorders secondary to obesity should be studied in populations of overweight women to demonstrate its effectiveness.     

Remodeling of the uterine artery during and early after pregnancy in the mouse

Biomechanics and Modeling in Mechanobiology - Pregnancy associates with dramatic changes in maternal cardiovascular physiology that ensure that the utero-placental circulation can support the...     

The effect of postpartum uterine lavage on foal heat pregnancy rate

Mares (n = 37) were treated on Days 2 and 4 post partum with a uterine lavage of 10 l of warm, sterile NaCl (0.9%) solution. Endometrial cytology and culture were performed on Day 7. Mares were bred on the first postpartum estrus by artificial insemination. Pregnancy rates were determined by ultrasound examination at Day 16 post ovulation. No differences were noted in degree of uterine inflammation or presence of uterine bacteria at Day 7 post partum between treated (n = 18) and control (n = 19) mares. Pregnancy rates at the first postpartum estrus for treated mares (55.5%) was not statistically different from that of control mares (68.4%). No advantage was noted in the use of intrauterine lavage with 10 l of warm sterile NaCl (0.9%) at Days 2 and 4 post partum as a means of improving foal heat pregnancy rate.     

The effect of postbreeding uterine lavage on pregnancy rate in mares

One stallion and 54 mares were used in an experiment to evaluate the effect of postbreeding uterine lavage on pregnancy rate in mares. All mares were inseminated with 250 x 10(6) progressively motile sperm every other day during estrus until detection of ovulation. Mares (n = 18) were randomly assigned to one of three treatment groups: 1) no postbreeding uterine lavage (control); 2) uterine lavage at 0.5 h postbreeding; or 3) uterine lavage at 2 h postbreeding. A dilute solution of povidone-iodine (PIS; 0.05%) previously determined to render spermatozoa immotile in vitro was used to lavage the mare uteri. One liter PIS, prewarmed to 40 degrees C, was used for each lavage. Pregnancy status of mares was determined at 21 d and 36 d post ovulation, using transrectal ultrasonography. The pregnancy rate of Group 1 (66.7%) was higher than that of Group 2 (22.2%; P<0.05) or Group 3 (33.3%); P<0.10). The pregnancy rates of Groups 2 and 3 were similar (P>0.70). Evaluation of endometrial biopsies obtained from a separate set of mares (n = 3) on Day 6 post ovulation, both before and after uterine lavage, revealed no difference in the accumulation of inflammatory cells, suggesting adverse effects of lavage on fertility may have been due to excessive removal of spermatozoa from the uterus during the lavage process or damage to oviductal spermatozoa.     

Regulation of alpha1-adrenoceptor-mediated contractions of uterine arteries by PKC: effect of pregnancy

Protein kinase C (PKC) plays an important role in the regulation of uterine artery contractility and its adaptation to pregnancy. The present study tested the hypothesis that PKC differentially regulates alpha(1)-adrenoceptor-mediated contractions of uterine arteries isolated from nonpregnant (NPUA) and near-term pregnant (PUA) sheep. Phenylephrine-induced contractions of NPUA and PUA sheep were determined in the absence or presence of the PKC activator phorbol 12,13-dibutyrate (PDBu). In NPUA sheep, PDBu produced a concentration-dependent potentiation of phenylephrine-induced contractions and shifted the dose-response curve to the left. In contrast, in PUA sheep, PDBu significantly inhibited phenylephrine-induced contractions and decreased their maximum response. Simultaneous measurement of contractions and intracellular free Ca(2+) concentrations ([Ca(2+)](i)) in the same tissues revealed that PDBu inhibited phenylephrine-induced [Ca(2+)](i) and contractions in PUA sheep. In NPUA sheep, PDBu increased phenylephrine-induced contractions without changing [Ca(2+)](i). Western blot analysis showed six PKC isozymes, alpha, beta(I), beta(II), delta, epsilon, and zeta, in uterine arteries, among which beta(I), beta(II), and zeta isozymes were significantly increased in PUA sheep. In contrast, PKC-alpha was decreased in PUA sheep. In addition, analysis of subcellular distribution revealed a significant decrease in the particulate-to-cytosolic ratio of PKC-epsilon in PUA compared with that in NPUA sheep. The results suggest that pregnancy induces a reversal of PKC regulatory role on alpha(1)-adrenoceptor-mediated contractions from a potentiation in NPUA sheep to an inhibition in PUA sheep. The differential expression of PKC isozymes and their subcellular distribution in uterine arteries appears to play an important role in the regulation of Ca(2+) mobilization and Ca(2+) sensitivity in alpha(1)-adrenoceptor-mediated contractions and their adaptation to pregnancy.