Myometrial Functions Research Articles

The Role of The Fallopian Tube in Performance Of The Main Myometrial Functions

The Role of The Fallopian Tube in Performance Of The Main Myometrial Functions

Prostacyclin Synthesis and Prostacyclin Receptor Expression in the Porcine Myometrium: Prostacyclin Potential to Regulate Fatty Acid Transporters, Cytokines and Contractility-Related Factors.

Simple SummaryProstacyclin (prostaglandin I2; PGI2) is an important modulator of vascular functions and is involved in various reproductive processes. PGI2 was also described as a modulator of uterine contractility in several species, including the pig. However, its synthesis and role in the myometrium of the porcine uterus are still not fully described. The objective of this study was to evaluate profiles of PGI2 synthesis and PGI2 receptor expression in the myometrium of gilts throughout the estrous cycle and during early pregnancy and to investigate the in vitro effect of PGI2 on the mRNA expression of factors engaged in smooth muscle contraction, nutrient transport, prostaglandin synthesis and action, and inflammatory response. The obtained results showed that the synthesis of PGI2 changes in the myometrium of pigs during both the estrous cycle and early pregnancy, resulting in much greater concentrations of PGI2 in cyclic than in pregnant gilts. Moreover, PGI2 stimulated the expression of fatty acid transporters and contractility-related calponin 1 and caldesmon 1, whereas it decreased cytokine expression. This study indicates that PGI2 may participate in the regulation of myometrial functions modulating the availability of factors involved in smooth muscle activity and inflammatory reaction in the uterus of pigs.Although prostacyclin (PGI2) has been well described as a regulator of smooth muscle activity, limited data are available concerning its role in the myometrium of pigs. The present research aimed to examine profiles of PGI2 synthase (PTGIS) and PGI2 receptor (PTGIR) expression and 6-keto PGF1α (a PGI2 metabolite) concentrations in the myometrium of gilts throughout the estrous cycle and during early pregnancy using qPCR, Western blot, and/or ELISA methods. Furthermore, myometrial explants were exposed to iloprost (a stable PGI2 analog) to investigate the effect of PGI2 on the mRNA expression of factors engaged in smooth muscle contraction, nutrient transport, prostaglandin synthesis and action, and inflammatory response. PTGIS mRNA expression was greater in cyclic than in pregnant gilts on days 11–12 after estrus and was accompanied by greater concentrations of 6-keto PGF1α detected in cyclic than in pregnant animals on days 11–20. Iloprost stimulated fatty acid transporters and contractility-related calponin 1 and caldesmon 1 mRNA expression and decreased interleukin 1β and tumor necrosis factor transcript abundance. The obtained results indicate a physiologically relevant role of PGI2 during the estrous cycle in the porcine myometrium with its importance for regulating the expression of contractility-, nutrient transport- and inflammatory response-related factors.

Myometrial progesterone receptor determines a transcription program for uterine remodeling and contractions during pregnancy.

The uterine myometrium expands and maintains contractile quiescence before parturition. While the steroid hormone progesterone blocks labor, the role of progesterone signaling in myometrial expansion remains elusive. This study investigated the myometrial functions of the progesterone receptor, PGR. Pgr ablation in mouse smooth muscle leads to subfertility, oviductal embryo retention, and impaired myometrial adaptation to pregnancy. While gross morphology between mutant and control uteri are comparable, mutant uteri manifest a decrease of 76.6% oxytocin-stimulated contractility in a pseudopregnant context with a reduced expression of intracellular calcium homeostasis genes including Pde5a and Plcb4. At mid-pregnancy, the mutant myometrium exhibits discontinuous myofibers and disarrayed extracellular matrix at the conceptus site. Transcriptome of the mutant mid-pregnant uterine wall manifests altered muscle and extracellular matrix profiles and resembles that of late-pregnancy control tissues. A survey of PGR occupancy, H3K27ac histone marks, and chromatin looping annotates cis-acting elements that may direct gene expression of mid-pregnancy uteri for uterine remodeling. Further analyses suggest that major muscle and matrix regulators Myocd and Ccn2 and smooth muscle building block genes are PGR direct downstream targets. Cataloging enhancers that are topologically associated with progesterone downstream genes reveals distinctive patterns of transcription factor binding motifs in groups of enhancers and identifies potential regulatory partners of PGR outside its occupying sites. Finally, conserved correlations are found between estimated PGR activities and RNA abundance of downstream muscle and matrix genes in human myometrial tissues. In summary, PGR is pivotal to direct the molecular program for the uterus to remodel and support pregnancy.

Expression and localization of follicle-stimulating hormone receptor in the yak uterus during different stages of the oestrous cycle.

Morphological changes of the uterus and alterations in its secretory activity under the influence of steroid hormones been well documented. The oestrous cycle is also associated with significant changes in plasma follicle-stimulating hormone (FSH), whose effects are mediated through its receptor (FSHR). Reports showed that in many mammals, FSHR was expressed in gonadal and extragonadal tissues including cervix, female reproductive tract, and pituitary gland. Follicle-stimulating hormone (FSH) signals through endothelial FSHR directly stimulate angiogenesis and involved in the timing of birth in human, and the presence of FSHR in the placenta is essential for normal pregnancy in mice. But little is known about FSHR expression in the yak uterus. The main objective of the present study was to determine the expression and localization of FSHR in the yak uterus during different phases of the oestrous cycle. Results showed that FSHR protein was localized in the surface and glandular epithelial cells, stroma cells, myometrial smooth muscle cells and blood vessel endothelial cells. The expression of FSHR protein peaked at oestrus, significantly decreased at dioestrus (p<0.05) and increased again at proestrus. FSHR mRNA was highly expressed at both proestrus and oestrus, and decreased at metestrus with the lowest values at dioestrus (p<0.05). In conclusion, FSHR expression in the yak uterus changed with the stage of the oestrous cycle suggesting that FSHR plays an essential role in regulating the endometrial and myometrial functions during the oestrus cycle in the yak.

Role of Stro1+/CD44+ stem cells in myometrial physiology and uterine remodeling during pregnancy.

Regulation of myometrial functions during pregnancy has been considered the result of the integration of endocrine and mechanical signals. Nevertheless, uterine regeneration is poorly understood, and the cellular source within the gravid uterus is largely unexplored.In this study, we isolated and quantified the myometrial stem cells (MSC) population from pregnant female Eker rat uteri, by using Stro1/CD44 surface markers. We demonstrated that prior parity significantly increased the percentage of Stro1+/CD44+ MSC because of injured tissue response. Interestingly, we established that Stro1+/CD44+ MSC respond efficiently to physiological cues when they were treated in vitro under different dose-dependent pregnant rat serum.Previous studies reveal strong regulatory links between O2 availability and stem cell function. Based on these premises, cell proliferation assays showed that isolated Stro1+/CD44+ MSC possess a higher proliferative rate under hypoxic versus normoxic conditions. We also detected a total of 37 upregulated and 44 downregulated hypoxia-related genes, which were differentially expressed in Stro1+/CD44+ MSC, providing an alternative approach to infer into complex molecular mechanisms such as energy metabolism, inflammatory response, uterine expansion, and/or remodeling.Since these cells preferentially grow under low oxygen conditions, we propose that the increase of the rat uterus during pregnancy involves myometrial oxygen consumption, thereby enhancing MSC proliferation. Moreover, pregnancy-induced mechanical stretching results in hypoxic conditions, ultimately creating an environment that promotes stem cell proliferation and further uterine enlargement, which is essential for a successful pregnancy. In summary, all of these data support that rat Stro1+/CD44+ MSC contribute to uterine enlargement during pregnancy.

A review of current practice in using Balloon Tamponade Technology in the management of postpartum haemorrhage

The use of various Balloon tamponade technologies has steadily increased over the last five years in the management of postpartum haemorrhage. New methodologies and applications have been included beyond the original descriptions. Furthermore, novel approaches and mechanisms of action have also been suggested. No comparative trials involving “uterine/fertility sparing” approaches such as Balloon Tamponade Technology have been performed comparing the safety, efficiency and long term effects on endometrial and myometrial functions. However, balloon tamponade technology is rapidly becoming accepted as a preferred second line approach following failed first line uterotonics in many obstetric units. This paper reviews the current use of various balloon tamponade technologies in the management of postpartum haemorrhage. Hypertension Research In Pregnancy

Somatic Stem Cells in the Myometrium and in Myomas

The human uterus mainly consists of two layers: an inner endometrium and an outer layer, the myometrium, made of smooth muscle. The uterus is characterized by its unique capacity for regeneration. This capacity permits cyclical regeneration and remodeling of the tissue over the course of a woman's reproductive life. During each menstrual cycle, the endometrium regenerates, and the uterus enlarges to make room for fetal growth. This cyclic physiologic pattern suggests that myometrial stem/progenitor cells are present in the tissue and play a role in myometrial functions. Our group (and others) recently characterized and isolated putative stem/progenitor cells in the myometrium. These findings are permitting a better understanding of myometrial physiology and pathology. We review current studies of myometrial stem/progenitor cells and suggestions that, in combination with hypoxia, these cells may contribute to uterine remodeling during pregnancy and the formation of myomas.

A close look at the contraction and relaxation of the myometrium; the role of calcium

The function and regulation of the myometrium, especially during pregnancy, labour and birth are important in reproductive physiology. It is crucial to understand the mechanisms that generate and modulate uterine contractility in order to be able to prevent and/or treat the problems related with the myometrium. A limited understanding of the cellular and molecular events underlying these phenomena complicates the situation. Various agonists, hormones, transmitters and/or chemicals are related to the regulation of the functions of the myometrium. Although notable advances regarding the key steps in receptor signalling explaining the actions of these factors have been achieved, a good deal of information is still necessary to understand this vital process. A better comprehension of myometrium physiology and the translation of research findings to clinical settings will help progress in women's health. In this review, we attempt to present a critical overview of myometrial functions and focus specifically on the role of calcium.

Endothelin-1: Physiological and pathological roles in myometrium

Endothelin-1 (ET-1), a member of endothelin peptide family is released by many different tissues including uterine smooth muscle. ET-1 acts through ETA and ETB receptors and is implicated in a wide range of biological and pathological functions that explain the great attention of the pharmacological industry for ET-1 receptors as potential therapeutic targets in vascular pathologies and cancers. It is now well established that ET-1 is also able to regulate myometrial functions. In the present review, we focused on ET axis and related signaling pathways involved in the regulation of myometrial contraction, as well as cell proliferation and survival. Such ET-1-mediated cellular functions play a critical role in normal pregnancy, preterm birth and uterine leiomyoma.

Integration of endocrine and mechanical signals in the regulation of myometrial functions during pregnancy and labour

In this review, we describe a new model to explain the regulation of myometrial function during pregnancy and labour. We propose that the myometrium undergoes dramatic changes in phenotype from early pregnancy until the onset of labour, characterized by an early proliferative phase, an intermediate phase of cellular hypertrophy and matrix elaboration, a third phase in which the cells assume a contractile phenotype and the final phase in which cells become highly active and committed to labour. The last phase of myometrial differentiation is postpartum uterine involution, completing the reproductive cycle following pregnancy and labour by returning the uterus to its non-pregnant receptive state. We further propose that phenotypic modulation of the uterine myocytes is the result of integration of endocrine signals and mechanical stimulation of the uterus by the growing fetus. Our previous studies have shown that these signals are important in regulating the onset of labour and we now have indications that they regulate earlier myometrial smooth muscle differentiation. We show that the high rate of myometrial cell proliferation in early pregnancy which reflects important aspects of many smooth muscle populations during development. The proliferative phenotype was associated with dramatic changes in the expression of IGF family proteins and coincided with an up-regulation of the anti-apoptotic pathway. Preliminary evidence suggests that myometrial hyperplasia was controlled by the PI3K-Akt-mTOR signaling pathway. The modulation of the mTOR pathway by rapamycin blocked the proliferative activity of the uterine myocytes. The growth and remodeling of the myometrium during pregnancy was associated with increased synthesis of extra cellular matrix (ECM) proteins and their corresponding integrin receptors. Our results show a decrease in expression of fibrillar collagens and a coordinated temporal increase in expression of components of the basement membrane near term associated with decreased progesterone levels and increased mechanical tension. The phenotypic modulation of uterine smooth muscle cells during pregnancy culminates at term when a myometrium-specific conversion commits these cells to the labour phenotype, characterized by increased excitability, spontaneous activity, responsiveness to agonists and effective coupling of the myocytes. The reinforcement of the ECM–integrin interaction contributes to myometrial hypertrophy and remodeling during late pregnancy and facilitates force transduction during the contractions of labour by anchoring hypertrophied SMCs to the uterine ECM. In addition, we suggest that myometrial cells play an important role in the generation and regulation of uterine inflammation, which is a characteristic feature of parturition. We provide here substantial evidence that myometrial cells can actively participate in the inflammatory process in the uterus by the release of the pro-inflammatory chemokine MCP-1. The increased production of MCP-1 in the term myometrium was associated with uterine occupancy and regulated by progesterone, suggesting that mechanical and endocrine signals integrate to regulate the expression of the chemokine and the induction of labour. A better understanding of the mechanisms regulating myometrial differentiation during pregnancy might inform the development of new therapeutic strategies for the management of preterm labour, which remains a leading cause of neonatal morbidity and mortality. Our data are obtained mostly from the rat, but we believe that they are generally applicable across species.

Ablation of connexin43 in uterine smooth muscle cells of the mouse causes delayed parturition

Gap junctions are characteristically increased in the myometrium during term and preterm delivery and are thought to be essential for the development of uterine contractions during labour. Expression of connexin43 (Cx43), the major myometrial gap junction protein, is increased during delivery. We have generated a mouse mutant (Cx43fl/fl:SM-CreERT2), in which the coding region of Cx43 can be specifically deleted in smooth muscle cells at any given time point by application of tamoxifen. By this approach, we were able to study long-term effects on myometrial functions that are necessary for parturition as well as gap junction intercellular communication in primary myometrial cell cultures. We found a prolongation of the pregnancy in 82% of tamoxifen-treated Cx43fl/fl:SM-CreERT2 mice as well as decreased dye coupling in cultured primary myocytes of these animals. Other parturition-specific parameters such as the regulation of oxytocin receptor, prostaglandin F receptor or progesterone remained unchanged. Our results indicate the important function of Cx43 during parturition in the living animal and suggest further strategies to investigate the role of connexins in uterine contractility in transgenic mice.

Regulation of myometrial smooth muscle functions.

Regulation of myometrial functions during gestation, labor and birth are in the forefront of research in reproductive sciences. The complexity of the problem is reflected by our scant understanding of the intimate cellular and molecular events underlying these phenomena, despite extensive efforts spanning several decades. Unlike other smooth muscles, the myometrium is, to a large extent, under hormonal control. Of these, the steroid hormones, progesterone and estrogen, play dominant roles in terms of uterine growth, the maintenance of quiescence during gestation and the preparation of the uterus for labor and delivery. In addition to steroid hormones, there are a number of factors that modulate myometrial contractility (oxytocin, prostaglandins, endothelin, platelet activating factor) and relaxation (corticotropin releasing hormone, prostacyclin, nitric oxide). Although notable advances have been made towards understanding some of the key steps in receptor signaling that define the actions of these factors, a good deal of new information is needed to fully understand this fundamental life process. Pharmaceutical agents have been used extensively to induce labor or to prolong pregnancy in the case of preterm labor that represents the major cause of perinatal morbidity and mortality. Because preterm labor is a syndrome of multiple etiologies, pharmacologic agents will have to be targeted accordingly. This review attempts to present a critical overview of these topics.

Sustained inhibition of rat myometrial gap junctions and contractions by lindane

BackgroundGap junctions increase in size and abundance coincident with parturition, forming an intercellular communication network that permits the uterus to develop the forceful, coordinated contractions necessary for delivery of the fetus. Lindane, a pesticide used in the human and veterinary treatment of scabies and lice as well as in agricultural applications, inhibits uterine contractions in vitro, inhibits myometrial gap junctions, and has been associated with prolonged gestation length in rats. The aim of the present study was to investigate whether brief exposures to lindane would elicit sustained inhibition of rat uterine contractile activity and myometrial gap junction intercellular communication.MethodsTo examine effects on uterine contraction, longitudinal uterine strips isolated from late gestation (day 20) rats were exposed to lindane in muscle baths and monitored for changes in spontaneous phasic contractions during and after exposure to lindane. Lucifer yellow dye transfer between myometrial cells in culture was used to monitor gap junction intercellular communication.ResultsDuring a 1-h exposure, 10 micro M and 100 micro M lindane decreased peak force and frequency of uterine contraction but 1 micro M lindane did not. After removal of the exposure buffer, contraction force remained significantly depressed in uterine strips exposed to 100 micro M lindane, returning to less than 50% basal levels 5 h after cessation of lindane exposure. In cultured myometrial myocytes, significant sustained inhibition of Lucifer yellow dye transfer was observed 24 h after lindane exposures as brief as 10 min and as low as 0.1 micro M lindane.ConclusionBrief in vitro exposures to lindane have long-term effects on myometrial functions that are necessary for parturition, inhibiting spontaneous phasic contractions in late gestation rat uterus and gap junction intercellular communication in myometrial cell cultures.

Myometrial characteristics of the syrian hamster uterine smooth muscle cell line, SHM.

We describe several characteristics of a novel smooth muscle cell line, SHM (Syrian hamster myometrium) derived from a primary uterine leiomyosarcoma which was induced by chronic estrogen plus androgen treatment of a female Syrian (golden) hamster. To determine the usefulness of the SHM cell line as a model for understanding myometrial function and its regulation, we have examined the morphologic and immunocytochemical properties of these cells, and the ability of uterotonic agonists to activate transmembrane signaling via phosphoinositide hydrolysis. The SHM cells exhibited a spindle-shape, smooth musclelike morphology when subconfluent, and a more compact, stellate shape at confluence. Like primary myocytes, SHM cells expressed the intermediate filament desmin and the contractile protein alpha smooth muscle actin, but not the epithelial antigen cytokeratin. Norepinephrine and bradykinin, which stimulate contraction and inositol polyphosphate production in the uterus, also stimulated inositol polyphosphate production in SHM cells. The maximal phosphoinositide signaling responses were lower in SHM cells compared with primary hamster uterine myocytes. We conclude that the SHM cell line exhibits primary uterine myocyte characteristics, and may therefore be a useful system for examining the mechanisms through which myometrial functions are regulated.

The control of myometrial functions during parturition with A β2 - mimeticcompound, PlanipartR

A betamimetic and tocolytic compound (Planipart R = 4-amino-α-[(tert.-butyl-amino)-methyl] 3-5-dichlor-benzylalcohol-hydrochloride; Boehringer Ingelheim, Vetmedica GmbH) was used to effectively interrupt or postpone parturition in 39 cows and heifers, 13 pigs and three sheep. Its fast action, long duration, and freedom of clinical side effects were confirmed in clinical and tocographical in-vivo studies. Parturition was interrupted during stage I and early stage II of labor. With declining effects of Planipart R, oxytocin can initiate renewed labor. Oxytocin is ineffective if the myometrium is under full control of Planipart, while Planipart R is ineffective when oxytocin (endogenous or exogenous) exerts its control on the myometrium. Deliveries after postponement or interruption seem subjectively to proceed faster and easier. No deleterious effects on mother or offsprings were observed in the postpartum phase or during lactation. Planipart may be used effectively in obstetrics and for biotechnical purposes.