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

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Abstract

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.

Section snippets

The problem: preterm birth

Preterm birth (birth at <37 completed weeks of gestation) is the most significant clinical problem facing contemporary clinical obstetrics in the developed world. It is the single most important cause of perinatal mortality and morbidity in industrialized countries: 60–80% of deaths of infants without congenital anomalies are related to preterm birth [1]. Preterm birth is also associated with cerebral palsy and other long-term health sequelae including cognitive impairment, blindness, deafness,

Studies of the initiation of labour

It is not surprising that research directed toward preterm delivery has focused on the onset of labour. Indeed, the vast majority of research investigations relating to myometrial function, including our own, have focused on events during the last few hours of pregnancy. Over the past decade our knowledge of the mechanisms leading to the onset of labour has increased dramatically (see [8] for detailed review). We have proposed that the fetal genome ultimately regulates the timing of parturition

Phenotypic modulation of SMCs

Smooth muscle cells (SMCs) of the uterus, bladder, circulatory, gastrointestinal, and respiratory systems are specialized contractile cells, virtually packed with contractile myofilaments and completely ready for contraction. At the same time they show remarkable cellular plasticity which differentiates them from cardiac and skeletal muscle, which undergo terminal and irreversible differentiation. There is extensive evidence showing that vascular SMCs are phenotypically modified in the

Myometrial proliferative phenotype

During early pregnancy, uterine myocytes proliferate very rapidly (as measured by increased incorporation of BrdU into myocytes and of proliferating cell nuclear antigen [PCNA] expression), predominantly in the longitudinal muscle layer of both gravid and non-gravid horns of unilaterally pregnant rats, suggesting that this proliferative phenotype is controlled by endocrine rather than mechanical signal [17]. In addition to proliferation there is increased expression of anti-apoptotic factors

Transition to the synthetic phenotype

Around day 14, proliferation ceases and the expression of the anti-apoptosis factor, Bcl-2, begins to decline (Fig. 1). At this point myocyte growth switches from proliferation to a phase of hypertrophy, termed the synthetic phase due to its association with increased synthesis of ECM and cellular growth.

The cause of the switch in phenotype is unknown, but it coincides with dramatic activation of the intrinsic apoptotic cascade that involves expression of initiator caspase-9 and effector

Myometrial synthetic phenotype

The synthetic phase of myometrial differentiation is characterized by growth that is due to (1) increase in cell size rather than proliferation and (2) the synthesis and deposition of interstitial matrix that forms the ground substance of the myometrium. During this period from day 15 to around day 21 there is a dramatic increase in the protein:DNA in the pregnant rat myometrium, indicative of hypertrophy. Importantly, this myocyte hypertrophy requires a degree of tension on the myometrial wall

Transition to the contractile phenotype

Around day 21 the myometrium undergoes a further differentiation into a contractile phenotype. At this time the rate of cellular hypertrophy appears to stabilize and there are marked changes within the myocyte and in the interaction between the myocyte and the underlying matrix as the muscle prepares for the process of labour. The transition to the contractile phenotype is associated with a dramatic change in the synthesis of matrix proteins. The synthesis of interstitial matrix that was

The labour phase

As the influence of P4 wanes the myometrium undergoes a final switch in phenotype as labour is initiated. We have previously described the series of molecular and biochemical events associated with labour and the role of endocrine and mechanical signals [18]. At this time, the myometrium becomes fully committed to the development of intense coordinated contractions that will bring about the delivery of the fetus(es). This period is associated with a significant increase in myometrial tension as

The role of myometrial smooth muscle cells in uterine inflammation

Recent evidence suggests that leukocytes infiltrate uterine tissues at or around the time of parturition implicating inflammation as a key mechanism of human labour. Leukocyte infiltration and migration is regulated by chemokines, an ever-growing family of chemotactic cytokines. Among pro-inflammatory cytokines that participate in the development of an inflammatory reaction in myometrium, Monocyte Chemoattractant Protein-1 (MCP-1, also known as Chemokine (C-C motif) Ligand 2, CCL-2) expression

Postpartum uterine involution

Postpartum uterine involution is a critical event as it completes the reproductive cycle following pregnancy and labour by returning the uterus to its normal non-pregnant state so the females can remain fertile (Fig. 6). Upon placenta shedding in labour, subsequent uterine transformation involves several processes similar to development and wound healing, specifically (1) substantial tissue reorganization by (2) MMPs induction, (3) ECM degradation and (4) apoptosis. IGF-I has been implicated in

Myometrial stem cells

There is a massive induction of apoptosis of the uterine myocytes during the phase of postpartum involution [17], suggesting that there must be a mechanism by which the SMCs, which are lost during this process, are replaced. This would require the generation of new SMCs in order to allow the uterus to quickly resume its normal, non-pregnant receptive conditions. Despite advancing knowledge in the field of myometrial function during pregnancy, the precise mechanism by which the larger,

A new model for the regulation of myometrial function during pregnancy and labour

The data described here have led us to propose that uterine myocytes exhibit a program of differentiation throughout pregnancy that encompasses at least four distinct cell phenotypes. These include an initial phase of myocyte proliferation, a synthetic phase involving interstitial ECM synthesis, focal adhesion remodeling, myocyte hypertrophy, a contractile phase of up-regulation of contraction-associated proteins and down-regulation of myometrial inhibitory pathways, and, finally the expression

Conflicts of interest

The authors declare that there are no conflicts of interest.

Funding source

CIHR grant # 37775.

Condensation

During pregnancy, the myometrium undergoes changes in cellular phenotype, characterized by an early proliferative phase, an intermediate phase of cellular hypertrophy, and a final contractile/labour phase.

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    This study was supported by a grant from the CIHR # 37775.

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