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Infectious Diseases in Obstetrics and Gynecology 5:98-105 (1997)(C) 1997 Wiley-Liss, Inc.

Molecular Mechanisms of Parturition

F. Ferr6U. 361 INSERM, Universitd Rend Descartes, Hdpita/ Cochin, Paris, France

ABSTRACT

The initial signal for triggering human parturition might be fetal but of trophoblastic origin. Con-comitantly, this placental signal would have as its target not only the uterus but also the fetus byactivating its hypothalamo-pituitary-adrenocortical axis. The latter would represent a second fetalsignal which, at the fetomaternal interface, would amplify and define in time the mechanismsresponsible for the onset of labor, implying changes in the myometrial and cervical extracellularmatrix associated with the accession of the contractile phenotype for myometrial cells. At eachphase of these processes in the utero-feto-placental system, the nature of these signals remains to beidentified. Is there a single substance, or rather, and more likely, a combination of several?We appear to be in the presence of dynamic systems of a neuro-immuno-hormonal type which

are difficult to describe. Nevertheless, steroid hormones appear to coordinate their successiveequilibriums until they become irreversible. Such irreversibility constitutes the essential sign ofparturition. Infect. Dis. Obstet. Gynecol. 5:98-105, 1997. (C) 1997 Wiley-Liss, Inc.

KEY WORDS

Human parturition, placenta, uterus, extracellular matrix, signaling factors, contractility

the act of "bringing a child into theworld is one of the essential keys to life and

to the survival of the species, we cannot help butbe amazed even today by the fact that most of the

physiological mechanisms of human parturition re-

main to be elucidated. Giving birth is not a trivialact. Indeed, the pathologies associated with it,whose etiologies remain poorly understood, can ex-

pose both mother and child to varying types of

grave complications. Premature birth, for instance,is an important unsolved health problem.

One of the reasons why the processes of humanparturition remain to some extent enigmatic is thatresults of research utilizing animal models, whichcan then be transposed to humans, are, in fact, veryrare. Indeed, there exists extreme species diversity,especially in endocrine balance, which conditions

the maintenance of gestation. In women, one par-ticularity would appear to lie in the absence of a

correlation between the evolution of available pa-rameters, such as the plasma level of steroid hor-

mones or of many other effectors of uterine activ-

ity, and the onset of labor. In this respect, it is onlyrecently that we have became aware of the speci-ficity of the human species, as current data reveal a

multitude of pertinent factors, be they genetic, hor-monal or environmental. This complexity, also pre-sent in the mechanisms of action of these factors,has for the moment escaped any simplifying prin-ciple, whatever the level of analysis of the biologi-cal systems which are targets in the maternal-fetal

system.

Nevertheless, although experimentation is lim-

ited by considerations of an ethical or practical na-

ture, the availability of molecular biological tech-

niques and of selective pharmacological tools, andthe development of human cell models in the same

way as those enabling better understanding of thedifferent components of uterine contraction,should facilitate an approach to this intricacy.The initial question raised is that of the hor-

monal determination of parturition. The second,

*Correspondence to: F. FerrY, U. 361 INSERM, Universit6 Ren6 Descartes, Pavilion Baudelocque, 123, Boulevard dePort-Royal, 75014 Paris, France, E-Mail [email protected]

Received October 1997Accepted 21 October 1997

MOLECULAR MECHANISMS OF PATURITION FERRY,

upon which we will place special emphasis, con-

cerns the molecular mechanisms which, in theuterus, underlie the two phenomena which charac-terize parturition: the onset of regular, rhythmicmyometrial contractions and dilatation of the cer-

vix.

HORMONAL DETERMINATIONOF PARTURITION

Much data has been obtained concerning themechanisms involved in the onset of parturition inseveral animal species. Nonetheless, it must beadmitted that some of these data have had the ef-fect of momentarily preventing other approaches inhumans. The most striking example is that of theewe, with the discovery of an initial signal from thefetal brain leading to a drop in placental productionof progesterone (which blocks uterine excitability)and an increase in production of estrogens (whichpromote uterine contractility), z For several years, a

number of groups vainly sought the existence ofidentical mechanisms in the human species. Atbirth, the fetus, depending on the species, is con-

fronted with extremely varied situations necessitat-ing different competences. Its survival dependsupon its degree of maturation in the broad sense ofthat term, since it can involve different functions.In the human species, where the fetus confrontsextra-uterine life in a state of relative immaturityand dependence, a fetal signal is difficult to iden-tify. In anencephalic fetuses, parturition occurs in a

natural manner at term, but is slightly more dis-persed in time than in normal fetuses. While a rolefor fetal membranes has been suggested, based on

their capacity to locally control the metabolism ofsteroid hormones, prostaglandins and cytokines,studies are currently focusing on the placenta andin particular on its endocrine tissue, the tropho-blast. One of the characteristics of this tissue is not

only its extraordinary capacity for synthesis of a

wide variety of biologically active substances suchas steroid and polypeptide hormones, eicosanoids,neurotransmitters, vasoactive peptides, growth fac-tors and cytokines, but also its capacity to expressmost of the receptors of these substances.3 Each ofthese substances has varying degrees of pleiotropicfunctions. By controlling growth, differentiation,the synthesis of other signaling factors, immunity,and contractile activity at the level of numerousfetal and maternal targets, they participate in the

development of the fetoplacental unit and in theadaptation by the maternal organism, primarily theuterus, at the gestational state.

The concept of fetoplacental unit, elaborated inthe human species and up to now limited to bio-synthetic, progesterone and estrogen pathways,4

has recently been enriched by the discovery ofother interactions. In the trophoblast, 11 [3-hydroxy-steroid-dehydrogenase, which catalyzes the inter-conversion of cortisol into cortisone, would appearto play a role in triggering parturition. The de-crease in the synthesis of placental cortisol wouldlead, at the end of pregnancy, to the activation ofthe fetal hypothalamic-pituitary-adrenocortical axisand synthesis of fetal cortisol. This would have theeffect of accelerating pulmonary maturation of thefetus and of contributing, along with other hor-mones, to the production of placental corticotropin-releasing hormone (CRH), one of the effects ofwhich is to activate uterine motility. This fetopla-cental "dialogue," which begins early on in preg-nancy, would reinforce the idea of the existence ofa close relationship between fetal development andthe duration of gestation in the human species andin certain primates,s

Of all the organs, it is the placenta which has thegreatest species specificity in terms of its morpho-logical, structural and functional characteristics.6

Indeed, there exist several ways of optimizing thefetomaternal exchanges through the placenta. Wemight thus raise the question as to whether thespecies diversity noted in the mechanisms of theonset of parturition might not, in part, be linked to

the mode of placentation (the human placenta is ofa hemochorial type).

At the fetomaternal interface, structures otherthan the villous trophoblast are able to express a

certain number of biologically active substancesand their receptors: extravillous and invasive tro-

phoblast, amniotic and decidual cells, and immunecells (macrophages, lymphocytes). The potentiali-ties of expression of myometrial cells are also beingexamined at present. It is within the intervillousblood space, the circulation which is specific to thehuman fetomaternal interface, that some of thesesubstances which control both the development ofthe fetus and uterine activity are found at highconcentrations at the end of pregnancy.7

In this context, which favors regulations of a

paracrine, autocrine and intracrine type, the role of

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 99

MOLECULAR MECHANISMS OF PATURITION FERRIC,

each substance in the control of uterine activity is

difficult to evaluate. This situation is accentuatedat the site of placental insertion, where interactionsbetween fetal and maternal cells are establishedwhich are both subtle and evolutive.8 Indeed, it isin the human species that the invasion of uterinetissue by trophoblast cells is the most extensive,colonizing the wall of the spiral uterine arteries andreaching the inner layer of the myometrium.

Although we are uncertain whether it was

chance alone which determined the diversity of theplacental structure and that of the fetomaternal in-terface according to the species, these phenomenawhich, in the human species are superimposedupon classical endocrine activity, could be one ofthe signs of evolution. In the pregnant woman, thehypothesis of local action of signaling factors origi-nate from intrauterine tissues in the control of uter-

ine motility would help to at least partly under-stand why their placental production, like theirconcentration in the maternal peripheral circula-tion, are often impossible to correlate with themaintenance of gestation, the triggering of laborand parturition.

BIOCHEMICAL CHANGES IN THE UTERUSAT THE END OF PREGNANCY.INTEGRATIVE PROCESSES FOR

SIGNALING FACTORS

During the final weeks of pregnancy, biochemicalmodifications affect the uterine cervix and themyometrium. While the beginning of labor seems

to occur rather suddenly "maturation" processestake place gradually, both at the level of thesmooth muscle fibers (predominant in the myome-trium) and that of the extracellular matrix (pre-dominant in the cervix). The latter dissociates,which enables the cervix to dilate. Indeed, we note

an increase in hydration which might be linked to

that of hyaluronic acid and dispersion of collagenfibers which may be connnected to variations in thedistribution of glycosaminoglycans and the releaseof proteolytic enzymes by cervical myofibroblasts.9

The presence of macrophages and polynuclearsmay contribute, via release of lipid mediators andof cytokines, to increasing the expression of metal-loproteinases, with such alterations being similar to

those of an inflammatory reaction.1 These same

processes, in the myometrium, tend to favor inter-cellular communications (gap junctions) and the ac-

cession of smooth muscle cells toward a highly ef-fective contractile phenotype, as witnesses by thecharacterization, in term myometrium, of isoformsof "marker" proteins of this phenotype (o-actin,desmin, SM1 and SM2 myosin heavy-chains) as

compared to the weak presence of non-muscularisoforms. 11

As observed for other smooth muscle cells, it is

probable that such modifications affect interactions

between extracellular matrix and myometrial cellsvia adhesion molecules (integrins, etc.), lz Thesetransmembrane glycoproteins, the assembly ofwhich is regulated by a small GTP-binding proteinRho, interfere with signaling pathways and regu-late cells morphology, migratory properties,growth, differentiation, and contractility. 13

Another poorly defined aspect is that of para-crine interactions of cervical myofibroblasts andmyometrial smooth muscle cells with the othercells which are found in uterus at the end of preg-nancy: those of the vascular system, and in particu-lar microcirculation, and those of the immune sys-tem (mast cells, eosinophils, neutrophils), which

are important sources of signaling factors.4 In con-

trast, we note the degeneration of nerve endings in

the human myometrium at term.

At the moment of parturition, control of the con-

tractile activity of the uterine muscle necessitates the

setting up of numerous powerful regulatory sys-tems acting not only upon expression of signals butalso upon that of proteins of the signaling path-ways: receptors, G proteins, effector proteins (en-zymes, ionic channels, etc.) which modulate thebalance between the intracellular second messen-

gers. While inositol triphosphate (IP3) and calcium

initiate contraction, cAMP and cGMP induce re-

laxation. These intracellular messengers can alsocontrol expression of inductible genes which helpto modify the cell phenotype and consequently the

responses to various stimuli.In the human myometrium, the basic mecha-

nisms of contraction do not appear to greatly differ

from those of other smooth muscles, ls’6 The keyenzyme is the myosin light-chain kinase (MLCK)which, when activated by the calcium-calmodulincomplex, phosphorylates the 20-kDa myosin light-chain. In this phosphorylated form, myosin inter-

acts with actin and induces contraction. However,when MLCK is itself phosphorylated by the pro-tein kinases (PK) such as calcium-calmodulin-

100 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY

MOLECULAR MECHANISMS OF PATURITION FERRI

dependent PKII, PKC, PKA and PKG which are

respectively, AMPc- and GMPc-dependent, the ca-

pacity of MLCK to activate myosin and thus to

produce contraction decreases. The drop in intra-cellular calcium (CaZ+i) leads to relaxation: dephos-phorylated myosin, under the effect of a specificphosphatase, thus becomes detached from actin.While this schema appears to be well established invitro, it does not always appear to apply as well invivo. Moreover, the relative importance of the dif-ferent regulatory pathways may vary according to

whether they involve spontaneous contractile ac-

tivity or that provoked by extracellular signals. Re-cent studies have underscored the fact that thestreching of the muscle, which is very marked at

the end of pregnancy, could stimulate the expres-sion and the activity of enzymes of the contractilemachinery, in particular by lowering the responsethreshold of the MLCK to CaZ+i, which would en-

hance contraction. The existence of other regula-tory pathways involving thin-filament binding pro-teins (caldesmon and calponin) is merely suggestedin the myometrium.

Various specific ionic channels are expressed bythe myometrium. Calcium channels, the conduc-tance of which can be activated by a variation intransmembrane potential (VOC, or voltage-operated channels) of the L (long-lasting) type or

of the T (transient) type, via attachment of a spe-cific ligand (ROC, or receptor-operated channels)or by a mechanical strain, 17 contribute to the in-crease in CaZ+i. The latter can also arise from in-tracellular sites whose storage capacity would in-crease during gestation. The sarcoplasmic reticu-lum, in close relationship with the caveolae of theplasma membrane, is, in the myometrium, themain site at which receptor proteins of inositol tri-

phosphate (IP3) and of ryanodine act as channelsenabling the calcium efflux necessary for contrac-

tion toward the cytoplasm. In contrast, at the levelof the plasma membrane and the sarcoplasmic re-

ticulum, several systems would contribute towardlowering the Cae+i, in particular the Na/Ca ex-

changer and the Cae+/ATPases which play a majorrole in the myometrium. These systems, which are

activated by cAMP, provoke relaxation. The im-pact of cGMP is much less evident, as is that of theseveral cytosolic proteins which bind calcium.

Activation ofphospholipase C (PLC) leads to hy-drolysis of phosphatidylinositol biphosphate (PIP2)

and to formation of two messengers, IP3 which mo-

bilizes CaZ+i and diacylglycerol (DAG), an activatorof PKC. This enzymatic system is the main path-way of transduction used by the prostaglandins,oxytocin, the otl-adrenergic agents and the endo-thelins, to induce contraction in the human myo-metrium at the term. 18’19 Endothelin-1, which invitro is as powerful a uterotonic agent as oxytocin,z

is the most efficient activator of PLC.el This actionis relayed by G proteins which are sensitive (Gi ?)and insensitive (Gq/ll) to the pertussis toxin,zz

Only the endothelin receptors of the ETA type

coupled with PLC are involved in contractility, z3

The proportion of these receptors increases at theend of pregnancy with respect to the ETu recep-tors,z6 whose function in the myometrium remainsunknown.PGEz and PGFzot, although they could bind to

different receptors, stimulate PLC activity via a

Gq/ll protein. Another G protein (Gi ?)could be

implicated in the activation of the channels (ROC)by the prostaglandins,zs The result would be a pre-liminary increase in CaZ+i necessary for later acti-vation by PGFzot of a CaZ-dependent PLC. 19 Con-versely at the level of the uterine cervix, PGE2, a

powerful stimulator of cAMP synthesis by the cer-

vical myofibroblasts, may play a crucial role in re-

laxation and in the processes of maturation ob-served at the end of pregnancy.26 Like the endo-thelins, oxytocin activates the myometrial PLC viaa Gq/11 protein and a G (Gi ?) protein,27 though no

preliminary influx of Ca2+ is necessary as in thecase of PGFzot. Nevertheless, the ROC channelscould enable oxytocin to increase the Cae+i. Thecoupling of the oxytocin receptor to a Gh proteinhas recently been revealed in the human myome-trium,z8 It is now known that it is a family of iso-

forms, the PLC-[3, which is implicated in the acti-vation of the receptors to seven transmembranedomains coupled to G proteins. Three isoforms,131, 132 and 133, are involved in the contraction ef-fect of oxytocin in the human myometrium. An-other family of isoforms, PLC-y, whose mode ofactivation differes from that of PLC-13, also leads to

mobilization of Cae+i. In the human myometrium,the EGF receptor, which possesses tyrosine kinase

activity, stimulates the PLC-y via phosphoryla-tion,z9,z The PLC-[3 and PLC-y activities wouldbe subject to different negative retrocontrolmechanisms, generally involving PKC for PLC-[3



and PKA for PLC-y, but this aspect has not yetbeen elucidated in the human gravid myometrium.

In addition, oxytocin and very likely the CRHand endothelins stimulate phospholipase Az activ-ity, leading to synthesis of endogenous prostaglan-dins in the human gravid myometrium. The latter,in turn, stimulate PLC-13, thereby amplifying theirdirect effects upon this enzymatic pathway.

In the course of the third trimester of pregnancy,a phenomenon ofheterologous desensitization to the re-

laxing agents: 132-adrenergic and prostaglandins,activators of adenylyl cyclase, has been revealed inthe human myometrium.31,32

This mechanism of desensitization also hasbearing on activation of adenyly cyclase by theCRH, in the human term myometrium. Like thecatecholamines and prostaglandins, the alterationin the coupling of certain of the CRH receptors to

the catalytic component of adenylyl cyclase via a

Gs protein has been observed.33 In the humanmyometrium at term, other mechanisms contributeto lowering the cAMP concentration. Coupling ofthe adrenergic 132 and or2 receptors to an adenylylcyclase inhibiting Gi protein has been ob-served.31,34 The decrease in the cAMP capacitiesfor synthesis observed at the end of pregnancycould still be accentuated at the level of its enzy-matic degradation. A family of isoforms of (PDE)phosphodiesterase cyclic nucleotide which specifi-cally degrades cAMP at high affinity, is abundantin the human myometrium at the end of preg-nancy.3s This hormone-sensitive PDE4 activity isthe point of impact of pharmacologic agents with

myorelaxing and anti-inflammatory properties.36

The nitric oxide (NO) pathway could be a linkwith the mechanisms responsible for maintenanceof the quiescent state in the uterus during preg-nancy. Indeed, its use in the treatment of threat-ened premature birth has been proposed. The NOsynthase system, which is very active in the gravidhuman uterus, decreases at the time of labor. How-ever, the role of cGMP in myometrial relaxationinduced by NO has not been entirely elucidated,a7

Other substances classically identified as growthfactors (IGFs, EGF) and gonadotropins (hCG),whose receptors have recently been revealed in thehuman myometrium, also appear to be regulators ofcontraction.8,9 This action would be due to stimu-lation of eicosano’l’d production and/or to the factthat the multiple signals use common or interacting

signaling pathways. Among various kinases, which

play a role in the signaling cascade, the role of MAPkinase and tyrosine kinases needs to be clarified.4

Because of these phenomena of "cross-talk,"the response to a given signal will vary considerablydepending on the other signals present and will bean activating or an inhibiting response, probablysynergic rather than additive. Moreover, it is nowclear that differential control of the expression andthe activity of the different protein isoforms, whichintervene at each stage of the transmission of thesignal, i.e., receptors, G proteins, enzymatic effec-tors, etc., ensure specificity and contribute to thediversity of the responses in terms of contractility.We are now seeking to better understand which

isoforms are determinant in the point of no return

which, in the human myometrium at term, charac-terizes the onset of labor, and which factors controltheir expression and function. From this point ofview, the steroid hormones hold a special positionamong the effectors of uterine activity.

It is classically considered that progesterone,due to its relaxing properties, is responsible for thestate of hypocontractility of the uterus during preg-nancy, in opposition to the contracting effect of

17[3-estradiol. The 17[3-estradiol/progesterone ra-

tio, which is higher in the human myometrium at

term than at the beginning of pregnancy, raises thequestion of the manner in which agonist and an-

tagonist relationships are exerted between thesetwo steroids, whether their effects upon uterinecontraction are genomic or non-genomic.

In the myometrium as in the cervix, the steroidhormone receptors exert their pleiotropic effects bymodulating the transcription of a number of targetgenes which code for the structural and contractileproteins, for enzymatic proteins responsible for theproduction of other direct or indirect effectors ofuterine activity (prostaglandins, cytokines, etc.), fordegradation proteins (collagenases, proteases, pep-tidases, phospholipases, etc.) and for various otherproteins implicated in intracellular transduction

(ionic channels, receptors, G proteins, etc.) and in-

tercellular communication (connexins of the gapjunctions). Results reported concerning the evolu-tion of steroid hormone receptors in the gravid hu-man myometrium are currently highly controver-

sial. The most recent of these indicate that these

receptors are present in the smooth muscle and thevessels of the myometrium at the end of preg-


MOLECULAR MECHANISMS OF PATURITION FERRY,

nancy, and that only the progesterone receptors de-crease during labor, whether or not it is prema-ture.41 It should be pointed out that up to now no

study has been made in human myometrium of theevolution especially during pregnancy of the iso-forms of progesterone and estrogen receptors, re-

cently revealed in other tissues, which could beassociated with different functions. The responsesof genes modulated by the steroid hormones oftennecessitate the interaction of their receptors withother transcription factors. We can thus understandhow difficult it is to dissociate the proper effects ofthe steroid hormones, whether they be direct or

indirect, from those of the other hormonal signals.This difficulty is even greater due to the complex-ity of the relationship between the steroid hor-mones and their receptors, which can partly explaintheir complementarity and their antagonism. In themyometrium, estrogens are necessary for synthesisof the progesterone receptors, while progesteroneinhibits the expression of estrogen receptors andthat of its own receptors. Like other nuclear recep-tors referred to as "orphans," the steroid hormone

receptors can be operational in the absence of a

ligand.In general, the effects of progesterone are di-

rectly opposite those of the estrogens, which in-duce the synthesis of signals and of proteins whichintervene in contraction. Nevertheless, this is not

always the case: the presence of progesterone is, infact, required during the induction of the synthesisof certain ionic channels by 1713-estradiol. Consid-ering that progesterone favors the expression of im-munosuppressive cytokines during gestation, it re-

mains to clarify what happens with the Th2/Thlcytokine balance in the different cell populationsof the uterus at time of parturition.

There unquestionably exist, in the myometri-urn, rapid non-genomic effects of steroid hormoneswhich to a certain extent interfere via second mes-

sengers with the genomic effects. Although the no-

tion of membrane receptors of steroid hormonesremains subject to controversy, progesterone de-creases and 17[3-estradiol increases the fluidity ofthe plasma membranes.These modifications couldboth influence the organization and function of themembrane proteins and modulate the flexibilitynecessary for morphological changes which thesmooth uterine fiber undergoes during the contrac-

tion-relaxation cycle. Hyperpolarizing progester-

one, by inhibiting the VOC type L channels re-

sponsible for the entry of calcium into the myome-trial cell and, consequently, for MLCK activity,relaxes the uterine muscle. Other calcium-calmodulin-dependent enzymes can also be inhib-

ited, among them a family of phosphodiesteraseisoforms which degrade cAMP and cGMP, both ofwhich are involved in relaxation. In the human spe-cies, while parturition occurs with high myometriallevels of progesterone, recent experiments none-

theless suggest that the relaxing effect of proges-terone upon the smooth uterine muscle is neutral-ized at the start of labor, or else is reversed duringparturition.4z,43

It is clearly evident at the present time that inthe human species, parturition is conditioned bythe progressive passage of the myometrium in a

quiescent state, where the functionality of the ad-

enylyl cyclase system predominates, toward othertransduction pathways such as that involving phos-pholipase C, the activation of which leads to mo-

bilization of CaZ+i and to contraction. Such results,when compared to those obtained in animals, un-

derscore the specificity of the species in terms ofthe response of these enzymatic systems to hor-monal signals in the pregnant myometrium. Theimpact of modifications observed in parallel at thelevel of the extracellular matrix upon phenotypicevolution of the uterine smooth fiber and its inter-

actions with other uterine cells must be taken intoaccount.

However, while all the substances present at thefetomaternal interface play a role in the uterine

motility taking place during the different phases of

parturition, none seems to play the initial role in

setting it off. For example, prostaglandins, whichexert a coordinated, efficient effect upon the myo-metrium and the uterine cervix, are widely used to

artificially induce labor, but no element enables us

to definitively state that they play a determing rolein the physiological onset of parturition.

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