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REVIEW |
Medical School, Institute of Cellular Medicine, University of Newcastle, 3rd Floor, William Leech Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK1 Division of Obstetrics and Gynaecology, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Clinical Sciences South Bristol, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK
Correspondence should be addressed to J Lartey; Email: jon.lartey{at}ncl.ac.uk
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Abstract |
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Introduction |
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The fundamental role of RHO proteins in multiple cell signalling pathways is well established and this is an area of rewarding research opportunities; however, it remains relatively unexplored in reproductive tissues. In this review, we have focused on RHO proteins that have been described in uterine tissues, but in some instances the experimental data are scarce and their possible role can only be described by analogy with evidence obtained in other systems. Our aim is to explain the relevance of RHO proteins in the control of myometrial smooth muscle contractility, especially in relation to the onset of labour. Although this approach can only provide a narrow perspective in the ever expanding field of small GTPases, we believe it is a framework of current understanding and a stimulus for research on this multifunctional family of proteins for scientists and clinicians interested in reproduction.
Premature birth is the most important cause of perinatal death and long term morbidity in the world today. Although an increasing proportion of premature births are induced secondary to pre-existing fetal and maternal conditions, over half of these deliveries are due to the spontaneous onset of uterine contractions (spontaneous preterm labour). So far, our ability to successfully treat women whose pregnancies are complicated by preterm labour is hampered by a lack of knowledge of the endocrine and biochemical factors that initiate human parturition.
The human uterus is a smooth muscle organ which undergoes considerable distension during gestation without expelling its contents. It is not clear what regulates this state of relative quiescence. During labour, it contracts in a regular and coordinated fashion to forcibly expel the fetus. Contraction in smooth muscle tissues is regulated by two key enzymes: calcium–calmodulin-dependent myosin light chain kinase (MYLK) which phosphorylates the regulatory 20 kDa myosin light chain (MYL) to generate increases in tension and contraction, and a trimeric protein phosphatase called myosin phosphatase (MLCP) which induces a state of relaxation through dephosphorylation of activated MYL (Somlyo & Somlyo 1994, Word 1995). Therefore, the force of contraction and MYL phosphorylation in the human uterus during labour is determined by the equilibrium between MYLK and MLCP. The mechanisms that regulate these two enzymes in the human uterus remain poorly understood.
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The RHO family |
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RHO GTPs belong to the RAS super family of GTP binding proteins. They function as molecular switches which regulate a wide variety of cellular functions ranging from membrane trafficking, gene transcription, cell growth, actin polymerisation, stress fiber formation and smooth muscle contraction.
The mammalian RHO family is made-up of at least ten different proteins namely RHO gene family member A (RHOA); RHO gene family member B (RHOB); RHO gene family member C (RHOC); RHO family GTPase 1–3 (RND1–3); RAS-related protein RAC1–2; cell division cycle 42 GTP-binding protein (CDC42); RHO gene family member D (RHOD); RHO gene family member F in filopodia (RIF) also known as RHOF; RHO gene family member Q (RHOQ) also known as TC10 and ADP-ribosylation factors (ARF1 and ARF6). Human RHOA, RHOB, RHOC and RHOD genes are located on chromosomes 3p21.3, 2p24, 1p13.1 and 11q14.3 respectively. RAC1, CDC42 and their close RHO family relation RHOG are found at 7p22, 1p36.1 and 11p15.5–p15.4 respectively. A dendritic tree representation of the human family of RHO GTP binding proteins is outlined in Fig. 1.
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Structure and regulation of RHO proteins |
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20–30 kDa in size. All RHO proteins have conserved residues at Gly14, Thr19, Phe30 and Gln63 which are required for GTP binding and hydrolysis. Their core structure includes an effector domain; four separate nucleotide binding regions which span the length of the core structure; a hypervariable region and a CAAX box motif, see Fig. 2. The effector domain changes conformation between the GTP- and GDP-bound states.
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Other monomeric GTP-binding proteins |
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RND proteins |
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RND3 was first identified by Foster et al. (1996) by using rat ARHGAP5 as bait in a yeast two hybrid assay. Other investigators subsequently described an RND3 protein which had 15 extra residues at its N-terminal end compared to the protein described by Foster et al. (Nobes et al. 1998). Human RND3 is located on chromosome 2q23.3. RND proteins have three guanine-binding motifs, two loops and three major residues that coordinate magnesium binding in the GTP state. They have an effector region in common with other RHO family members but they possess key structural differences within the catalytic domain which distinguish them from other RHO proteins. Unlike RHO proteins, RND proteins almost have no GTPase activity and exist in a constitutively active GTP-bound state (Foster et al. 1996, Nobes et al. 1998, Wennerberg et al. 2003). RND proteins have a CAAX box motif and a terminal methionine which implies that they undergo farnesylation.
Other new GTPase deficient, constitutively active, proteins including GTP-binding protein overexpressed in skeletal muscle (GEM) and Ras-related associated with diabetes (RRAD) have now been located on chromosomes 16q22 and 8q13–q21 respectively, Fig. 1.
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Regulation of RND protein activity |
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RND2 is usually cytosolic and preferentially localises to early endosomes where it binds to vacuolar protein sorting 4A (VPS4A) to regulate endosomal trafficking, whereas RND3 also localizes to perinuclear structures like the Golgi (Tanaka et al. 2002). After farnesylation, RND proteins are equally distributed between plasma membrane and the cytosol (Riento et al. 2003).
It is thought that RND3 exists in two conformations: a phosphorylated cytosolic-bound form with an extended half-life, which is associated with increased disruption of RHOA actin filaments; and an unphosphorylated form which is found in both cytosolic and membranous compartments (Riento et al. 2003, 2005). ROCK-mediated phosphorylation prolongs the half-life of RND3 and translocates the protein from the membrane to the cytosol where it disrupts RHOA stress fibers (Riento et al. 2005). The resultant RND phosphorylation requires an activated RHOA/ROCK and a protein kinase C (PRKC) pathway (Riento et al. 2005). Platelet-derived growth factor (PDGF) stimulation activates ROCK through a PRKC-dependent mechanism to cause phosphorylation of RND3 at Ser7 and Ser11. RND3 phosphorylation is inhibited by both ROCK and PRKC inhibitors (Riento et al. 2005). PRKC-induced phosphorylation increases RND activity by prolonging the half-life and stability of the phosphorylated protein and in some instances C-terminal phosphorylation causes membrane translocation (Berzat et al. 2005).
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RHO and RND effector interactions |
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ROCKs have four functional domains: an N-terminal kinase domain, a central coiled-coil domain which contains a RHO-binding domain (RBD) and a C-terminal pleckstrin homology (PH) domain, Fig. 4. The kinase domain binds to the PH and RBD domains to form an autoinhibitory closed inactive loop. Binding of active GTP-bound RHOA to the RBD leads to autophosphorylation and disruption of the autoinhibitory interaction between the C-terminal PH and RBD domains and the N-terminal kinase domain. The activated kinase adopts an open conformation that enables it to bind downstream targets.
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Activated ROCK binds to a number of downstream targets including myosin phosphatase RHO interacting protein (Surks et al. 2003, 2005), zip kinase also known as death-associated protein kinase 3 (DAPK3; Hagerty et al. 2007), integrin linked kinase (ILK; Kiss et al. 2002, Muranyi et al. 2002) and the PRKC inhibitory phosphoprotein CPI-17 or PPP1R14A (Kitazawa et al. 2000, 2003, Eto et al. 2001) to regulate MYL phosphorylation.
ROCKs regulate actin myofilament assembly by binding to actin nucleators and polymerizers such as DIAPH1, LIM domain kinase 1 and ERM (ezrin, radixin and moesin) proteins. Dysregulation of these actin-binding proteins can result in different disorders. For instance, mutations in DIAPH1 gene have been implicated in non-syndromic deafness (Lynch et al. 1997) and premature ovarian failure (Bione et al. 1998). We have recently characterised DIAPH1, DIAPH2 and DAPK3 expression in the human uterus during pregnancy and noted interesting changes in expression during labour (Lartey et al. 2007, Lartey & Lopez Bernal 2009a). It is not certain how these proteins regulate uterine smooth muscle MYL phosphorylation and contraction and their function needs to be investigated.
The two ROCK isoforms have their own distinct functions in the human placenta and in the developing fetus. ROCK2 deficient (ROCK2–/–) mice usually die in utero due to placental dysfunction and intrauterine growth restriction caused by thrombus formation in the placenta. ROCK1–/– mice have a different phenotype and usually survive pregnancy and labour to die post-natally from filamentous actin accumulation leading to impairment in the closure of the umbilical vein (Rikitake et al. 2005). Analysis of ROCK2 null mice suggests that ROCK1 does not compensate for the loss of ROCK2 function (Thumkeo et al. 2003).
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GPCR activation of RHOA/ROCK proteins in smooth muscle cells |
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12/13 heterotrimeric proteins. The ‘active’ heterotrimeric G12/13 protein complex binds to ARHGEFs through a regulator of G-protein signalling (RGS) domain and sets off a downstream cascade by catalysing nucleotide exchange on ARHGEF1 and ARHGEF12. Thus, ARHGEFs with RGS domains function both as GTPase activating proteins and as effectors for G12/13 (Suzuki et al. 2009). Ligand-bound GPCR–G13–ARHGEF1 complex has a number of downstream actions: i) to stimulate GTP exchange of RHOA, leading to ROCK1 activation; and ii) activation of phospholipase D which cleaves phosphatidylcholine to yield phosphatidic acid and diacylglycerol. The latter stimulates the PRKCB-dependent phosphoprotein PPP1R14A which inhibits the PPP1c catalytic subunit of MLCP. Therefore, GPCR receptor activation results in ROCK and PRKCB-mediated inhibition of MLCP to cause increases in MYL phosphorylation and contraction at a constant [Ca2+]i, see Fig. 5.
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RHO and RND protein regulation of uterine contractility |
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During pregnancy, the myometrial contractile apparatus undergoes several changes that enable it to adapt to the physiological alterations in size, stretch and tension due to the growing fetus. These changes during gestation prime the myometrium for the increase in contractile activity required for normal labour. Although myometrial levels of actin, myosin, calponin and the steady state levels of MYL phosphorylation do not alter during pregnancy, tissue strips from pregnant women generate greater levels of tension at any given level of MYL phosphorylation in comparison with strips from non-pregnant women (Word et al. 1993, Riley et al. 2005). Pregnant myometrium is more sensitive to the effects of calcium and agonists like OXT than non-pregnant myometrium. In the rat, pregnant myometrium develops greater levels of tension than non-pregnant myometrium at a given level of MYL phosphorylation after exposure to a range of stimulants including OXT, prostaglandins (PGE2 and PGF2), carbachol or high K+ (Kim et al. 1998). The mechanism of the increased response to contractile agonists in pregnancy is not completely understood, but it is likely to involve Ca2+ sensitization and be multi-factorial in origin. Moreover, other contractile proteins like caldesmon are elevated in pregnant compared to non-pregnant rat myometrium and may mediate this heightened contractile activity (Li et al. 2003). However, treating permeabilised rat myometrial strips with Ca2+ and calyculin-A (a phosphatase inhibitor) produced similar increases in force in non-pregnant and pregnant myometrial strips (Kim et al. 1998). This suggests that the increase in force generated in myometrial smooth muscle during pregnancy is due to inhibition of a phosphatase presumably myosin phosphatase.
The first physiological experiments which demonstrated the effect of RND protein on contraction in smooth muscle tissues were performed in permeabilised rat ileal muscle strips and showed that co-transfection of RHOA and RND1 reverses RHOA mediated Ca2+ sensitization (Loirand et al. 1999). Treating rat ileal strips with progesterone and oestrogen increased their RND1 membrane-bound content. These changes in RND1 expression led to a reduction in agonist-induced Ca2+ sensitization. The action of RND1 was independent of [Ca2+]i and did not affect the calcium-force response curve or the force of contraction generated by the myosin phosphatase inhibitor calyculin-A. Subsequently, other investigators suggested that the increase in steroid hormones during gestation causes a time-dependent increase in Rnd1 mRNA expression in rat uterus (Kim et al. 2003). They noted that Rnd1 mRNA levels fell to pre-pregnancy levels at day 1 post partum. In line with previous observations they suggested that the increase in Rnd1 mRNA expression may function to inhibit RHOA Ca2+ sensitization and maintain uterine quiescence required during gestation. Pacaud's group used cDNA micro array, real-time PCR and immunoblotting to show that RND3 mRNA and protein expression was upregulated in mid-pregnant rabbit myometrium and suggested that the mid-pregnant increase in RND3 expression was associated with inhibition of RHOA mediated Ca2+ sensitization (Cario-Toumaniantz et al. 2003).
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Relevance to human myometrium |
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The potential regulatory role for RHO proteins in uterine smooth muscle contraction was first highlighted by demonstrating an increase in Rock1 and Rock2 mRNA expression in rat myometrium during pregnancy (Niiro et al. 1997). Other investigations subsequently reported ROCK1 and ROCK2 mRNA and protein expression in pregnant and non-pregnant human myometrium (Moore et al. 2000, Moran et al. 2002, Friel et al. 2005, Riley et al. 2005). Myometrial RHOA, ROCK1 and ROCK2 levels in women are invariant among non-pregnant, pregnant not in labour, spontaneous labour and spontaneous preterm labour groups (Lartey et al. 2006d).
Myometrial ROCK activity was elevated after treatment with the caspase-3 inhibitor Z-DEVD-FMK which prevents cleavage of ‘active’ p160ROCK1 to the ‘inactive’ p130ROCK1 (Moore et al. 2002). Chronic thromboxane receptor stimulation with U46619 [GenBank] increased p160ROCK1 expression and these changes were reversed by pretreatment with SQ29458, a thromboxane receptor antagonist (Moore et al. 2002). Agonist activation of RHOA enhances ROCK activity by increasing the stability of the p160ROCK1 (Moore & Lopez Bernal 2003).
There is evidence of other RHO effectors in human myometrium. A constitutively active p34 protein fragment of the RHO effector p21 protein activated kinase 2 (PAK2) is elevated in human myometrium during pregnancy (Moore et al. 2000). The expression of PKN (previously known as PRKC-like protein; Mukai & Ono 1994) and its downstream target PPP1R14A are both elevated in human myometrium during pregnancy (Ozaki et al. 2003, Lartey et al. 2007). The human formin protein DIAPH1 expression is upregulated in spontaneous labour whole tissue homogenates (Lartey et al. 2007).
Tonic versus phasic contractions
Smooth muscle tissues like the uterus and the gut contract in two ways: ‘phasic’ contractions which are transient, and ‘tonic’ more sustained contractions (Murthy et al. 2003). During labour the uterus contracts in a predominantly phasic manner but also requires periods of sustained tension (i.e. tonic contraction) in between the phasic contractions which occur approximately every 2 min. In vitro experiments with human uterine muscle strips showed that ROCK inhibition with Y27632 was maximal during tonic rather than phasic agonist- and K+-stimulated contractions (Kupittayanant et al. 2001). This has led some workers to conclude that RHOA-induced Ca2+-independent contractions primarily regulate the strength of tonic contractions and may not play a significant role in augmenting the phasic activity of myometrial tissue in labour (Kupittayanant et al. 2001).
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Coupling of RHO activation, membrane translocation and myometrial contraction |
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Exposure of myometrial tissue to stimulatory GPCR agonists, e.g. OXT, carbachol, activates RHOA and ROCK to produce Ca2+-independent increases in tension (Taggart et al. 1999, Kupittayanant et al. 2001, Tahara et al. 2002, 2005, Woodcock et al. 2004). LPA is a classical RHO agonist that increases MYL phosphorylation in myometrial tissue strips (Moore et al. 2000). Recent experiments demonstrating that LPA increases GTP–RHOA levels in treated human myometrial smooth cells suggest that LPA-induced MYL phosphorylation may in part be due to RHOA activation (Lartey et al. 2007). These experiments highlighted the potential role of agonist-induced RHO activation and MYL phosphorylation in human uterine smooth muscle contraction.
One of the key experiments linking GPCR receptor stimulation to protein translocation in uterine smooth muscle cells demonstrated that carbachol-induced Ca2+ sensitisation resulted in PRKCB, RHOA and ROCK translocation to the plasma membrane (Taggart et al. 1999). Carbachol stimulated increases in the force of contraction and MYL phosphorylation at a constant [Ca2+]i were reversed by the ROCK inhibitor Y27632. The same authors showed that contractile agonists like carbachol and OXT cause membrane translocation of RHOA in rat myometrial cells (Oh et al. 2003).
Our experiments have demonstrated increases in RHOA, RHOG, RND2 and RND3 membrane-bound proteins in pregnant myometrium relative to non-pregnant myometrium (Lartey et al. 2006c). This suggests that the changes in myometrial cell shape, size and function during pregnancy are reflected by alterations in RHO protein activation. We observed increases in RHOA membrane translocation in human myometrial tissue strips after OXT and carbachol treatment under both tension free and isometric conditions (Lartey & López Bernal 2008a, 2008b, 2008c). Curiously, both OXT and carbachol also produced marked increases in RND1 and RND2 membrane translocation (Lartey & Lopez Bernal 2008a).
The RND2 results are quite remarkable as this protein was only confined to the cytosolic fraction of unstimulated tissue strips in all pregnant samples used in our study. At first glance, these findings are contrary to the concurrent increases in RHOA translocation and presumed activation observed in the stimulated uterine strips. However, it is noted that RND2 can function both as a RHOA antagonist and agonist (Tanaka et al. 2006a). RND2 is usually cytosolic but is recruited to a membrane compartment presumed to be early endosomes by an effector protein called VPS4A. Therefore, the differences in RND membrane translocation caused by OXT may be as a consequence of its involvement in GPCR receptor/vesicular trafficking (Tanaka et al. 2002). More work is required to understand RHO and RND functions in myometrial cells during pregnancy and in labour. A summary of RND interacting proteins and their mechanisms of actions are presented in Table 1.
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Physiological uterotones such as OXT and PGF2 enhance myometrial sensitivity to Ca2+ through a RHOA–ROCK-dependent mechanism (Woodcock et al. 2004, 2006). We have mapped the effects of OXT and carbachol on RHO protein targets downstream of ROCK1. OXT-induced tension and contraction in human myometrial strips under isometric conditions are associated with concurrent increases in PPP1R12A-Thr696 and MYL-Ser19/Thr18 phosphorylation (Lartey & López Bernal 2008a, 2008b, 2008c). Pregnancy is associated with a marked upregulation in the expression of native and activated forms of the PRKCB-dependent inhibitory phospho-protein PPP1R14A (Ozaki et al. 2003, Lartey et al. 2007). We have shown that OXT can induce changes in PPP1R14A–Thr38 phosphorylation in human uterine smooth muscle cells (Lartey et al. 2007).
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Involvement of RHO proteins in uterine quiescence and abnormal labour |
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ARF–GTP-binding proteins regulate GPCR receptor desensitization (Mukherjee et al. 2000). ARF–GEFs catalyse the nucleotide exchange on the ARF–GDP-bound GPCR complex allowing the receptor to internalize (Salvador et al. 2001). Recent experiments from our laboratory have found changes in ARF6 and PSCD3 (an ARF6 GEF) mRNA and protein expression in preterm myometrium from pregnancies complicated by pre-eclampsia and intrauterine growth restriction, suggesting for the first time that different mechanisms may regulate receptor trafficking during normal and complicated pregnancies (Lartey & Lopez Bernal 2008b).
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Novel RHO effector mechanisms during pregnancy and in labour |
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in labour. PKN1, the first RHOA effector to be discovered (Mukai et al. 1994, Palmer et al. 1994) was also present in our myometrial samples. Its expression was upregulated in all the pregnant groups compared to non-pregnant groups. PKN1 expression was mirrored by a similar increase in one of its downstream targets, namely phosphoThr38–PPP1R14A. This represents another mechanism of Ca2+ sensitization in pregnant myometrial tissue. Thus, the PKN1–PPP1R14A and the RHOA–ROCK–RND pathways may converge on MLCP at PPP1c and PPP1R12A sites respectively and crucially can function independently of each other, see Fig. 5.
We have found that the expression of other RHO effectors such as DIAPH1 and DIAPH2 (Watanabe et al. 1997, 1999) is altered with human labour (Lartey et al. 2007). DIAPH1 and DIAPH2 are human formin proteins involved in actin reorganization and have been linked to RHOB and RHOD formation of endosomal vesicles (Murphy et al. 1996, Gasman et al. 2003). The role of actin polymerisation in uterine myofilament remodelling during gestation and in priming the contractile apparatus for labour is not well understood and is an area of considerable research interest.
Protein kinases other than ROCK can inhibit MLCP activity by phosphorylating PPP1R12A at Thr696. The candidates kinases include PAK (Takizawa et al. 2002), distrophia-myotonica protein kinase (Muranyi et al. 2001), ILK (Muranyi et al. 2002), and DAPK3 (MacDonald et al. 2001a). We used immunoblotting and immunohistochemistry to characterize DAPK3 expression in our human tissue samples. Our preliminary findings indicate that DAPK3 may undergo differential signalling and activation during labour (J Lartey & A López Bernal, unpublished observations). DAPK3 may cause Ca2+-independent contraction by either phosphorylation of the PPP1R12A subunit of myosin phosphatase at Thr696 (MacDonald et al. 2001a, Niiro & Ikebe 2001, Borman et al. 2002), activation of PPP1R14A by phosphorylation at Thr38 (MacDonald et al. 2001b) or direct phosphorylation of MYL at Ser19 and Thr18 (Murata-Hori et al. 1999).
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Pharmacological regulation of the RHO pathway |
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and OXT activate GPCRs to promote Ca2+ release and entry into the cells, promoting Ca2+–calmodulin-dependent MYLK activation. Moreover, these agonists generate increases in tension at a constant activity of intracellular Ca2+. We have shown that myometrial GTP–RHOA and ROCK activity are elevated during spontaneous preterm labour (Lartey et al. 2007). Thus, it is conceivable that inhibition of ROCK activity may lead to attenuation of the tension that may be associated with spontaneous preterm labour. Several compounds have been manufactured to inhibit ROCK function. The most widely used N-(4-pyridyl)-4-(1-aminoethyl) cyclohexane carboxamide Y27632 is a highly potent, cell-permeable pyridine derivative which acts as an ATP-competitive inhibitor with equal potency against ROCK1 and ROCK2 (Uehata et al. 1997). Y27632 inhibits agonist-induced phosphorylation of myosin phosphatase and MYL to disrupt RHOA mediated stress fibers and cause smooth muscle relaxation (Uehata et al. 1997). However, Y27632 and other similar compounds like Y32885 inhibit other related kinases like PRK1 and PRK2 at concentrations required for ROCK inhibition (Davies et al. 2000). This multi kinase inhibition is also observed with another ROCK inhibitor compound HA 1077 (AT877 or fasudil hydrochloride; Amano et al. 1999, Niggli 1999). Therefore, the potential of ROCK inhibitors to relax the uterus may be limited due to their lack of kinase specificity. Further research is required on the effect of ROCK inhibitors on myometrial tissue during agonist-induced and spontaneous contractions in normal and preterm labour. Furthermore, we need to determine the transcription factors and ERE/PREs that control the remarkable increases in RHO and RND protein expressions and activity during pregnancy and labour. We also need to elucidate whether oestrogen stimulation or a functional progesterone withdrawal, or both, can produce changes in uterine smooth muscle Ca2+ sensitization in women as demonstrated in some animal species as there can be quite marked changes in RHO protein expression and function among species. Moreover, steroids may induce changes in the activity of signalling enzymes that result in post-translational modification or phosphorylation of the proteins to precipitate labour. There are predicted putative oestrogen and progesterone response elements of human RND genes, see Fig. 9.
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RHO proteins and uteroplacental vascular disease |
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Conclusion |
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Declaration of interest |
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Funding |
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Acknowledgements |
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Received April 23, 2009
First decision June 2, 2009
Accepted July 8, 2009
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Abstract
Introduction
