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Review ArticleLysophosphatidic Acid (LPA) Signaling inHuman and Ruminant Reproductive Tract

Izabela WocBawek-Potocka1 Paulina RawiNska1

Ilona Kowalczyk-Zieba1 Dorota Boruszewska1 Emilia Sinderewicz1

Tomasz WaVniewski2 and Dariusz Jan Skarzynski1

1 Department of Reproductive Immunology and Pathology Institute of Animal Reproduction and Food ResearchPolish Academy of Sciences Tuwima 10 Street 10-747 Olsztyn Poland

2Department of Gynecology and Obstetrics Faculty of Medical Sciences University of Warmia and MasuriaZolnierska 14 C Street 10-561 Olsztyn Poland

Correspondence should be addressed to Izabela Wocławek-Potocka iwoclawek-potockapanolsztynpl

Received 14 October 2013 Accepted 24 January 2014 Published 12 March 2014

Academic Editor Graca Ferreira-Dias

Copyright copy 2014 Izabela Wocławek-Potocka et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Lysophosphatidic acid (LPA) through activating its G protein-coupled receptors (LPAR 1ndash6) exerts diverse cellular effects that inturn influence several physiological processes including reproductive function of the female Studies in various species of animalsand also in humans have identified important roles for the receptor-mediated LPA signaling in multiple aspects of human andanimal reproductive tract function These aspects range from ovarian and uterine function estrous cycle regulation early embryodevelopment embryo implantation decidualization to pregnancy maintenance and parturition LPA signaling can also havepathological consequences influencing aspects of endometriosis and reproductive tissue associated tumors The review describesrecent progress in LPA signaling research relevant to human and ruminant reproduction pointing at the cow as a relevant modelto study LPA influence on the human reproductive performance

1 Introduction

The present paper focuses particularly on one of the simplestand most potent lysophospholipids lysophosphatidic acid(LPA) and summarizes recent knowledge on its biologicalimpact on human and ruminant reproduction

2 Lysophosphatidic Acid Productionand Receptor-Mediated Signaling

Lysophosphatidic acid is a simple phospholipid that exertsmany physiological and pathological actions on variouscell types such as cell proliferation and differentiation [1]cytoskeletal rearrangement [2] cell-to-cell interactions [3]and tumorigenesis [4]

So far LPA has been detected in many various biologicalfluids such as serum and plasma [5ndash7] tears [8] ascites [9]

seminal plasma [10] and follicular fluid [11] Moreover it canalso be produced in various cell types like endometrial cells[12 13] ovarian cells [12 14ndash16] mast cells [17] erythrocytes[18] neurons [19] and many others [20]

While the precise mechanism of LPA metabolism withinmost types of cells is still unclear two general pathways ofLPA production have been demonstrated In the first pathwayphosphatidic acid (PA) is produced fromphospholipids (PLs)by phospholipase D (PLD) also called autotaxin (ATX) orfrom diacylglycerol by diacylglycerol kinase [21] In bothpathways there is deacylation of PA to LPA by phospholipase(PLA)-type enzymes In the second pathway PLs are firstconverted to lysophospholipids (LPLs) by the action ofsecretory (sPLA

2) PS-PLA

1 and lecithin-cholesterol acyl-

transferase (LCAT) and then the LPL is converted to LPAby ATX [22] The first pathway is mainly involved in cellularLPA production while the second pathway is involved in LPA

Hindawi Publishing CorporationMediators of InflammationVolume 2014 Article ID 649702 14 pageshttpdxdoiorg1011552014649702

2 Mediators of Inflammation

production in extracellular body fluids especially in serumand plasma These various ways of LPA synthesis reflectmultiple levels of regulationmdashor deregulation in the organ-ism being at different physiological or pathological statusmdashcancers [4] pregnancy [23] hypertension [24] prostatedisease or obesity [25] Moreover LPA-dependent differentsignaling pathways have clear therapeutic repercussions sincepharmaceutical drugs targeting certain enzymes would differfrom those targeting other LPA biosynthetic pathways [2627]

In mammals LPA exerts its action via at least six highaffinity transmembrane G-protein-coupled receptor (GPCR)types LPAR1ndashLPAR6 and possibly through a nuclear recep-tor PPAR120574 [22 28ndash31] These LPARs are expressed in variousorgans and cells [21] For example LPAR1 is highly expressedin the nervous system [32] LPAR2 in immune organs suchas the thymus and spleen [33] and LPAR3 in reproductiveorgans such as the ovary and uterus [7 16 34 35] On theother hand LPAR4 LPAR5 and LPAR6 are expressed widelybut at relatively low levels In that aspect we can find LPAR4expression in the ovary [30] LPAR5 expression in the smallintestine spleen dorsal root ganglion and embryonic stemcells [36]However there is alsomuch evidence of an aberrantexpression of LPA receptors in certain diseases meaningespecially different types of cancer [37 38]

The influence of LPA on the reproductive system functionof the female has been examined and described for about 30years Since the first reports published by Jarvis et al [39] inwomen various abnormalities in reproductive performanceon different regulatory levels due to LPA signaling and LPARsknockout have been also reported in many farm animalsincluding ruminants [34 35 40]

3 Effects of Lysophosphatidic Acid onthe Reproductive Performance in Human

31 The Possibility of LPA Synthesis and LPARs Expressionin the Reproductive Tissues Physiologically LPA and itsactive LPARs have been documented to be present in femalereproductive organs such as uterus [20 41 42] ovary [4344] and placenta [43 45 46] as well as in the amnion-derivedcells in vitro [47] Interestingly serum ATX level was higherin women than in men [48] suggesting possible influence ofLPA on the female reproduction

32 LPA Signaling in the Human Ovary LPA signaling hasbeen extensively studied in the physiology of human ovaryFollicular fluid of the human preovulatory follicle containslysophospholipase DmdashATX which is responsible for localLPA production from lysophosphatidylcholine (LPCs) [49]However LPA in ovaries is produced not only from follicularfluidrsquos LPCs but also from LPCs in granulosa cells andoocytes In follicular fluid taken from women programmedfor in vitro fertilization the amount of LPA increases with thetime of incubationwithATX in 37∘C [11] SerumATX activityfrom patients receiving ovarian stimulation was higher thanin women with natural cycles [44] Moreover Chen et al[44] demonstratedmRNA expression of three LPA receptors

LPAR1 LPAR2 and LPAR3 in the granulosa-lutein cells fromwomen undergoing in vitro fertilization LPAR4 was alsohighly expressed in the cortex of the human ovary [30]

LPA signaling plays many crucial roles in ovarian func-tion such as ovulation for example Before ovulation LPAelevated the level of IL-8 expressed its chemotactic activityfor neutrophils started the inflammatory reaction and inconsequence led to tissue degradation and rupture of thefollicle [50] During the luteal phase human ovary exhibitscomplete tissue remodeling with the stages of growth dif-ferentiation and regression [51] In the early luteal phasegranulosa and theca cells form corpus luteum with highlevel of angiogenesis LPA through the upregulation of IL-8 and IL-6 stimulated the multistep process of new vesselsformation in the CL [42] Moreover LPA induced expressionof angiogenic cytokines IL-6 and IL-8 in granulosa-luteincells fromwomen undergoing in vitro fertilization [42]Thusthe authors concluded that the induction of these cytokinesby LPA through its receptor and nuclear factor-kappaB-dependent pathway in the stimulated ovaries may contributeto ovarian hyperstimulation syndrome [42]

33 LPA Signaling during Pregnancy More than a decadeago Tokumura et al [49] suggested the involvement ofLPA signaling in maintenance of human pregnancy Theseauthors demonstrated increasing levels of LPA and serumATXlysoPLD activity during pregnancy [49] The elevatedlevels of serum LPA found during pregnancy were reportedto arise from both the placenta and the fetus [49] In thehuman placenta LPA can be produced locally by trophoblastsATX and thereby control trophoblast proliferation differ-entiation feto-maternal immune interaction and placentalvascular remodeling [46] During early pregnancy placentaproduces many new vessels which are crucial for fetal-maternal exchange LPA through induction of IL-8 couldstimulate the process of angiogenesis in the placenta [45]Kim et al [47] also found that LPA modulated cellularactivity and stimulated proliferation of human amnion cellsin vitroMoreover Jarvis et al [39] documented high lysoPLDactivity in human placental tissues with the highest in theamnion The authors suggested that high lysoPLD activityin the amnion proclaimed that LPA might be involved inthe regulation of labor due to the direct implications ofthis membrane in the initiation of the labor [39] More-over Jeng et al [52] demonstrated that LPA upregulatedtranscriptional activity of oxytocin (OT) receptors in vitrowhich resulted in sensitization of myometrial cells to OT Inuterus in the end of gestation the sensitivity of myometriumto OT increases robustly which in turn induces uterinecontractions leading to labor Other important process ininduction and maintenance of smooth muscle contraction isstress fiber formation LPA enhanced stress fiber formationin human myometrial cells in vitro and thereby increased theefficiency of uterine contractions in the beginning of labor[53]

The process of embryo implantation includes interactionbetween the endometrium and the embryo (adhesion andinvasion) inflow of innate immune cells and vascularization

Mediators of Inflammation 3

LPA has been presented to be involved in implantation onmany various levels In human decidual cells LPA increasedembryo outgrowth as the result of RhoA signaling [54] Italso stimulated chemotaxis of NK cells and monocytes byinducing the transcription of MCP-1 and GRO-120572 respec-tively and thereby contributed to regulation of the innateimmunity of the fetus [45] Iwasawa et al [46] documentedthat LPA activated lymphocytes and dendritic cells thatinduced inflammatory reaction which is essential in theprocess of implantation Moreover in an in vitro modelof embryo implantation LPA increased the outgrowth ofembryos on decidual cells [54] Through IL-8 stimulationLPA participated in new vessels formation around theembryo [45]

The pleiotropic roles of LPA in the function of thereproductive tract are demonstrated not only by the increasedamount of LPA in body fluids and in the area of reproductiveorgans but also by the tissue-specific regulated expression ofits receptors Wei et al [55] demonstrated that LPAR3 levelsdecreased in the middle and late secretory endometrium(when the implantation occurs) of women with endometrio-sis Decreased LPAR3 expression was correlated with theexpression of other uterine receptivity biomarkers such asosteopontin or HOXA10 all regulated by progesterone (P4)[55] The authors claimed that reduced expression of thesegenes may explain P4 resistance associated with endometrio-sis [55]

LPA signaling can also have adverse effects during preg-nancy Li et al [56] detected high levels of LPAR2 and LPAR3gene expression in the placentas of patients with gestationalhypertension and preeclampsia Moreover it has been doc-umented that LPA elevated arterial blood pressure [57] andvasoconstriction [58] Taking into consideration increasinglevels of LPA during pregnancy [49] and LPA involvementin elevating blood pressure we might suppose the adverseeffects of this lipid in the terminating stages of pregnancyIn addition accumulation of LPA in blood contributed toplatelet-monocyte coaggregate formation [59] as well asenhanced platelet aggregation and adhesion [60] which inturn might have resulted in thrombosis during pregnancyTokumura et al [61] also presented the direct association ofelevated levels of LPA in blood circulation with inductionandor progression of systemic vascular dysfunction seen inpatients with preterm labor or preeclampsia On the otherhand LPA might also contribute indirectly to infection-related preterm labor via the induction of arachidonic acid(AA) metabolites Mikamo et al [62] presented elevatedlevels of LPC the substrate for LPA and AA in humanuterine endometrial cells exposed to extracts from pathogensinvolved in intrauterine infection

34 LPA Signaling in the Reproductive Tissue AssociatedTumors and Other Disorders of Reproductive Functions LPAsignaling may also play a role in pathogenesis of both benignand malignant endometrial tumors Billon-Denis et al [63]presented LPA influence on the growth of leiomyomas orfibroids Treatment of leiomyoma tumor-derived cell linewith LPA entailed DNA synthesis through ERK activation

[63] The authors also proposed that LPA produced inleiomyomas in vivo may have been involved in tumor cellproliferation [63] There are also reports indicating that LPApromoted endometrial cancer invasion via the induction ofmatrix metalloproteinase-7 (MMP-7) [64 65] Rapizzi et al[66] used the cervical cancer cell line HeLa to study the rolesof LPA in cervical cancer In these studies LPA inducedHeLacell migration and survival [66]

LPA signaling may also play a role in breast cancerprogression Kitayama et al [67] suggested the involvementof the upregulation of LPAR2 but not LPAR1 or LPAR3 in themammary gland carcinoma pathogenesis in the breast cancerof postmenopausal women Other studies from breast cancercell lines indicated that both LPAR1 and LPAR2 mediatedLPA-induced chemotaxis in breast carcinoma cells [68] LPAsignaling was also involved in breast cancer cell proliferation[69] Boerner et al [70] demonstrated that LPA-dependentoverexpression of EGF receptor (a prognostic indicator ofa poor outcome in tumors) was involved in breast cancerprogression [70]

Ovarian cancer is the most thoroughly studied cancerwith respect to LPA signaling in carcinogenesis There aretwo types of data in the literature demonstrating the directand indirect roles of LPA in the pathogenesis of the tumorsSutphen et al [71] and Xu et al [72] demonstrated thatelevated levels of LPA in the plasma and ascites of ovariancancer patients promoted ovarian cancer cell proliferationLPA signaling may also exert its role in ovarian cancersindirectly through regulating telomerase involved in tumorprogress [73] IL-6 and IL-8 involved in tumor angiogenesis[74] or COX-2 correlated with possibility of metastasis [75]

Moreover the regulation of LPARs may also play asignificant role in LPA signaling in ovarian cancer Wanget al [76] proved that LPAR2 and LPAR3 were upregulatedin ovarian cancer tissues Sengupta et al [77] demonstratedthat LPAR3 was a key receptor for mediating the chemotacticactivity of LPA in ovarian tumors On the other hand LPAR1was demonstrated to be the key receptor in mediating asciticLPA effects on other cells [78]

Overlooking the available data in the literature on therole of LPA in human reproduction we can summarizethat the past decade shaded new light on the importanceof LPA signaling not only under physiological but alsopathological conditions LPA is produced locally inhuman reproductive tissues and controls ovarian cycleand pregnancy as well as various abnormalities in the femalereproductive tract Engagement of LPA in the maintenanceof pregnancy manifests by its action on the uterus ovaryfetal membranes and placenta LPA can also affect thefetus itself by controlling the process of implantation andvascularization of the embryo However there are alsoreports on adverse effects of LPA in the female reproductionespecially during tumorigenesis Since in the availableliterature there are often registered opposite effects of LPAon the reproductive performance in human as well asthe research on human tissues is ethically restricted andnew LPA-targeted therapeutic strategies are demanded itis important to find a good animal model to study LPAinfluence on the function of the female reproductive organs


4 Relevance of a Cow Model toHuman Reproductive Performance

Properly designed studies to examine the effects of LPAon the reproductive performance in humans should bedone in human subjects However this is very hard toaccomplish since human studies are difficult to carry outbecause of their typical complexity and dependence onmostly retrospective data rather than the treatment-basedoutcomes measured in animal models including the bovineone Moreover all the complications in the design andinterpretation of human studies combined with the ethicalissues regarding experimentation in humans continuouslyincrease interest in studies that utilize animal models Onthe other hand the relevance of studies performed in animalmodels to human health has been questioned many times inthe literature since in almost all animals used as a modelmany weak points can be found Taking above argumentsinto consideration it has been well documented in theliterature that the cow can be one of the quite relevantanimal models for studying human reproduction In thebovine reproduction we can find many similar aspects in theovarian physiology early embryo development pregnancyas well as assisted reproductive techniques [79 80] There-fore we believe that the cow model has broad applicabil-ity and may be used to extend investigations to differentphysiologicpathologic states and to other species includinghumans Moreover the bovine model ensures a greateravailability of biological material compared to studies inhuman

5 Effects of Lysophosphatidic Acid on theReproductive Performance in Ruminants

51 The Possibility of LPA Synthesis and LPARs Expression inthe Reproductive Tissues In the bovine ovary Boruszewskaet al [81] demonstrated ATX and PLA2 expression in bovinegranulosa cells which documented the possibility of LPAsynthesis in bovine follicles with ATX playing the major rolein this process (Figure 1) LPA was also detected in picomoleconcentrations in the bovine CL throughout the estrous cycleand early pregnancy [16]The concentration of LPA in the CLincreased from days 2ndash4 to days 17ndash19 of the estrous cycle andduring the estrous cycle was significantly higher than duringearly pregnancy [16] The detected presence of LPA as well asenzymes responsible for LPA synthesis and specific LPARs inthe CL tissue and the follicle indicate that bovine ovary canbe a site of LPA synthesis during the estrous cycle and earlypregnancy [7 16 81]

In ruminant uterus the influence of LPA on the endome-trial function was studied for the first time by Liszewska etal [34] in sheep This study revealed the involvement of LPAsignaling in early embryo development The authors foundincreased levels of LPA in ovine uterus at the time of earlypregnancy suggesting that LPA signaling contributed to thecross-talk between mother and embryo at the beginning ofgestation [34]

In the cow we were the first to demonstrate that LPAis locally produced and released from bovine endometriumduring estrous cycle and early pregnancy [7] We foundsignificantly higher concentration of LPA in the blood takenfrom uterine vein on days 17ndash19 of the estrous cycle thanin the blood from jugular vein Moreover we found highconcentrations of LPA in the endometrial tissue [7] LPAconcentration in the bovine endometrium did not differeither during estrous cycle or early pregnancy (before implan-tation) however it was significantly higher on days 17ndash19 ofpregnancy than on days 17ndash19 of the estrous cycle

Studying intracellular localization of the enzymes respon-sible for endometrial LPA synthesis we demonstrated thatATX and PLA

2were immunoexpressed both in epithelial

and stromal cells [82 Figure 1] Boruszewska et al [82] alsofound that LPA concentration was significantly higher inepithelial than instromal cells and ATX and PLA

2expression

was higher in epithelial than instromal cells in bovineendometrium This study demonstrated that epithelial cellsare the main source of LPA in the bovine endometrium[82] Similarly in sheep Liszewska et al [34] found api-cal localization of ATX in glandular and luminal cells ofendometrium The authors also found that ATX activity wasorientated towards the uterine lumen Liszewska et al [34]also documented that ATX level was 4- to 5-fold higher inthe ovine uterus than in the trophectoderm The authorspostulated that LPA detected in the ovine uterus may bedue to ATX activity on the maternal side [34] Howeverin ovine conceptuses elevating expression of ATX was alsodemonstrated which documented that the trophectodermmay also contribute to the production of LPA during preg-nancy [34] The data obtained in cows and sheep stronglysuggest thatepithelial cells of the bovine endometrium are themain source of LPA inthese species However a supportingrole of stromal cells in LPA synthesis cannot be excluded

The potential role of LPA depends on both its localconcentration and the distribution of LPARs in the area ofreproductive tissues In the bovine follicle Boruszewska etal [81] detected all types of LPARs at mRNA level in gran-ulosa cells (Figure 1) However LPAR1 transcript abundancewas approximately 16- to 23-fold higher than expression ofLPAR2 LPAR3 and LPAR4 mRNA [81] In the bovine CLfour types of LPARs were detected both during the estrouscycle and early pregnancy [16] However of the four LPARsexamined LPAR2 and LPAR4 were expressed the moststrongly in the bovine CL [16 Figure 1] In the bovine CLhigh expression of LPAR4 compared with the other receptorsduring the estrous cycle and early pregnancy as well as thedynamic changes of LPAR2 and LPAR4 during early preg-nancy probably accounts for the contribution of LPA to dif-ferent events during the estrous cycle and pregnancy namelythe contribution to P4 secretion modulation of interferon(IFN)120591 action during early pregnancy [16] or modulation ofluteolysing cytokines action in the CL at the late luteal stage[83] The data obtained by Kowalczyk-Zieba et al [16] in thebovine CL do not completely agree with the results of Budnikand Brunswig-Spickenheier [84] who showed that LPAexerted its actions on bovine luteal cells only via LPAR2 ThemRNAexpression of all LPARs in granulosa cells aswell luteal


ATX

LPA

LPA

LPA

LPA

LPA

LPA

LPALPA

LPA

Ca2+

PGFS

PGES

PGF2120572

PGE2

LPAR1

UterusOvary

PLA2

PLA2ATXFollicle

FSH

FSHRLPALPAR1

LPAR2LPAR3

LPAR4

LPAR1 LPAR2LPAR3 LPAR4

CYP19A117120573HSD AndrogenE2

IFN120574

Bax

ApoptosisFasFasL

Casp3

TNFR1

IFN120591OAS1ISG15

CLSteroidogenic CL cells

CholesterolStar

P450sccPregnenolone

3120573HSD

P4

LPAATX PLA2

TNF120572

Figure 1 Schematic model illustrating the possible lysophosphatidic acid signaling in the bovine reproductive tract (LPAmdashlysophosphatidicacid LPARmdashlysophosphatidic acid receptor PGFSmdashprostaglandin F

2120572synthase PGESmdashprostaglandin E

2synthase ATXmdashautotaxin

PLA2mdashphospholipase A

2 FSHmdashfollicle stimulating hormone FSHRmdashfollicle stimulating hormone receptor E

2mdashestradiol CYP19A1mdash

cytochrome P450 aromatase 17120573HSDmdash17120573-hydroxysteroid dehydrogenase TNF120572mdashtumor necrosis factor 120572 TNFR1mdashtumor necrosis factor120572 receptor type 1 IFN120574mdashinterferon 120574 IFN120591mdashinterferon 120591 Casp3mdashcaspase 3 FasFasLmdashFas antigenFas ligand OAS1mdash251015840-oligoadenylatesynthase ISG15mdashubiquitin-like IFN-stimulated gene 15 kDa protein StARmdashStAR protein P450 sccmdashcytochrome P450 3120573HSDmdash3120573-hydroxysteroid dehydrogenase PGF

2120572mdashprostaglandin F

2120572 PGE

2mdashprostaglandin E

2 and P4mdashprogesterone) LPA derived from the blood

plasma and produced in the uterus and ovary induces auto- and paracrine actions on the bovine endometrium corpus luteum (CL) and thefollicle In the bovine endometrium LPA acting via LPAR1 induces PGE

2and inhibits PGF

2120572actions In the ovarian follicle LPA stimulates

E2production and FSH action in granulosa cells via increased expression of the FSHR and 17120573-HSD In the bovine CL LPA stimulates P4

secretion through stimulation of 3120573HSD LPA augments IFN120591-dependent stimulation of ISG15 and OAS1 expression in the steroidogeniccells of the bovine CL LPA suppresses TNF120572 and IFN120574 induced luteal cell apoptosis via inhibition of the stimulatory effect of the cytokineson the expression of Bax FasmdashFasL system TNFR1 and Casp3 activity in the cultured steroidogenic luteal cells which orientates the cellstowards the survival state

cells indicates that the bovine follicle and the CL represents atarget for LPA action in the bovine reproductive system

In sheep Liszewska et al [85] demonstrated that theexpression of LPAR1 and LPAR3 in the ovine endometriumwas regulated according to the estrous cycle On the otherhand at day 12 of pregnancy expression of both LPAR1and LPAR3 in the endometrium was significantly reduced incomparison with day 12 of the estrous cycle [85] The authorssupposed that the decrease of LPARs expression in theendometriumwas the result of the beginning of rapid growthand elongation of the ovine embryo as well as modulationby various factors from conceptus origin [85] Howeverin the ovine trophectoderm during the peri-implantationperiod LPAR1 and LPAR3 expression was the most abundantat the time of embryo implantation [34]Moreover Liszewska

et al [34] demonstrated perinuclearnuclear and membranelocalizations of LPAR1 in ovine conceptuses and trophec-toderm cells cultivated in vitro whereas LPAR3 was foundonly in the cell membrane in both systems In the ovineuterus LPAR1 was predominantly present in the stromaltissue whereas LPAR3 was mostly detected in the epithelialstructures [85] In the bovine endometrial tissue only LPAR1expression was detected [7] LPAR1 expression increasedfrom early to late luteal stage of the estrous cycle and reachedthe highest level at late luteal stage and on days 17ndash19 ofearly pregnancy [7] On the other hand LPA1 expression ondays 8ndash10 of pregnancy was lower than that on days 17ndash19 ofpregnancy but higher than on days 8ndash10 of the estrous cycle[7] Boruszewska et al [82] found higher LPAR1 expression instromal than in epithelial cellsThese results are in agreement


with the fact that LPA on days 8ndash10 and 16ndash18 of the estrouscycle and early pregnancy stimulated prostaglandin (PG) E

2

synthesis only in the in vitro cultured stromal cells [13 40]Theoverall results suggest that LPA in bovine endometrium isproducedmainly by epithelial cells and affectsmostly stromalcells acting via LPAR1

Studying receptor and intracellular mechanism of LPAaction in the ovine trophectoderm cells Liszewska et al [34]found that LPA stimulated the phosphorylation of ERK12in vitro and a specific antagonist of LPAR1 and LPAR3receptors (VPC32183) blocked this effect This study directlyevidenced that LPARs operate and are functionally coupledto signal transduction mechanisms in trophectoderm cells[34] In other cell types the activation of ERK12 accountsfor the proliferative effect of LPA [86] Therefore Liszewskaet al [34] claim that LPA amongst other factors in theuterus may be involved in the elongation of the conceptusduring the peri-implantation period in the sheep as well asin mediating the cellular differentiation required for ovineembryo implantation Liszewska et al [34 85] also reportedthat LPA stimulated changes in the organization of actinand tubulin architecture in ovine trophectoderm cells as wellas in uterine epithelial cells in vitro Therefore the authorssuggested that LPA may be involved in the mechanismsregulating morphological changes both in the embryo andthe uterus during conceptus adhesion to the uterus inewes during the implantation process Liszewska et al [3485]

The studies concerning receptor and intracellular mecha-nisms of LPA action in the bovine endometrial cells revealedthat LPA stimulated PGE

2production cell viability and

intracellular calcium ionmobilization in the cultured stromalendometrial cells via LPAR1 receptor activation [87]

In ruminants the dynamic LPA synthesis and LPARsexpression and action in the follicle CL and uterus suggestthat LPA plays autocrine andor paracrine roles in thereproductive tract acting via various active LPARs

52 LPA Influence on Estradiol (1198642) Production and Follicle

Stimulating Hormone (FSH) Action in Granulosa Cells of theBovine Ovarian Follicle In bovine follicles Boruszewska etal [81] were the first to demonstrate the influence of LPA onE2synthesis and secretion in the granulosa cells (Figure 1)

The authors documented that LPA and LPA together withFSH stimulated E

2production by cultured granulosa cells

in vitro [81 Figure 1] Since E2promotes follicular develop-

ment by regulating steroid production and the expression ofgonadotrophin receptors in the bovine granulosa cells [88ndash90] Boruszewska et al [81] presumed that LPA participatedin ovarian follicle growth and differentiation It has beenwell documented that E

2secretion is stimulated by FSH [91

92] which acts by binding to specific transmembrane FSHreceptor (FSHR) [88 89] Boruszewska et al [81] documentedthat LPA and LPA together with FSH stimulated FSHR geneexpression in bovine granulosa cells

Boruszewska et al [81] also investigated the effect ofLPA on the E

2synthesis pathway Granulosa cells are able

to convert thecal androgens to E2by cytochrome P450 aro-

matase (CYP19A1) and 17120573-hydroxysteroid dehydrogenase-(17120573-HSD-) catalyzed reactions [88 90 92 93] In the studyof Boruszewska et al [81] LPA did not influence CYP19A1transcript level while treatment with LPA FSH and LPAtogether with FSH resulted in increased 17120573-HSD mRNAexpression in granulosa cells (Figure 1)

Concluding LPA stimulates E2production and FSH

action in granulosa cells of the bovine ovarian follicle viaincreased expression of the FSHR and 17120573-HSD genes whichin turn might account for the participation of LPA in ovarianfollicle growth and differentiation

53 The Action of LPA on Bovine CL during the Luteal Phaseof Estrous Cycle and Early Pregnancy In ruminants in vivoaction of LPA was only examined in the cow [7 40] Inthese studies it was demonstrated that LPA administeredinto aorta abdominalis affected P4 and PG secretion duringthe luteal phase of the estrous cycle The dose of 1120583g LPAadministered into the aorta abdominalis stimulated P4 andPGE2concentration in the blood [7]Woclawek-Potocka et al

[7] also showed that the inhibition of endogenous LPA actionvia the infusion of LPA1 receptor antagonist (Ki16425) causedthe decrease of P4 and PGE

2concentrations which suggested

LPA influence on both endometrium and the CL MoreoverWoclawek-Potocka et al [40] found that in the heifers infuseddeeply into the vagina near the cervix of the uterus with 1mgLPA spontaneous luteolysis was prevented and the func-tional lifespan of the CL was prolonged in comparison withanimals of the control group (Figure 2)The possibility of LPAaction on P4 synthesis in the steroidogenic cells of the bovineCL was confirmed in the in vitro studies of Kowalczyk-Ziebaet al [16]The authors found that LPA stimulated P4 secretionvia stimulation of 3120573-hydroxysteroid dehydrogenase5Δ-4Δisomerase (3120573HSD) expression in steroidogenic CL cells [16]

We also found that LPA did not express only directluteotropic action [16] but also indirect luteoprotective roleinhibiting cytokine mediated regression of the bovine CL[83]We examined the possibility of LPA-dependentmodula-tion of tumor necrosis factor (TNF)120572 and IFN120574 actions at thelate luteal stagemdashwhen the luteolysing cytokines act themostIt has been documented before that TNF120572 togetherwith IFN120574can serve as mediators of luteolytic actions of PGF

2120572via

inhibiting P4 production and stimulating apoptosis of thecultured bovine luteal cells [94ndash96] Physiologically in theorganism not only activated macrophages and lymphocytesproduce TNF120572 and IFN120574 but also fibroblasts and endothelialcells [97 98] Penny et al [97] and Sakumoto et al [99]demonstrated that total amount of TNF120572 and IFN120574 risesignificantly just after initiation of luteolysis as the reasonof a great amount of lymphocytes infiltrating the CL atthis time Moreover Skarzynski et al [100] demonstratedbefore that TNF120572 in low concentrations caused luteolysis(decreased P4 level) which could be augmented by variousfactors including IFN120574 Concerning the possibility of LPA-dependent modulation of TNF120572 and IFN120574 actions at the lateluteal stage Woclawek-Potocka et al [83] demonstrated thatLPA reversed the inhibitory effect of TNF120572 and IFN120574 on P4


0 3 6 9 12 15 18 21 24 270

10

20

30

40

Saline

Treatment

Days of the estrus cycle

Prog

este

rone

(ng

mL)

LPA (1mg)VPC 32183 (1mg)

Figure 2 Concentrations of progesterone in peripheral bloodplasma of heifers infused with saline (grey bars) LPA (1mg line) orLPA (1mg) together with blocker of LPARs (VPC32183 1mg dottedline) on day 15 of the estrous cycle (Adapted from [40])

synthesis in the cultured bovine steroidogenic cells Thesedata are consistent with previous data obtained in vivo thatLPA administered into aorta abdominalis or intravaginallyincreased P4 secretion in the cows during the luteal phase ofthe estrous cycle [7 40 Figure 2] In heifers LPA-dependentprevention of the spontaneous luteolysis and prolongation ofthe functional lifespan of the CL in vivo were also reportedbefore [40] These results seem to be important becausethe midluteal stage represents a critical period in the CLlifespan for P4 secretion [101] Woclawek-Potocka et al [83]hypothesized that at the midluteal stage of estrous cycle ifthe female becomes pregnant that continued secretion of P4from the CL can be directly supported by LPA or indirectlyby reversing luteolyting action of TNF120572 and IFN120574

Woclawek-Potocka et al [83] also documented that LPAsuppressed TNF120572- and IFN120574-induced luteal cell apoptosis(Figure 1) which is known to occur during structural lute-olysis [102 103] In the bovine CL it was demonstrated thatLPA inhibited the stimulatory effect of TNF120572 and IFN120574on the expression of one of the mitochondrial regulatoryproteins Bax which in turn orientates the cells towards thesurvival state [83] In addition apoptosis on the receptorlevel can also be initiated via TNF super family receptors(TNFRs) Sakumoto et al [99] and Taniguchi et al [96]demonstrated that TNF120572 induced apoptotic cell death ofcultured bovine luteal cells mainly acting via TNFR1 whereasTNFR2 is the type of the receptor associated mainly withthe prosurvival action of this cytokine in the organism [104]In the study of Woclawek-Potocka et al [83] LPA inhibitedonly the stimulatory effect of TNF120572 and IFN120574 on TNFR1expression in the cultured steroidogenic luteal cells on days8ndash12 of the estrous cycle The Fas antigen (Fas) also belongsto the TNF super family receptors which together with Fasligand (FasL) transmit basic signals controlling intercellularapoptosis pathway [105] Woclawek-Potocka et al [83] foundthat in the presence of LPA TNF120572 and IFN120574 did not stimulateFas and FasL expression in the cultured steroidogenic lutealcells on days 8ndash12 of the estrous cycle Moreover it has beendocumented before that the inhibition of intraluteal P4 actionby various specific antagonists amplified Fas L-mediated

apoptosis viathe increase of Fas and initiation of caspase(Casp)8 and Casp3 expressions as well as Casp3 activity incultured bovine luteal cells [106]High levels ofCasp8 directlyinitiate cleavage of an effector Casp3 thereby initiatingthe execution phase of apoptosis [107] During apoptosisexecuted through the mitochondrial pathway active Casp8stimulates the binding of proapoptotic Casp to mitochondriaand inhibits association of antiapoptotic Bcl-2 This leads tothe leakage of cytochrome c from the mitochondria into thecytosol which in turn promotes formation of the apoptosomeand triggers activation of the effector Casp3 [107] In thebovine CL LPA decreased cleaved Casp3 activity inducedby TNF120572 and IFN120574 [83] However in the bovine CL theonset of apoptosis is not observed until P4 production hasdeclined [108 109] In this aspect Woclawek-Potocka etal [83] surmised that in the bovine CL in the presenceof LPA P4 secretion was supported and also TNF120572 andIFN120574 could not induce apoptosis (Figure 1) Moreover LPAreversed TNF120572- and IFN120574-induced apoptosis via inhibitionof the stimulatory effect of the cytokines on the expressionof Bax Fas-FasL system TNFR1 and Casp3 activity in thecultured steroidogenic luteal cells which orientated thesecells towards the survival state [83]

The influence of LPA on early pregnancy in the cow wasalso examined [40] Woclawek-Potocka et al [40] demon-strated that LPA had strong effect on P4 and PGE

2secretion

on days 15ndash18 of early pregnancy (Figure 3) Moreover theauthors proved that blocking the effect of endogenous LPAby administration of VPC32183 significantly decreased preg-nancy rate compared with control and LPA-treated heifers[40 Figure 3] LPA-induced PGE

2secretion in vivo may

indirectly support CL function [110 111] and have roles inestablishing and maintaining pregnancy [112 113] Thus theauthors suggested that LPA could be a luteoprotective factorin the bovine endometrium during both the estrous cycleand early pregnancy establishment in the cow [40] The dataobtained in the above studies seem to be important becausethe examined time frame (days 15ndash18) represent a criticalperiod in the establishment of pregnancy This is the timeof the highest IFN120591 production by the conceptus just beforeimplantation therefore the interactions between LPA andIFN120591 cannot be excluded

The interactions between LPA and IFN120591 were studiedin vitro by Kowalczyk-Zieba et al [16] in bovine CL Theauthors investigated whether LPA had a direct effect on P4secretion from bovine luteal cells and whether it modulatedIFN120591 action in the luteal cells in vitro [16] Kowalczyk-Zieba et al [16] found that LPA stimulated P4 secretionfrom steroidogenic CL cells of the midluteal phase throughstimulation of 3120573HSD expression in these cells (Figure 1)These results are important because the midluteal stagerepresents a critical period in the CL lifespan for secretionof P4 [114] Kowalczyk-Zieba et al [16] hypothesized that atthe examined time of estrous cycle if the female becomespregnant continued secretion of P4 from the CL can be alsosupported by LPA However Kowalczyk-Zieba et al [16] didnot find any modulation of IFN120591 action on P4 secretionin the luteal cells of the bovine CL On the other handKowalczyk-Zieba et al [16] proved that LPA augmented IFN


0

10

20

30

Pregnant heifersNonpregnant heifers

75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast

0 3 6 9 12 15 18 21Days after artificial insemination

x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183

Days after artificial insemination

Prog

este

rone

(ng

mL)

z

(c)

Figure 3 Concentrations of progesterone in peripheral blood plasma of pregnant (black dots) and nonpregnant (white squares) heifersinfused with saline (a) 1mg of LPA (b) or 1mg of VPC32183 (c) All reagents were infused every 24 hours from day 15 to day 18 afterinsemination into the vagina Different letters in the top right corner indicate significant differences (119875 lt 005) between treated groups (119899 = 8for each group of heifers) (Adapted from [40])

120591-dependent stimulation of ubiquitin-like IFN-stimulatedgene 15 kDa protein (ISG15) and 251015840-oligoadenylate synthase(OAS1) expression in the steroidogenic cells of the bovine CL(Figure 1) These two genes are expressed in the bovine CL ofboth cyclic and pregnant cows regardless of pregnancy statusbut are upregulated only during early pregnancy [115 116]

The data obtained in cows prove that LPA can be anadditional auxiliary luteotropic factor acting in the CL andin the endometrium during both the estrous cycle and earlypregnancy establishment

54 The Influence of LPA on PG Synthesis in the BovineEndometrium In ruminants uterine PGs are crucial compo-nents in the regulation of estrous cycle and early pregnancyProstaglandin F

2120572is the major luteolytic agent whereas

PGE2has luteoprotective and antiluteolytic properties [111

117] Therefore achieving an optimal PGF2120572

to PGE2ratio

is essential for endometrial receptivity maintenance of CLaction and P4 secretion as well as accurate pregnancy

establishment [118] The dynamic PG synthesis and actionin the bovine endometrium [111 117 118] and possibleinteractions between LPA and PGs as well as mechanisms ofLPA synthesis [119 120] were well evidenced in the literatureWoclawek-Potocka et al [7] tested the hypothesis whetherLPA signaling affected endometrial AA metabolism not onlyin rodents [120ndash122] and human [123] but also in cattle In thebovine endometrium positive correlation between LPAR1and PGES expression at early pregnancy was demonstrated[7] Moreover LPAR1 expression was negatively correlatedwith the expression of PGFS during early pregnancy [7] Theauthors claimed that these correlations explained that PGE

2

and LPA act similarly and that PGF2120572

and LPA act differentlyduring early pregnancy in cow [7]

There are also data in the literature on the intracellularand enzymatic mechanisms of LPA- dependent stimulationof PG synthesis in the bovine endometrium [7 40 Figure1] In the bovine uterus LPA stimulated PGE

2synthesis via

PGES mRNA stimulation only in stromal cells on days 8ndash10 and 16ndash18 of the estrous cycle and pregnancy [13 40]


Moreover LPA inhibited PGF2120572

synthesis via PGFS mRNAstimulation only in epithelial cells on days 8ndash10 and 16ndash18of pregnancy [13 40] Thus Woclawek-Potocka et al [13]suggested that LPA is an additional luteoprotective factor inthe bovine endometrium during both the estrous cycle andearly pregnancy Since PGE

2stimulates CL function [110 111]

and has roles in establishing andmaintaining pregnancy [112124] LPA via stimulation of its synthesis may be an impor-tant factor contributing to the establishment of pregnancy inthe bovine endometrium Woclawek-Potocka et al [13] alsosuggested that this effect might be additionally augmentedby LPA-dependent inhibition of PGF

2120572synthesis during early

pregnancyThe above data seem to be important because theexamined time frames are crucial phases during early preg-nancy First days 8ndash10 represent the time of immunologicalpregnancy establishment as shown by Kelemen et al [125]Barnea et al [126] and Majewska et al [127] Moreover days8ndash10 after conception have recently been considered to becrucial in terms of early embryonic loss In cattle the majorpercentage of embryo loss occurs before day 16 followingbreeding with some evidence pointing to greater lossesbefore day 8 in high-producing dairy cows [128] On theother hand second examined time framemdashdays 16ndash18 of earlypregnancy represent the time of the highest IFN120591 productionby the conceptus just before implantation Therefore theinteractions between LPA and IFN120591 at these phases cannotbe excluded

The data obtained in cows is consistent to a certain extentwith data obtained in ovine trophectoderm cultured cells inwhich LPA induced PGF

2120572and PGE

2release [34] However

the authors of this study excluded the possibility of the effectof LPA on PG release via changes in the mRNA expressionof PGES and PGFS Liszewska et al [34] claimed that in thecase of trophectoderm cells the phosphorylation of PLA2 byextracellular signal regulated kinase (ERK) is a critical stepin the sequence of events leading to mobilization of AA aswas demonstrated previously by An et al [129] in Jurkat Tcells in humans Liszewska et al [34] hypothesized that introphectoderm cells LPA-mediated phosphorylation of ERKmay have caused rapid activation of PLA

2that resulted in a

burst of PG synthesis independent of any modifications ingene expression However there are also reports in humanand rats that LPA increased PGE

2synthesis in humanmono-

cytic and ovarian cancer cells [130 131] aswell as ratmesangialcells [132 133] via upregulation of PTGS2Moreover in micetargeted deletion of LPAR3 receptor resulted in implantationdefects accompanied by a reduction in PTGS2 expression andthe levels of PGE

2and PGI

2[120]

Despite different intracellular mechanisms of LPA-induced PG synthesis in the cow and ewe a new biologicalfunction for LPA interaction with PGs in the contribution ofpregnancy establishment in cows and in the regulation of theimplantation process and embryonic development in eweswas designated in ruminants

6 Conclusion and Future Perspectives

There is overwhelming evidence in many studies using aruminant model that LPA signaling can have significant

consequences for reproductive health The effects of LPAdepend on many various conditions such as the target tissueand physiological status of the animal as well as the phase ofthe estrous cycle or pregnancy However the most importantissue connected with LPA signaling is the fact that thereis the possibility of LPA synthesis directly in the area ofthe reproductive tissues Therefore it is crucial to examinecarefully the effects of this biologically active compound onreproductive outcomes using animal models that can themost closely mimic reproductive processes in human

In spite of many limitations in conducting well-designedhuman studies information gathered from already publishedones combined with the large number of the studies alreadyavailable in ruminants clearly demonstrate that LPA has theability to influence the reproductive performance of an adultfemale

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by Grants-in-Aid for Sci-entific Research from the Polish National Science Cen-tre (201205ENZ903480) Dorota Boruszewska and IlonaKowalczyk-Zieba were supported by the European Unionwithin the European Social Fund (DrINNO3)

References

[1] T B Pustilnik V Estrella J R Wiener et al ldquoLysophosphatidicacid induces urokinase secretion by ovarian cancer cellsrdquoClinical Cancer Research vol 5 no 11 pp 3704ndash3710 1999

[2] W H Moolenaar ldquoLysophosphatidic acid a multifunctionalphospholipid messengerrdquo The Journal of Biological Chemistryvol 270 no 22 pp 12949ndash12952 1995

[3] N Fukushima J A Weiner J J A Contos et al ldquoLysophos-phatidic acid influences the morphology andmotility of youngpostmitotic cortical neuronsrdquo Molecular and Cellular Neuro-science vol 20 no 2 pp 271ndash282 2002

[4] K-S Kim S Sengupta M Berk et al ldquoHypoxia enhanceslysophosphatidic acid responsiveness in ovarian cancer cellsand lysophosphatidic acid induces ovarian tumor metastasis invivordquo Cancer Research vol 66 no 16 pp 7983ndash7990 2006

[5] J Aoki A Taira Y Takanezawa et al ldquoSerum lysophosphatidicacid is produced through diverse phospholipase pathwaysrdquoTheJournal of Biological Chemistry vol 277 no 50 pp 48737ndash48744 2002

[6] T Sano D Baker T Virag et al ldquoMultiple mechanismslinked to platelet activation result in lysophosphatidic acid andsphingosine 1-phosphate generation in bloodrdquo The Journal ofBiological Chemistry vol 277 no 24 pp 21197ndash21206 2002

[7] I Woclawek-Potocka J Komiyama J S Saulnier-Blache et alldquoLysophosphatic acid modulates prostaglandin secretion in thebovine uterusrdquo Reproduction vol 137 no 1 pp 95ndash105 2009

[8] K Liliom Z Guan J-L Tseng D M Desiderio G TigyiandM AWatsky ldquoGrowth factor-like phospholipids generated


after corneal injuryrdquo American Journal of PhysiologymdashCellPhysiology vol 274 no 4 pp C1065ndashC1074 1998

[9] A Tokumura T Kume K Fukuzawa et al ldquoPeritoneal fluidsfrom patients with certain gynecologic tumor contain elevatedlevels of bioactive lysophospholipase D activityrdquo Life Sciencesvol 80 no 18 pp 1641ndash1649 2007

[10] KHama K Bandoh Y Kakehi J Aoki andHArai ldquoLysophos-phatidic acid (LPA) receptors are activated differentially bybiological fluids possible role of LPA-binding proteins inactivation of LPA receptorsrdquo FEBS Letters vol 523 no 1ndash3 pp187ndash192 2002

[11] A Tokumura M Miyake Y Nishioka S Yamano T Aonoand K Fukuzawa ldquoProduction of lysophosphatidic acids bylysophospholipase D in human follicular fluids of in vitrofertilization patientsrdquo Biology of Reproduction vol 61 no 1 pp195ndash199 1999

[12] Z Shen J Belinson R EMorton Y Xu and Y Xu ldquoPhorbol 12-myristate 13-acetate stimulates lysophosphatidic acid secretionfrom ovarian and cervical cancer cells but not from breast orleukemia cellsrdquo Gynecologic Oncology vol 71 no 3 pp 364ndash368 1998

[13] I Woclawek-Potocka E Brzezicka and D J SkarzynskildquoLysophosphatic acid modulates prostaglandin secretion in thebovine endometrial cells differently on days 8ndash10 of the estrouscycle and early pregnancyrdquo The Journal of Reproduction andDevelopment vol 55 no 4 pp 393ndash399 2009

[14] A M Eder T Sasagawa M Mao J Aoki and G B MillsldquoConstitutive and lysophosphatidic acid (LPA)-induced LPAproduction role of phospholipase D and phospholipase A

2rdquo

Clinical Cancer Research vol 6 no 6 pp 2482ndash2491 2000[15] C Luquain A Singh L Wang V Natarajan and A J Morris

ldquoRole of phospholipase D in agonist-stimulated lysophospha-tidic acid synthesis by ovarian cancer cellsrdquo Journal of LipidResearch vol 44 no 10 pp 1963ndash1975 2003

[16] I Kowalczyk-Zieba D Boruszewska J S Saulnier-Blache et alldquoLysophosphatidic acid action in the bovine corpus luteummdashan in vitro studyrdquoThe Journal of Reproduction and Developmentvol 58 no 6 pp 661ndash671 2012

[17] K Mori J Kitayama J Aoki et al ldquoSubmucosal connectivetissue-type mast cells contribute to the production of lysophos-phatidic acid (LPA) in the gastrointestinal tract through thesecretion of autotaxin (ATX)lysophospholipase D (lysoPLD)rdquoVirchows Archiv vol 451 no 1 pp 47ndash56 2007

[18] O Fourcade M-F Simon C Viode et al ldquoSecretory phospho-lipase A

2generates the novel lipid mediator lysophosphatidic

acid inmembranemicrovesicles shed from activated cellsrdquoCellvol 80 no 6 pp 919ndash927 1995

[19] N Fukushima J A Weiner and J Chun ldquoLysophosphatidicacid (LPA) is a novel extracellular regular of cortical neuroblastmorphologyrdquo Developmental Biology vol 228 no 1 pp 6ndash182000

[20] X Ye and J Chun ldquoLysophosphatidic acid (LPA) signal-ing in vertebrate reproductionrdquo Trends in Endocrinology ampMetabolism vol 21 no 1 pp 17ndash24 2010

[21] S Okudaira H Yukiura and J Aoki ldquoBiological roles oflysophosphatidic acid signaling through its production byautotaxinrdquo Biochimie vol 92 no 6 pp 698ndash706 2010

[22] J Aoki A Inoue and S Okudaira ldquoTwo pathways for lysophos-phatidic acid productionrdquo Biochimica et Biophysica Acta vol1781 no 9 pp 513ndash518 2008

[23] H Seo Y Choi J Shim M Kim and H Ka ldquoAnalysis of thelysophosphatidic acid-generating enzyme ENPP2 in the uterus

during pregnancy in pigsrdquo Biology of Reproduction vol 87 no4 article 77 2012

[24] M-Z Cui ldquoLysophosphatidic acid effects on atherosclerosisand thrombosisrdquo Clinical Lipidology vol 6 no 4 pp 413ndash4262011

[25] P Kulkarni and R H Getzenberg ldquoHigh-fat diet obesity andprostate disease the ATX-LPA axisrdquo Nature Clinical PracticeUrology vol 6 no 3 pp 128ndash131 2009

[26] SWillier E Butt and T G Grunewald ldquoLysophosphatidic acid(LPA) signaling in cell migration and cancer invasion a focusedreview and analysis of LPA receptor gene expression on the basisof more than 1700 cancer microarraysrdquo Biology of the Cell vol105 no 8 pp 317ndash333 2013

[27] E Barbayianni V Magrioti P Moutevelis-Minakakis and GKokotos ldquoAutotaxin inhibitors a patent reviewrdquo Expert OpiniononTherapeutic Patents vol 23 no 9 pp 1123ndash1132 2013

[28] K Bandoh J Aoki H Hosono et al ldquoMolecular cloning andcharacterization of a novel human G-protein-coupled receptorEDG7 for lysophosphatidic acidrdquo The Journal of BiologicalChemistry vol 274 no 39 pp 27776ndash27785 1999

[29] D-S Im C E Heise M A Harding et al ldquoMolecular cloningand characterization of a lysophosphatidic acid receptor Edg-7expressed in prostaterdquo Molecular Pharmacology vol 57 no 4pp 753ndash759 2000

[30] K Noguchi S Ishii and T Shimizu ldquoIdentification ofp2y9GPR23 as a novel G protein-coupled receptor for lyso-phosphatid-ic acid structurally distant from the Edg familyrdquoThe Journal of Biological Chemistry vol 278 no 28 pp 25600ndash25606 2003

[31] TMMcIntyre A V Pontsler A R Silva et al ldquoIdentification ofan intracellular receptor for lysophosphatidic acid (LPA) LPAis a transcellular PPAR

120574agonistrdquo Proceedings of the National

Academy of Sciences of the United States of America vol 100 no1 pp 131ndash136 2003

[32] W Xie M Matsumoto J Chun and H Ueda ldquoInvolvement ofLPA1receptor signaling in the reorganization of spinal input

through Abeta-fibers in mice with partial sciatic nerve injuryrdquoMolecular Pain vol 4 article 46 2008

[33] S An T Bleu O G Hallmark and E J Goetzl ldquoCharacteriza-tion of a novel subtype of human G protein-coupled receptorfor lysophosphatidic acidrdquo The Journal of Biological Chemistryvol 273 no 14 pp 7906ndash7910 1998

[34] E Liszewska P Reinaud E Billon-Denis O Dubois P Robinand G Charpigny ldquoLysophosphatidic acid signaling duringembryo development in sheep involvement in prostaglandinsynthesisrdquo Endocrinology vol 150 no 1 pp 422ndash434 2009

[35] J H Seo M Kim Y Choi C-K Lee and H Ka ldquoAnalysisof lysophosphatidic acid (LPA) receptor and LPA-inducedendometrial prostaglandin-endoperoxide synthase 2 expres-sion in the porcine uterusrdquo Endocrinology vol 149 no 12 pp6166ndash6175 2008

[36] KKotarsky A Boketoft J Bristulf et al ldquoLysophosphatidic acidbinds to and activates GPR92 a G protein-coupled receptorhighly expressed in gastrointestinal lymphocytesrdquo The Journalof Pharmacology and Experimental Therapeutics vol 318 no 2pp 619ndash628 2006

[37] D Shida T Watanabe J Aoki et al ldquoAberrant expressionof lysophosphatidic acid (LPA) receptors in human colorectalcancerrdquo Laboratory Investigation vol 84 no 10 pp 1352ndash13622004


[38] K Hama J Aoki M Fukaya et al ldquoLysophosphatidic acidand autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA

1rdquoThe Journal of Biological Chem-

istry vol 279 no 17 pp 17634ndash17639 2004[39] A A Jarvis C Cain and E A Dennis ldquoPurification and

characterization of a lysophospholipase from human amnionicmembranesrdquo The Journal of Biological Chemistry vol 259 no24 pp 15188ndash15195 1984

[40] I Woclawek-Potocka I Kowalczyk-Zieba and D J SkarzynskildquoLysophosphatidic acid action during early pregnancy in thecow in vivo and in vitro studiesrdquo The Journal of Reproductionand Development vol 56 no 4 pp 411ndash420 2010

[41] H Guo F Gong K L Luo and G X Lu ldquoCyclic regulationof LPA

3in human endometriumrdquo Archives of Gynecology and

Obstetrics vol 287 no 1 pp 131ndash138 2013[42] S-U Chen H Lee D-Y Chang et al ldquoLysophosphatidic acid

mediates interleukin-8 expression in human endometrial stro-mal cells through its receptor and nuclear factor-120581B-dependentpathway a possible role in angiogenesis of endometrium andplacentardquo Endocrinology vol 149 no 11 pp 5888ndash5896 2008

[43] X Ye ldquoLysophospholipid signaling in the function and pathol-ogy of the reproductive systemrdquo Human Reproduction Updatevol 14 no 5 pp 519ndash536 2008

[44] S-U Chen C-H Chou H Lee C-N Ho C-W Lin andY-S Yang ldquoLysophosphatidic acid up-regulates expression ofinterleukin-8 and -6 in granulosa-lutein cells through its recep-tors and nuclear factor-120581B dependent pathways implicationsfor angiogenesis of corpus luteum and ovarian hyperstim-ulation syndromerdquo The Journal of Clinical Endocrinology ampMetabolism vol 93 no 3 pp 935ndash943 2008

[45] S-U Chen C-H Chou K-H Chao et al ldquoLysophosphatidicacid up-regulates expression of growth-regulated oncogene-120572 interleukin-8 and monocyte chemoattractant protein-1 inhuman first-trimester trophoblasts possible roles in angiogen-esis and immune regulationrdquo Endocrinology vol 151 no 1 pp369ndash379 2010

[46] Y Iwasawa T Fujii T Nagamatsu et al ldquoExpression of auto-taxin an ectoenzyme that produces lysophosphatidic acid inhuman placentardquo American Journal of Reproductive Immunol-ogy vol 62 no 2 pp 90ndash95 2009

[47] J I Kim E J Jo H-Y Lee et al ldquoStimulation of early geneinduction and cell proliferation by lysophosphatidic acid inhuman amnion-derived WISH cells role of phospholipase D-mediated pathwayrdquo Biochemical Pharmacology vol 68 no 2pp 333ndash340 2004

[48] K Nakanaga K Hama and J Aoki ldquoAutotaxinmdashan LPAproducing enzyme with diverse functionsrdquo The Journal ofBiochemistry vol 148 no 1 pp 13ndash24 2010

[49] A Tokumura YKanayaMMiyake S YamanoM Irahara andK Fukuzawa ldquoIncreased production of bioactive lysophospha-tidic acid by serum lysophospholipase D in human pregnancyrdquoBiology of Reproduction vol 67 no 5 pp 1386ndash1392 2002

[50] AArici EOral O Bukulmez S BuradaguntaO Engin andDL Olive ldquoInterleukin-8 expression and modulation in humanpreovulatory follicles and ovarian cellsrdquo Endocrinology vol 137no 9 pp 3762ndash3769 1996

[51] L T Budnik and A K Mukhopadhyay ldquoLysophosphatidic acidantagonizes the morphoregulatory effects of the luteinizinghormone on luteal cells possible role of small Rho-G-proteinsrdquoBiology of Reproduction vol 65 no 1 pp 180ndash187 2001

[52] Y-J Jeng S L Soloff G D Anderson and M S SoloffldquoRegulation of oxytocin receptor expression in cultured human

myometrial cells by fetal bovine serum and lysophospholipidsrdquoEndocrinology vol 144 no 1 pp 61ndash68 2003

[53] W Gogarten C W Emala K S Lindeman and C A Hirsh-man ldquoOxytocin and lysophosphatidic acid induce stress fiberformation in human myometrial cells via a pathway involvingRho-kinaserdquoBiology of Reproduction vol 65 no 2 pp 401ndash4062001

[54] S Shiokawa K Sakai Y Akimoto et al ldquoFunction of thesmall guanosine triphosphate-binding protein RhoA in theprocess of implantationrdquo The Journal of Clinical Endocrinologyamp Metabolism vol 85 no 12 pp 4742ndash4749 2000

[55] Q Wei J B St Clair T Fu P Stratton and L K NiemanldquoReduced expression of biomarkers associated with the implan-tation window in women with endometriosisrdquo Fertility andSterility vol 91 no 5 pp 1686ndash1691 2009

[56] L-X Li W Zhou Y-H Qiao M Wang and J-H ZhangldquoExpression and significance of Edg4 and Edg7 in the placentasof patients with hypertensive disorder complicating pregnancyrdquoZhonghua Fu Chan Ke Za Zhi vol 42 no 6 pp 386ndash389 2007

[57] A Tokumura K Fukuzawa and H Tsukatani ldquoEffects ofsynthetic and natural lysophosphatidic acids on the arterialblood pressure of different animal speciesrdquo Lipids vol 13 no8 pp 572ndash574 1978

[58] G Tigyi L Hong M Yakubu H Parfenova M Shibata andC W Leffler ldquoLysophosphatidic acid alters cerebrovascularreactivity in pigletsrdquoAmerican Journal of PhysiologymdashHeart andCirculatory Physiology vol 268 no 5 pp H2048ndashH2055 1995

[59] N Haseruck W Erl D Pandey et al ldquoThe plaque lipidlysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood involvement ofP2Y1and P2Y

12receptorsrdquo Blood vol 103 no 7 pp 2585ndash2592

2004[60] A C Eriksson P A Whiss and U K Nilsson ldquoAdhesion

of human platelets to albumin is synergistically increased bylysophosphatidic acid and adrenaline in a donor-dependentfashionrdquoBloodCoagulationampFibrinolysis vol 17 no 5 pp 359ndash368 2006

[61] A Tokumura T Kume S Taira K Yasuda and H KanzakildquoAltered activity of lysophospholipase D which produces bioac-tive lysophosphatidic acid and choline in serum from womenwith pathological pregnancyrdquo Molecular Human Reproductionvol 15 no 5 pp 301ndash310 2009

[62] H Mikamo K Kawazoe Y Sato A Imai and T TamayaldquoPreterm labor and bacterial intraamniotic infection arachi-donic acid liberation by phospholipase A

2of Fusobacterium

nucleatumrdquo American Journal of Obstetrics amp Gynecology vol179 no 6 pp 1579ndash1582 1998

[63] E Billon-Denis Z Tanfin and P Robin ldquoRole of lysophos-phatidic acid in the regulation of uterine leiomyoma cellproliferation by phospholipase D and autotaxinrdquo Journal ofLipid Research vol 49 no 2 pp 295ndash307 2008

[64] J M Hope F-Q Wang J S Whyte et al ldquoLPA receptor 2mediates LPA-induced endometrial cancer invasionrdquo Gyneco-logic Oncology vol 112 no 1 pp 215ndash223 2009

[65] F-Q Wang E V Ariztia L R Boyd et al ldquoLysophospha-tidic acid (LPA) effects on endometrial carcinoma in vitroproliferation invasion and matrix metalloproteinase activityrdquoGynecologic Oncology vol 117 no 1 pp 88ndash95 2010

[66] E Rapizzi C Donati F Cencetti P Pinton R Rizzuto and PBruni ldquoSphingosine 1-phosphate receptors modulate intracel-lular Ca2+ homeostasisrdquo Biochemical and Biophysical ResearchCommunications vol 353 no 2 pp 268ndash274 2007


[67] J Kitayama D Shida A Sako et al ldquoOver-expression oflysophosphatidic acid receptor-2 in human invasive ductalcarcinomardquo Breast Cancer Research vol 6 no 6 pp R640ndashR646 2004

[68] M Chen L N Towers and K L OrsquoConnor ldquoLPA2(EDG4)

mediates Rho-dependent chemotaxis with lower efficacy thanLPA1(EDG2) in breast carcinoma cellsrdquo American Journal of

PhysiologymdashCell Physiology vol 292 no 5 pp C1927ndashC19332007

[69] W Imagawa G K Bandyopadhyay and S Nandi ldquoAnalysis ofthe proliferative response to lysophosphatidic acid in primarycultures of mammary epithelium differences between normaland tumor cellsrdquo Experimental Cell Research vol 216 no 1 pp178ndash186 1995

[70] J L Boerner J S Biscardi C M Silva and S J ParsonsldquoTransactivating agonists of the EGF receptor require Tyr 845phosphorylation for induction of DNA synthesisrdquo MolecularCarcinogenesis vol 44 no 4 pp 262ndash273 2005

[71] R Sutphen Y Xu G DWilbanks et al ldquoLysophospholipids arepotential biomarkers of ovarian cancerrdquo Cancer EpidemiologyBiomarkers amp Prevention vol 13 no 7 pp 1185ndash1191 2004

[72] Y Xu Z Shen D W Wiper et al ldquoLysophosphatidic acid as apotential biomarker for ovarian and other gynecologic cancersrdquoThe Journal of the American Medical Association vol 280 no 8pp 719ndash723 1998

[73] Y Bermudez H Yang B O Saunders J Q Cheng S V Nicosiaand P A Kruk ldquoVEGF- and LPA-induced telomerase in humanovarian cancer cells is Sp1-dependentrdquo Gynecologic Oncologyvol 106 no 3 pp 526ndash537 2007

[74] C-H Chou L-H Wei M-L Kuo et al ldquoUp-regulation ofinterleukin-6 in human ovarian cancer cell via a GiPI3K-AktNF-120581B pathway by lysophosphatidic acid an ovariancancer-activating factorrdquo Carcinogenesis vol 26 no 1 pp 45ndash52 2005

[75] J Symowicz B P Adley M M M Woo N Auersperg LG Hudson and M S Stack ldquoCyclooxygenase-2 functionsas a downstream mediator of lysophosphatidic acid to pro-mote aggressive behavior in ovarian carcinoma cellsrdquo CancerResearch vol 65 no 6 pp 2234ndash2242 2005

[76] P Wang X Wu W Chen J Liu and X Wang ldquoThe lysophos-phatidic acid (LPA) receptors their expression and significancein epithelial ovarian neoplasmsrdquoGynecologic Oncology vol 104no 3 pp 714ndash720 2007

[77] S Sengupta Y-J Xiao and Y Xu ldquoA novel laminin-inducedLPA autocrine loop in the migration of ovarian cancer cellsrdquoThe FASEB Journal vol 17 no 11 pp 1570ndash1572 2003

[78] A Sako J Kitayama D Shida et al ldquoLysophosphatidic acid(LPA)-induced vascular endothelial growth factor (VEGF) bymesothelial cells and quantification of host-derived VEGF inmalignant ascitesrdquo Journal of Surgical Research vol 130 no 1pp 94ndash101 2006

[79] G P Adams and R A Pierson ldquoBovine model for study ofovarian follicular dynamics in humansrdquoTheriogenology vol 43no 1 pp 113ndash120 1995

[80] A Bettegowda O V Patel K-B Lee et al ldquoIdentification ofnovel bovine cumulus cell molecular markers predictive ofoocyte competence functional and diagnostic implicationsrdquoBiology of Reproduction vol 79 no 2 pp 301ndash309 2008

[81] D Boruszewska E Sinderewicz I Kowalczyk-Zieba D JSkarzynski and I Woclawek-Potocka ldquoInfluence of lysophos-phatidic acid on estradiol production and follicle stimulating

hormone action in bovine granulosa cellsrdquo Reproductive Biol-ogy vol 13 no 4 pp 344ndash347 2013

[82] D Boruszewska I Kowalczyk-Zieba K Piotrowska-Tomala etal ldquoWhich bovine endometrial cells are the source of and targetfor lysophosphatidic acidrdquo Reproductive Biology vol 13 no 1pp 100ndash103 2013

[83] I Woclawek-Potocka I Kowalczyk-Zieba M Tylingo DBoruszewska E Sinderewicz and D J Skarzynski ldquoEffects oflysophopatidic acid on tumor necrosis factor 120572 and interferon120574 action in the bovine corpus luteumrdquo Molecular and CellularEndocrinology vol 377 no 1-2 pp 103ndash111 2013

[84] L T Budnik and B Brunswig-Spickenheier ldquoDifferential effectsof lysolipids on steroid synthesis in cells expressing endogenousLPA2receptorrdquo Journal of Lipid Research vol 46 no 5 pp 930ndash

941 2005[85] E Liszewska P Reinaud O Dubois and G Charpigny

ldquoLysophosphatidic acid receptors in ovine uterus during estrouscycle and early pregnancy and their regulation by progesteronerdquoDomestic Animal Endocrinology vol 42 no 1 pp 31ndash42 2012

[86] I Ishii J J A Contos N Fukushima and J Chun ldquoFunctionalcomparisons of the lysophosphatidic acid receptors LPA1VZG-1EDG-2 LPA2EDG-4 and LPLPA3EDG-7 in neuronal celllines using a retrovirus expression systemrdquoMolecular Pharma-cology vol 58 no 5 pp 895ndash902 2000

[87] I Woclawek-Potocka K Kondraciuk and D J SkarzynskildquoLysophosphatidic acid stimulates prostaglandin E

2production

in cultured stromal endometrial cells through LPA1receptorrdquo

Experimental Biology andMedicine vol 234 no 8 pp 986ndash9932009

[88] B Bao H A Garverick G W Smith M F Smith B E Salfenand R S Youngquist ldquoChanges in messenger ribonucleic acidencoding luteinizing hormone receptor cytochrome P450-sidechain cleavage and aromatase are associated with recruitmentand selection of bovine ovarian folliclesrdquo Biology of Reproduc-tion vol 56 no 5 pp 1158ndash1168 1997

[89] A C O Evanst and J E Fortune ldquoSelection of the dominantfollicle in cattle occurs in the absence of differences in theexpression of messenger ribonucleic acid for gonadotropinreceptorsrdquo Endocrinology vol 138 no 7 pp 2963ndash2971 1997

[90] J E Fortune ldquoBovine theca and granulosa cells interact topromote androgen productionrdquoBiology of Reproduction vol 35no 2 pp 292ndash299 1986

[91] C G Gutierrez B K Campbell and R Webb ldquoDevelopmentof a long-term bovine granulosa cell culture system inductionand maintenance of estradiol production response to follicle-stimulating hormone and morphological characteristicsrdquo Biol-ogy of Reproduction vol 56 no 3 pp 608ndash616 1997

[92] J M Silva and C A Price ldquoEffect of follicle-stimulatinghormone on steroid secretion and messenger ribonucleic acidsencoding cytochromes P450 aromatase and cholesterol side-chain cleavage in bovine granulosa cells in vitrordquo Biology ofReproduction vol 62 no 1 pp 186ndash191 2000

[93] M Sahmi E S Nicola J M Silva and C A Price ldquoExpressionof 17120573- and 3120573-hydroxysteroid dehydrogenases and steroido-genic acute regulatory protein in non-luteinizing bovine gran-ulosa cells in vitrordquo Molecular and Cellular Endocrinology vol223 no 1-2 pp 43ndash54 2004

[94] A Friedman S Weiss N Levy and R Meidan ldquoRole of tumornecrosis factor 120572 and its type I receptor in luteal regressioninduction of programmed cell death in bovine corpus luteum-derived endothelial cellsrdquo Biology of Reproduction vol 63 no6 pp 1905ndash1912 2000


[95] M G Petroff B K Petroff and J L Pate ldquoMechanismsof cytokine-induced death of cultured bovine luteal cellsrdquoReproduction vol 121 no 5 pp 753ndash760 2001

[96] H Taniguchi Y Yokomizo and K Okuda ldquoFas-Fas ligandsystem mediates luteal cell death in bovine corpus luteumrdquoBiology of Reproduction vol 66 no 3 pp 754ndash759 2002

[97] L A Penny D Armstrong T A Bramley R Webb R ACollins and E D Watson ldquoImmune cells and cytokine pro-duction in the bovine corpus luteum throughout the oestrouscycle and after induced luteolysisrdquo Journal of Reproduction andFertility vol 115 no 1 pp 87ndash96 1999

[98] N Abbas L-P Zou S-H Pelidou B Winblad and J ZhuldquoProtective effect of Rolipram in experimental autoimmuneneuritis protection is associated with down-regulation of IFN-120574 and inflammatory chemokines as well as up-regulation of IL-4in peripheral nervous systemrdquo Autoimmunity vol 32 no 2 pp93ndash99 2000

[99] R Sakumoto B Berisha N Kawate D Schams and K OkudaldquoTumor necrosis factor-120572 and its receptor in bovine corpusluteum throughout the estrous cyclerdquo Biology of Reproductionvol 62 no 1 pp 192ndash199 2000

[100] D J SkarzynskiMM BahKMDeptula et al ldquoRoles of tumornecrosis factor-120572 of the estrous cycle in cattle an in vivo studyrdquoBiology of Reproduction vol 69 no 6 pp 1907ndash1913 2003

[101] G D Niswender J L Juengel P J Silva M K Rollyson andE W McIntush ldquoMechanisms controlling the function and lifespan of the corpus luteumrdquo Physiological Reviews vol 80 no 1pp 1ndash29 2000

[102] R Meidan R A Milvae S Weiss N Levy and A FriedmanldquoIntraovarian regulation of luteolysisrdquo Journal of Reproductionand Fertility vol 54 pp 217ndash228 1999

[103] J L Pate and P L Keyes ldquoImmune cells in the corpus luteumfriends or foesrdquoReproduction vol 122 no 5 pp 665ndash676 2001

[104] M Fotin-Mleczek F Henkler D Samel et al ldquoApoptoticcrosstalk of TNF receptors TNF-R2-induces depletion ofTRAF2 and IAP proteins and accelerates TNF-R1-dependentactivation of caspase-8rdquo Journal of Cell Science vol 115 no 13pp 2757ndash2770 2002

[105] S Nagata ldquoApoptosis by death factorrdquo Cell vol 88 no 3 pp355ndash365 1997

[106] KOkuda andR Sakumoto ldquoMultiple roles of TNF super familymembers in corpus luteum functionrdquo Reproductive Biology andEndocrinology vol 1 article 95 2003

[107] C Scaffidi S Fulda A Srinivasan et al ldquoTwo CD95 (APO-1Fas) signaling pathwaysrdquoThe EMBO Journal vol 17 no 6 pp1675ndash1687 1998

[108] J L Juengel H A Garverick A L Johnson R S Youngquistand M F Smith ldquoApoptosis during luteal regression in cattlerdquoEndocrinology vol 132 no 1 pp 249ndash254 1993

[109] B R Rueda K I Tilly T R Hansen P B Hoyer and J L TillyldquoExpression of superoxide dismutase catalase and glutathioneperoxidase in the bovine corpus luteum evidence supporting arole for oxidative stress in luteolysisrdquo Endocrine vol 3 no 3 pp227ndash232 1995

[110] T G Kennedy ldquoProstaglandin E2 adenosine-31015840 51015840-cyclic

monophosphate and changes in endometrial vascular perme-ability in rat uteri sensitized for the decidual cell reactionrdquoBiology of Reproduction vol 29 no 5 pp 1069ndash1076 1983

[111] J A Mccracken E E Custer and J C Lamsa ldquoLuteolysis aneuroendocrine-mediated eventrdquo Physiological Reviews vol 79no 2 pp 263ndash323 1999

[112] FW Bazer ldquoMediators of maternal recognition of pregnancy inmammalsrdquo Proceedings of the Society for Experimental Biologyand Medicine vol 199 no 4 pp 373ndash384 1992

[113] F W Bazer T E Spencer and T L Ott ldquoInterferon 120591a novel pregnancy recognition signalrdquo American Journal ofReproductive Immunology vol 37 no 6 pp 412ndash420 1997

[114] G D Niswender R H Schwall T A Fitz C E Farin and H RSawyer ldquoRegulation of luteal function in domestic ruminantsnew conceptsrdquo Recent Progress in Hormone Research vol 41 pp101ndash151 1985

[115] L Yang X L Wang P C Wan et al ldquoUp-regulation ofexpression of interferon-stimulated gene 15 in the bovine corpusluteumduring early pregnancyrdquo Journal ofDairy Science vol 93no 3 pp 1000ndash1011 2010

[116] N Forde F Carter T E Spencer et al ldquoConceptus-inducedchanges in the endometrial transcriptome how soon does thecow know she is pregnantrdquo Biology of Reproduction vol 85 no1 pp 144ndash156 2011

[117] E Asselin A KGoffH Bergeron andMA Fortier ldquoInfluenceof sex steroids on the production of prostaglandins F

2120572and E

2

and response to oxytocin in cultured epithelial and stromal cellsof the bovine endometriumrdquo Biology of Reproduction vol 54no 2 pp 371ndash379 1996

[118] C W Weems Y S Weems and R D Randel ldquoProstaglandinsand reproduction in female farm animalsrdquo The VeterinaryJournal vol 171 no 2 pp 206ndash228 2006

[119] B H Shah and K J Catt ldquoRoles of LPA3and COX-2 in

implantationrdquo Trends in Endocrinology amp Metabolism vol 16no 9 pp 397ndash399 2005

[120] X Ye K Hama J J A Contos et al ldquoLPA3-mediated lysophos-

phatidic acid signalling in embryo implantation and spacingrdquoNature vol 435 no 7038 pp 104ndash108 2005

[121] K Hinokio S Yamano K Nakagawa et al ldquoLysophosphatidicacid stimulates nuclear and cytoplasmic maturation of goldenhamster immature oocytes in vitro via cumulus cellsrdquo LifeSciences vol 70 no 7 pp 759ndash767 2002

[122] Z Liu and D R Armant ldquoLysophosphatidic acid regulatesmurine blastocyst development by transactivation of receptorsfor heparin-binding EGF-like growth factorrdquo Experimental CellResearch vol 296 no 2 pp 317ndash326 2004

[123] S K Dey H Lim S K Das et al ldquoMolecular cues toimplantationrdquo Endocrine Reviews vol 25 no 3 pp 341ndash3732004

[124] G E Mann and G E Lamming ldquoRelationship between mater-nal endocrine environment early embryo development andinhibition of the luteolytic mechanism in cowsrdquo Reproductionvol 121 no 1 pp 175ndash180 2001

[125] K Kelemen A Paldi H Tinneberg A Torok and J Szekeres-Bartho ldquoEarly recognition of pregnancy by the maternalimmune systemrdquo American Journal of Reproductive Immunol-ogy vol 39 no 6 pp 351ndash355 1998

[126] E R Barnea Y J Choi and P C Leavis ldquoEmbryo-maternalsignaling prior to implantationrdquo Early Pregnancy vol 4 no 3pp 166ndash175 2000

[127] M Majewska A Chelmonska-Soyta M M Bah I Woclawek-Potocka andD J Skarzynski ldquoLymphocyte subsets distributionin peripheral blood and endometrium during early pregnancyin cowsrdquo Reproduction in Domestic Animals vol 42 article 1122007

[128] M G Diskin and D G Morris ldquoEmbryonic and early foetallosses in cattle and other ruminantsrdquo Reproduction in DomesticAnimals vol 43 supplement 2 pp 260ndash267 2008



[130] F DrsquoAquilio M Procaccini V Izzi et al ldquoActivatory propertiesof lysophosphatidic acid on human THP-1 cellsrdquo Inflammationvol 30 no 5 pp 167ndash177 2007


[132] C N Inoue H G Forster and M Epstein ldquoEffects oflysophosphatidic acid a novel lipid mediator on cytosolic Ca2+and contractility in cultured rat mesangial cellsrdquo CirculationResearch vol 77 no 5 pp 888ndash896 1995

[133] C O A Reiser T Lanz F Hofmann G Hofer H D Rupprechtand M Goppelt-Struebe ldquoLysophosphatidic acid-mediatedsignal-transduction pathways involved in the induction of theearly-response genes prostaglandin GH synthase-2 and Egr-1a critical role for the mitogen-activated protein kinase p38 andfor Rho proteinsrdquo Biochemical Journal vol 330 no 3 pp 1107ndash1114 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


production in extracellular body fluids especially in serumand plasma These various ways of LPA synthesis reflectmultiple levels of regulationmdashor deregulation in the organ-ism being at different physiological or pathological statusmdashcancers [4] pregnancy [23] hypertension [24] prostatedisease or obesity [25] Moreover LPA-dependent differentsignaling pathways have clear therapeutic repercussions sincepharmaceutical drugs targeting certain enzymes would differfrom those targeting other LPA biosynthetic pathways [2627]

In mammals LPA exerts its action via at least six highaffinity transmembrane G-protein-coupled receptor (GPCR)types LPAR1ndashLPAR6 and possibly through a nuclear recep-tor PPAR120574 [22 28ndash31] These LPARs are expressed in variousorgans and cells [21] For example LPAR1 is highly expressedin the nervous system [32] LPAR2 in immune organs suchas the thymus and spleen [33] and LPAR3 in reproductiveorgans such as the ovary and uterus [7 16 34 35] On theother hand LPAR4 LPAR5 and LPAR6 are expressed widelybut at relatively low levels In that aspect we can find LPAR4expression in the ovary [30] LPAR5 expression in the smallintestine spleen dorsal root ganglion and embryonic stemcells [36]However there is alsomuch evidence of an aberrantexpression of LPA receptors in certain diseases meaningespecially different types of cancer [37 38]

The influence of LPA on the reproductive system functionof the female has been examined and described for about 30years Since the first reports published by Jarvis et al [39] inwomen various abnormalities in reproductive performanceon different regulatory levels due to LPA signaling and LPARsknockout have been also reported in many farm animalsincluding ruminants [34 35 40]

3 Effects of Lysophosphatidic Acid onthe Reproductive Performance in Human

31 The Possibility of LPA Synthesis and LPARs Expressionin the Reproductive Tissues Physiologically LPA and itsactive LPARs have been documented to be present in femalereproductive organs such as uterus [20 41 42] ovary [4344] and placenta [43 45 46] as well as in the amnion-derivedcells in vitro [47] Interestingly serum ATX level was higherin women than in men [48] suggesting possible influence ofLPA on the female reproduction

32 LPA Signaling in the Human Ovary LPA signaling hasbeen extensively studied in the physiology of human ovaryFollicular fluid of the human preovulatory follicle containslysophospholipase DmdashATX which is responsible for localLPA production from lysophosphatidylcholine (LPCs) [49]However LPA in ovaries is produced not only from follicularfluidrsquos LPCs but also from LPCs in granulosa cells andoocytes In follicular fluid taken from women programmedfor in vitro fertilization the amount of LPA increases with thetime of incubationwithATX in 37∘C [11] SerumATX activityfrom patients receiving ovarian stimulation was higher thanin women with natural cycles [44] Moreover Chen et al[44] demonstratedmRNA expression of three LPA receptors

LPAR1 LPAR2 and LPAR3 in the granulosa-lutein cells fromwomen undergoing in vitro fertilization LPAR4 was alsohighly expressed in the cortex of the human ovary [30]

LPA signaling plays many crucial roles in ovarian func-tion such as ovulation for example Before ovulation LPAelevated the level of IL-8 expressed its chemotactic activityfor neutrophils started the inflammatory reaction and inconsequence led to tissue degradation and rupture of thefollicle [50] During the luteal phase human ovary exhibitscomplete tissue remodeling with the stages of growth dif-ferentiation and regression [51] In the early luteal phasegranulosa and theca cells form corpus luteum with highlevel of angiogenesis LPA through the upregulation of IL-8 and IL-6 stimulated the multistep process of new vesselsformation in the CL [42] Moreover LPA induced expressionof angiogenic cytokines IL-6 and IL-8 in granulosa-luteincells fromwomen undergoing in vitro fertilization [42]Thusthe authors concluded that the induction of these cytokinesby LPA through its receptor and nuclear factor-kappaB-dependent pathway in the stimulated ovaries may contributeto ovarian hyperstimulation syndrome [42]

33 LPA Signaling during Pregnancy More than a decadeago Tokumura et al [49] suggested the involvement ofLPA signaling in maintenance of human pregnancy Theseauthors demonstrated increasing levels of LPA and serumATXlysoPLD activity during pregnancy [49] The elevatedlevels of serum LPA found during pregnancy were reportedto arise from both the placenta and the fetus [49] In thehuman placenta LPA can be produced locally by trophoblastsATX and thereby control trophoblast proliferation differ-entiation feto-maternal immune interaction and placentalvascular remodeling [46] During early pregnancy placentaproduces many new vessels which are crucial for fetal-maternal exchange LPA through induction of IL-8 couldstimulate the process of angiogenesis in the placenta [45]Kim et al [47] also found that LPA modulated cellularactivity and stimulated proliferation of human amnion cellsin vitroMoreover Jarvis et al [39] documented high lysoPLDactivity in human placental tissues with the highest in theamnion The authors suggested that high lysoPLD activityin the amnion proclaimed that LPA might be involved inthe regulation of labor due to the direct implications ofthis membrane in the initiation of the labor [39] More-over Jeng et al [52] demonstrated that LPA upregulatedtranscriptional activity of oxytocin (OT) receptors in vitrowhich resulted in sensitization of myometrial cells to OT Inuterus in the end of gestation the sensitivity of myometriumto OT increases robustly which in turn induces uterinecontractions leading to labor Other important process ininduction and maintenance of smooth muscle contraction isstress fiber formation LPA enhanced stress fiber formationin human myometrial cells in vitro and thereby increased theefficiency of uterine contractions in the beginning of labor[53]

The process of embryo implantation includes interactionbetween the endometrium and the embryo (adhesion andinvasion) inflow of innate immune cells and vascularization





















2expression




ATX

LPA

LPA

LPA

LPA

LPA

LPA

LPALPA

LPA

Ca2+

PGFS

PGES

PGF2120572

PGE2

LPAR1

UterusOvary

PLA2

PLA2ATXFollicle

FSH

FSHRLPALPAR1

LPAR2LPAR3

LPAR4



IFN120574

Bax

ApoptosisFasFasL

Casp3

TNFR1

IFN120591OAS1ISG15


CholesterolStar

P450sccPregnenolone

3120573HSD

P4

LPAATX PLA2

TNF120572









2120572 PGE




2and inhibits PGF









2


























2120572via



0 3 6 9 12 15 18 21 24 270

10

20

30

40

Saline

Treatment


Prog

este

rone

(ng

mL)







2secretion






0

10

20

30


75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast


x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183


Prog

este

rone

(ng

mL)

z

(c)








to PGE2ratio



2




2synthesis via










2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































2expression




ATX

LPA

LPA

LPA

LPA

LPA

LPA

LPALPA

LPA

Ca2+

PGFS

PGES

PGF2120572

PGE2

LPAR1

UterusOvary

PLA2

PLA2ATXFollicle

FSH

FSHRLPALPAR1

LPAR2LPAR3

LPAR4



IFN120574

Bax

ApoptosisFasFasL

Casp3

TNFR1

IFN120591OAS1ISG15


CholesterolStar

P450sccPregnenolone

3120573HSD

P4

LPAATX PLA2

TNF120572









2120572 PGE




2and inhibits PGF









2


























2120572via



0 3 6 9 12 15 18 21 24 270

10

20

30

40

Saline

Treatment


Prog

este

rone

(ng

mL)







2secretion






0

10

20

30


75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast


x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183


Prog

este

rone

(ng

mL)

z

(c)








to PGE2ratio



2




2synthesis via










2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























2expression




ATX

LPA

LPA

LPA

LPA

LPA

LPA

LPALPA

LPA

Ca2+

PGFS

PGES

PGF2120572

PGE2

LPAR1

UterusOvary

PLA2

PLA2ATXFollicle

FSH

FSHRLPALPAR1

LPAR2LPAR3

LPAR4



IFN120574

Bax

ApoptosisFasFasL

Casp3

TNFR1

IFN120591OAS1ISG15


CholesterolStar

P450sccPregnenolone

3120573HSD

P4

LPAATX PLA2

TNF120572









2120572 PGE




2and inhibits PGF









2


























2120572via



0 3 6 9 12 15 18 21 24 270

10

20

30

40

Saline

Treatment


Prog

este

rone

(ng

mL)







2secretion






0

10

20

30


75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast


x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183


Prog

este

rone

(ng

mL)

z

(c)








to PGE2ratio



2




2synthesis via










2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ATX

LPA

LPA

LPA

LPA

LPA

LPA

LPALPA

LPA

Ca2+

PGFS

PGES

PGF2120572

PGE2

LPAR1

UterusOvary

PLA2

PLA2ATXFollicle

FSH

FSHRLPALPAR1

LPAR2LPAR3

LPAR4



IFN120574

Bax

ApoptosisFasFasL

Casp3

TNFR1

IFN120591OAS1ISG15


CholesterolStar

P450sccPregnenolone

3120573HSD

P4

LPAATX PLA2

TNF120572









2120572 PGE




2and inhibits PGF









2


























2120572via



0 3 6 9 12 15 18 21 24 270

10

20

30

40

Saline

Treatment


Prog

este

rone

(ng

mL)







2secretion






0

10

20

30


75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast


x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183


Prog

este

rone

(ng

mL)

z

(c)








to PGE2ratio



2




2synthesis via










2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















2


























2120572via



0 3 6 9 12 15 18 21 24 270

10

20

30

40

Saline

Treatment


Prog

este

rone

(ng

mL)







2secretion






0

10

20

30


75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast


x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183


Prog

este

rone

(ng

mL)

z

(c)








to PGE2ratio



2




2synthesis via










2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0 3 6 9 12 15 18 21 24 270

10

20

30

40

Saline

Treatment


Prog

este

rone

(ng

mL)







2secretion






0

10

20

30


75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast


x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183


Prog

este

rone

(ng

mL)

z

(c)








to PGE2ratio



2




2synthesis via










2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0

10

20

30


75 pregnancySaline

Prog

este

rone

(ng

mL)

lowast lowast

lowastlowast


x

(a)

0

10

20

30


75 pregnancyLPA

Prog

este

rone

(ng

mL)

lowastlowast


y

(b)

0 3 6 9 12 15 18 210

10

20

30


37 pregnancy

VPC 32183


Prog

este

rone

(ng

mL)

z

(c)








to PGE2ratio



2




2synthesis via










2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























2120572and PGE



2that resulted in a




2and PGI

2[120]








Acknowledgments


References

















2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























2rdquo
































































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































2of Fusobacterium
































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































2production



































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































2120572and E

2


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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