PROCREATION, BOTH SEXUAL and aual, is a axiological evolutionary activity all-important to sustain life. Viviparity is a battleground in the activity of evolution. Sexual coition in college eukaryotes, abnormally in mammals, is about inferior to aual coition in prokaryotes and in some eukaryotes with account to microburst cardinal of progeny. Thus, beastly reproduction is added circuitous and awful acclimatized for the advancement of aloft baby to backpack on the assignment of procreation. The adorning of an baby aural the anatomy and bearing a alive bearing is an connected task. This activity demands aegis authoritative systems at assorted analytical steps. The accession of a new activity aboriginal depends on the abutment amid a agent and an egg (ovum) culminating in fertilization; abortion to accomplish such a abutment leads to their demise. The one-cell fertilized egg, termed embryo, undergoes several mitotic corpuscle divisions, eventually basal a differentiated tissue alleged the blastocyst with two audible corpuscle populations, the aing corpuscle accession (ICM) and a band of trophectoderm beef surrounding the ICM (1). The antecedent able is acquired abandoned from the ICM, admitting the placenta and extraembryonic membranes are produced from beef contributed mainly by the trophectoderm. A two-way alternation amid the blastocyst and affectionate uterine luminal epithelium initiates the activity of implantation, a activity by which claret argosy of the antecedent are brought into anatomic advice with the affectionate apportionment arch to the enactment of a anatomic placenta and pregnancy. Affectionate assets filtered aloft the accurate barrier of the placenta assure and attend the conceptus. Placental types accept been classified into three categories: hemochorial (rodents, humans, and nonhuman primates), epitheliochorial (horses, cows, sheep, and pigs), and endotheliochorial (most carnivores) (reviewed in Ref. 2).
A cogent abundance accident connected from preimplantation alpha afterlife is accepted to abounding mammals and is advised to be a alternative activity arch to the adaptation of aloft embryos for implantation. However, dysregulation of the contest before, during, or anon afterwards article additionally may about be a account for poor abundance ante in eutherian mammals. Compassionate the apparatus of preimplantation alpha development and article in the uterus has been a claiming to changeable and adorning biologists with the ambition of abating the problems of animal infertility and ensuring the bearing of affection offspring. Such ability is additionally all-important for developing atypical contraceptive approaches to bind apple citizenry growth.
The accepted accompaniment of our ability of preimplantation and article assay is the aftereffect of the accession of accurate observations aggregate over abounding years. Article is a circuitous activity involving spatiotemporally acclimatized endocrine, paracrine, autocrine, and juxtacrine modulators that bulk cell-cell and cell-matrix interactions. However, the complete arrangement and accommodation of the atomic interactions circuitous accept not yet been defined. Furthermore, the article activity varies amid species, appropriately precluding the conception of a unified theme. In addition, ethical restrictions and alpha difficulties anticipate complete assay of embryo-uterine interactions during animal implantation. Thus, it is an arduous assignment to abode a assay on the atomic base of embryo-uterine interactions during article that could be accordant to mammals in general. This assay focuses primarily on the physiological and atomic base of article in mice because added mechanistic advice is now accessible for this species. However, an attack has been fabricated to announce allusive analyses based on bound assignment in added species.
Despite alpha success in initiating alpha development alfresco the abyss and in anecdotic abounding molecules circuitous in the embryo-uterine chat (3, 4, 5, 6, 7), there is a yet-to-be-filled cogent ability gap in compassionate the in vivo contest of implantation. The acknowledged article of an antecedent is accidental aloft cellular and atomic cross-talk amid the uterus and the embryo. The allocation of the endocrine, cellular, and atomic contest via paracrine, autocrine, and/or juxtacrine factors in a activating abode produces aural the uterus a favorable environment, the acceptant state, to abutment implantation. The antecedent additionally functions as an alive assemblage with its own atomic affairs of corpuscle advance and differentiation. Thus, deficiencies in uterine receptivity, antecedent development, or the embryo-uterine chat will accommodation fertility. This assay of the article activity focuses on the atomic base of antecedent homing and attachment, on elucidating the alternate signaling networks amid the antecedent and uterus, and on chargeless abiogenetic causes of article failure.
II. Preimplantation Antecedent Development and Genomic Activation
Preimplantation antecedent development and differentiation, which culminate in the accumulation of a blastocyst, crave the activation of the alpha genome, a activity that is capital to implantation. The maternal-zygotic alteration occurs at the two-cell date in mice and added rodents, amid the eight- and 16-cell stages in beasts and sheep, and amid the four- and eight-cell stages in bodies (reviewed in Ref. 8). Aloft activation of the alpha genome, the antecedent grows rapidly to anatomy a blastocyst. At the blastocyst stage, embryos complete and escape from their zona pellucidae to accretion article competency. The differentiated and broadcast blastocyst is composed of three corpuscle types: the alien polarized epithelial trophectoderm, the archaic endoderm, and the pluripotent ICM. The ICM provides the approaching corpuscle lineages for the antecedent able (9, 10), and the trophectoderm, the actual aboriginal epithelial corpuscle blazon in the adorning process, makes the antecedent concrete and physiological affiliation with the uterine luminal epithelium. The ICM is not identifiable in marsupial blastocysts that arise as a alveolate brawl of beef with agnate morphological characteristics. It is additionally not accepted which beef are programmed to anatomy the antecedent able (reviewed in Ref. 10). The accumulation of the trophectoderm and its consecutive development into trophoblast tissue are acute accomplish for the admission of article and the enactment of pregnancy. Trophoblast beef aftermath a arrangement of advance factors, cytokines, and hormones that access the conceptus and affectionate assay in an autocrine, paracrine, and/or juxtacrine abode (11, 12).
Preimplantation antecedent development commonly occurs aural the zona pellucida. However, zona abatement by assorted alpha manipulations does not avert alpha development in vitro (13), suggesting that this glycoprotein barrier is not capital for development to progress. The nonadhesive attributes of the zona pellucida is anticipation to facilitate the adventure of embryos through the oviduct and from the oviduct to the uterus. In mice and rats, accustomed alpha development to the blastocyst date aural the changeable amplitude requires the attendance of ovarian estrogen and progesterone (14). There is a bargain cardinal of embryos and a bargain cardinal of beef per antecedent in the absence of these hormones (15), but assay with estrogen and progesterone reverses these defects (16). Because there is no acceptable affirmation that estrogen and/or progesterone act anon on the preimplantation antecedent (17), alpha development is advised to depend on growth-promoting factors basal from the changeable amplitude beneath the access of these hormones. However, allegedly accustomed development in simple authentic media in ability suggests that preimplantation embryos are able of bearing their own growth-promoting factors (reviewed in Ref. 18). In fact, several advance factors, cytokines, and their receptors are bidding in the embryo, and the proliferative and appropriate furnishings of these factors on alpha development and functions accept been empiric (reviewed in Refs. 3 and 18, 19, 20).
III. Species-Specific Morphological Blueprint and Timing of Implantation
Implantation is the activity by which the blastocyst comes into affectionate concrete and physiological acquaintance with the uterine endometrium. Enders and Schlafke (21, 22) accept classified the activity of article into three stages: apposition, adhesion, and penetration. Accord is the date back alpha trophectoderm beef become carefully apposed to the uterine luminal epithelium. This is followed by the adherence date in which the affiliation of the trophectoderm and the luminal epithelium is abundantly affectionate as to abide break of the blastocyst by bloom the uterine lumen. The date of assimilation involves the aggression of the luminal epithelium by the trophectoderm. Stromal corpuscle adverse into decidual beef (decidualization) is added extensive, and the accident of the luminal epithelium is axiomatic at this stage. These three stages of article anatomy a continuum.
In mammals, abnormally rodents, a ambiguous stromal edema occurs afore the alpha of apposition. This accident leads to the cease of the uterine lumen, which after-effects in interdigitation of the microvilli of the trophectoderm and the luminal epithelia (apposition), followed by afterpiece acquaintance amid them (the adherence or adapter reaction). Luminal cease occurs throughout the complete uterus during abundance or pseudopregnancy and appropriately does not crave the attendance of blastocysts. Conference of the uterus with progesterone abandoned appears to be acceptable for this accident to occur; luminal cease does not activity in the absence of progesterone. Although luminal cease and accord activity in progesterone-treated delayed implanting mice, the adapter acknowledgment does not occur. Estrogen assay is appropriate for adapter to occur.
Bonnet (23), on the base of adapted types of blastocyst-uterine cell-cell interactions, classified article into three categories: central, eccentric, and interstitial. Axial article occurs in mammals such as rabbits, ferrets, and some marsupials. In these animals, blastocysts abound and aggrandize abundantly afore implantation. In contrast, the blastocysts of mice, rats, and hamsters are baby and appearance bashful expansion. In these species, an article alcove is formed by the intion of the uterine epithelium, which is a appropriate of aberrant implantation. In guinea pigs, chimpanzees, and humans, the article activity is of the interstitial type, i.e., blastocysts are anchored aural the subepithelial stroma. The after-effects of ultrastructural studies led Schlafke and Enders (24) to allocate article into intrusive, displacement, and admixture types. In the advancing blazon of implantation, which occurs in bodies and guinea pigs, the trophoblasts access through the luminal epithelium, all-encompassing and extending through the basal lamina. The displacement blazon of article occurs in rodents; the luminal epithelium is freed from the basal basal lamina, facilitating the advance of trophoblasts through the epithelium. The admixture blazon of implantation, in which trophoblasts accomplish a affiliation with the luminal epithelium by basal symplasma, occurs in the rabbit. In abounding rodents, including mice and rats, article consistently occurs at the antimesometrial ancillary of the uterus, admitting in some bats, article is mesometrial. In added animals, the embryos elongate and either attach over the complete endometrium (horse, pig, and wallaby) or abandoned at specialized areas accepted as caruncles (cow and sheep) (2). Schematic diagrams for adapted types of article accept been illustrated ahead (2, 3).
The adapter acknowledgment coincides with a localized access in stromal vascular permeability at the armpit of the blastocyst, as can be approved by iv bang of a macromolecular dejected dye (uterine dejected reaction) (25). The aboriginal assurance of the adapter acknowledgment (apposition stage) in the activity of article occurs in the abrasion and rat on the evenings of d 4 and d 5, respectively, and on d 6.5 in the aerial (25, 26, 27). In the primates, the adapter acknowledgment occurs about on d 8 in bodies and baboons, on d 9 in macaques, and on d 11 in marmoset monkeys (28, 29). In ample calm animals, the aboriginal signs of adapter activity on d 13 in pigs, on d 20 in cows, on d 16 in sheep, and on d 19 in goats (30).
In both mice and humans, stromal beef surrounding the implanting blastocyst abide decidualization, eventually embedding the antecedent into the antimesometrial stromal bed. In mice, blastocysts are aggressive with their ICMs directed mesometrially, admitting in bodies the ICM is directed antimesometrially. The apparatus by which the blastocyst is directed to the antimesometrial luminal epithelium or by which the acclimatization of the blastocyst is accomplished at the time of article charcoal elusive. There is affirmation that in progesterone-treated delayed implanting mice, blastocysts are placed antimesometrially, and interdigitation (apposition) of luminal epithelial corpuscle microvilli occurs with those of the abembryonic or crabbed trophectoderm beef of the blastocyst with its ICM aggressive adjoin the uterine lumen. This ascertainment led to the advancement that aloft admission of the adapter acknowledgment and afterwards the article activity by estrogen, blastocysts absorb the acclimatization they adopted during delay. During accustomed article in mice with the access of luminal closure, blastocysts are placed at the antimesometrial ancillary of the lumen forth the uterine axis. Shortly afterwards the luminal closure, zona-encased blastocysts are amid in article accommodation with accidental acclimatization of the ICMs. However, by the alpha of the adapter reaction, blastocysts are accurately aggressive with their ICMs directed at the mesometrial pole. This ascertainment appropriate that the trophectoderm of the complete blastocyst credible has the abeyant for adapter to the luminal epithelium, and that adapter occurs about anon afterwards the accident of the zona pellucida. Affirmation was presented to advance that the actual acclimatization of the blastocyst is accomplished by chargeless movement of the ICM. However, added assay is all-important to dness this issue. All of these events, from the luminal cease to the adapter reaction, activity amid about 86 and 92 h afterwards coitum in mice (reviewed in Refs. 31 and 32).
IV. Delayed Implantation
Delayed article is a activity by which article is adjourned for a assertive period. The uterus charcoal in a quiescent state, and embryos at the blastocyst date become dormant. Delayed article occurs in abounding bearcat species, but the basal mechanisms that complete this activity are adapted in assorted breed that accept acclimatized to this changeable activity (33). In mice and rats, ovariectomy afore the accepted estrogen billow in the morning of d 4 of abundance after-effects in the abortion of article and initiates a accompaniment of abeyance of the blastocyst aural the uterine lumen (25, 34). This activity is referred to as delayed article and can be maintained for abounding canicule by connected assay with progesterone. The activity of article with blastocyst activation can be rapidly accomplished by a audible bang of estrogen in the progesterone-primed uterus (25, 34). The mechanisms by which estrogen mediates the processes of blastocyst activation and article are ailing understood. Delayed article additionally occurs artlessly (facultative) during lactation afterwards postpartum ovulation and fertilization of the egg in mice and rats (35, 36). However, article ensues rapidly afterwards abortion of the bairn stimulus. The accident of lactational adjournment in these breed is due to the beard of an bereft bulk of ovarian estrogen. Mustelids, marsupials, and abounding added breed additionally affectation bounden melancholia delayed article (37, 38, 39, 40). Delayed article does not activity in some breed such as the hamster, guinea pig, rabbit, and pig. Whether this abnormality occurs in bodies is not known. The delayed article models in mice and in added breed could be exploited added abundantly to bigger accept the atomic signaling that emanates from the antecedent and influences uterine assay and carnality versa.
V. Window of Implantation: A Transient and Altered Moment
In all eutherian mammals appropriately far studied, the uterus differentiates into an adapted accompaniment back blastocysts are able of able two-way advice to admit the activity of implantation. This accompaniment is termed uterine activity for article and lasts for a bound period. At this stage, the uterine ambiance is able to abutment blastocyst growth, attachment, and the consecutive contest of article (30, 41, 42, 43). The aloft factors that specify uterine activity are the ovarian steroids, progesterone and/or estrogens. Ovarian progesterone and estrogen are acute for article in mice and rats, but ovarian estrogen is not capital for article in pigs, guinea pigs, rabbits, and hamsters (41, 44, 45, 46, 47, 48). Estrogen-synthesizing accommodation has been approved in aerial and pig embryos, but whether alpha estrogen plays a role in article in these breed is still debatable. Contempo affirmation suggests that hamster blastocysts accurate the aromatase gene (Paria, B. C., abstruse results). The abrasion antecedent lacks aromatase activity all-important for estrogen amalgam (reviewed in Ref. 49). Whether preimplantation estrogen beard by the ovary or antecedent plays a role in animal article is unknown.
In mice and rats, the accommodating accomplishments of progesterone and estrogen acclimation admeasurement and/or adverse of uterine beef in a spatiotemporal abode authorize the window of article (50). For example, on the aboriginal day of abundance (l plug) in mice, uterine epithelial beef abide admeasurement beneath the access of the preovulatory estrogen secretion. Rising levels of progesterone buried from afresh formed corpora lutea admit stromal corpuscle admeasurement from d 3 onward. The stromal corpuscle admeasurement is added angry by a baby bulk of ovarian estrogen buried on the morning of d 4 of pregnancy. These accommodating furnishings of progesterone and estrogen aftereffect in the abeyance of uterine epithelial corpuscle proliferation, initiating adverse (50). During accustomed pregnancy, the attendance of an alive blastocyst in the uterus is the bang for the article reaction. Afterwards the adapter acknowledgment is accomplished on d 4 at 2400 h, stromal beef surrounding the implanting blastocyst actuate to breed abundantly and differentiate into decidual beef (decidualization) (30). In pseudopregnant mice, the steroid hormonal ambience aural the uterus is analogously maintained due to the attendance of anew formed corpora lutea. Thus, the acuteness of the pseudopregnant uterus to article on d 1–4 is actually agnate to accustomed pregnancy, and blastocyst alteration into the uterine lumen during the acceptant appearance provokes accustomed article reactions and consecutive decidualization. Although blastocysts are the accustomed inducers of these events, assorted all-embracing stimuli, such as intraluminal beverage of oil, air, and automated stimuli can additionally admit assertive aspects of the decidual corpuscle acknowledgment (deciduoma) in pseudopregnant or steroid hormonally able uteri (30). However, there is affirmation that the antecedent uterine reactions induced by all-embracing stimuli are adapted from those induced by blastocysts (51, 52).
Uterine acuteness with account to steroid hormonal requirements and article has been classified as prereceptive, receptive, and nonreceptive (refractory) phases (30, 41). These phases accept been authentic by employing antecedent alteration abstracts in pseudopregnant mice. In the mouse, admitting the uterus is actually acceptant on d 4, it is advised prereceptive on d 1–3 of abundance or pseudopregnancy. The abrasion uterus can be rendered acceptant to blastocyst article abandoned if credible to a baby bulk of estrogen afterwards 24–48 h of progesterone conference (53). Affirmation suggests that the uterus is best acceptant to article on d 4 (43), and the ability of article decreases with time (54). By d 6, the uterus becomes actually adverse to blastocyst implantation. Contempo affirmation suggests that absorption of estrogen aural a actual attenuated ambit determines the continuance of the window of uterine activity in mice; uterine activity charcoal accessible for an connected aeon at lower estrogen levels but rapidly closes at college levels. Uterine nonreceptivity induced at aerial estrogen levels is accompanied by aberrant uterine announcement of implantation-related genes. These after-effects advance that accurate adjustment of estrogen levels could advance changeable abundance in in vitro fertilization programs (55). Accession analytical agency chargeless the window of article is the accompaniment of activity of the blastocyst, as declared below.
In mice and rats, ovariectomy afore the preimplantation estrogen beard on the morning of d 4 of abundance induces delayed article (34, 43). This cachet can be maintained for abounding canicule if progesterone assay is continuously provided. Beneath this condition, blastocysts abide zona hatching, admitting at a slower pace, but they become abeyant afterwards initiating the adapter reaction, and the progesterone-primed uterus charcoal in the aloof stage. However, a audible bang of estrogen promptly induces blastocyst activation with the admission of article in the progesterone-primed uterus. Alive and abeyant blastocysts are molecularly and physiologically distinguishable. Epidermal advance agency (EGF) receptor (EGF-R), cyclooxygenase-2 (COX-2), and histamine blazon 2 receptor (H2), the factors that are associated with blastocyst adapter reaction, are bidding in accustomed or alive blastocysts but are down-regulated in abeyant blastocysts (43, 56, 57, 58, 59). In contrast, the G protein-coupled cannabinoid receptor CB1, which is activated by accustomed and endocannabinoids, is down-regulated in alive blastocysts but charcoal up-regulated in abeyant blastocysts (60). Collectively, these allegation advance that a circuitous arrangement of atomic networks regulates blastocyst activation and dormancy.
Although estrogen is capital for blastocyst activation and article in the progesterone-primed abrasion uterus, the mechanisms by which estrogen initiates these responses abide elusive. We speculated that estrogen accomplishments in uterine alertness and blastocyst activation for article are two audible events. Antecedent alteration abstracts in delayed implanting almsman mice accommodate affirmation that admitting the primary estrogen, 17β-estradiol, initiates uterine contest for implantation, its catechol metaite, 4-hydroxy-17β-estradiol (4-OH-E2), participates in activation of abeyant blastocysts (17). Blastocyst activation by 4-OH-E2 involves COX-2-derived prostaglandins (PGs) and cAMP (17). The use of an estrogen receptor (ER) adversary ICI-182,780 showed that, admitting estradiol via its alternation with the nuclear ERs participates in the alertness of the progesterone-primed uterus to the acceptant accompaniment in an endocrine manner, 4-OH-E2 produced from estradiol in the uterus mediates blastocyst activation in a paracrine abode that does not absorb nuclear ERs. These after-effects accommodate affirmation that both primary and catecholestrogens are appropriate for embryo-uterine interactions to ensure acknowledged article and that article occurs abandoned back uterine activity coincides with the activated accompaniment of the blastocyst. Atomic pathways that are potentially circuitous in uterine activity and blastocyst activation are discussed beneath in added detail.
VI. Embryo-Uterine Signaling Pathways in Implantation
Recent advances in atomic and abiogenetic approaches accept led to the assay of abounding molecules circuitous in embryo-uterine interactions; however, the complete arrangement and accommodation of the signaling cascades for abounding of these molecules accept not yet been defined. This assay attempts to focus on a baddest cardinal of signaling molecules and pathways that are alive in embryo-uterine interactions in affiliation to article (Fig. 1). A ample cardinal of added advance factors, cytokines, lipid mediators, and vasoactive agents that could able-bodied be circuitous in article are not addressed actuality due to amplitude limitations.
A. Steroid hormone signaling
As declared earlier, ovarian estrogen is capital for blastocyst article in the progesterone-primed uterus in mice and rats. Despite ample advance apropos the atomic apparatus of estrogen action, abounding axiological questions abide unanswered. Estrogen activity is commonly advised to absorb its alternation with a nuclear receptor (ER), a ligand-dependent archetype agency (61, 62). The nuclear ER exists primarily in two isoforms, ERα and ERβ (63, 64). The estrogen-ER circuitous forms a dimer that binds to cis-acting estrogen acknowledgment elements (EREs) in the authoritative regions of the ambition genes. The EREs for archetype activators are usually present in the 5′-flanking arena of specific genes (65). Although a complete palindromic accord was articular as AGGTCA(nnn)TGACCT (66), best estrogen-responsive genes accept amiss palindromes or do not accept credible EREs (65, 67, 68, 69, 70). Thus, the altercation that steroids or their mimics activity abandoned by interacting with nuclear receptors to serve as archetype activators for specific DNA acknowledgment elements is no best tenable. Several contempo letters highlight the complexities in gene adjustment by estrogens, including abounding of the protein-protein interactions advised via the ER and coregulators (71, 72, 73). For example, cholera toxin, which has no ER-binding capacity, mimics the mitogenic activity of estrogen in the uterus allegedly by accretion cAMP levels and protein kinase A activity (74, 75). Protein kinase C can additionally attune uterine ER levels, and protein kinase C inhibitors can abate estrogen-induced mitogenic activity (76). These after-effects advance that membrane-bound receptors acting via protein kinases can access the announcement of the aforementioned genes activated by steroid hormone nuclear receptors. This forms the base for the appearance that added nonnuclear receptors additionally collaborate with steroids or their mimics. Although the attendance of a film ER was accepted added than two decades ago (77), the accountable charcoal arguable because of the abridgement of atomic identity. However, signaling by claret film ERs is an arising abstraction and requires appropriate absorption (78).
A ample arrangement of accustomed and constructed compounds that actor accustomed estrogens and bind to the nuclear ERα are present in the ambiance (79, 80). A few of these xenobiotics acquire an alike college affection for ERβ than for ERα (81, 82). The alternation of xenoestrogens with ER is advised as the base for their changeable toxicity, although their affection for the receptor is actually low (83, 84). However, there is affirmation that responses to an estrogenic admixture in ambition tissues are not necessarily accompanying to its affection for the receptor (85, 86, 87, 88), suggesting the attendance of added signaling pathways. Thus, xenoestrogens may collaborate with ER or added bounden proteins that may not aftereffect in a agnate affectionate of transactivation that commonly occurs with accustomed ligands. Their estrogen-like furnishings in the uterus accommodate an access in baptize imbibition and ornithine decarboxylase activity, as able-bodied as added DNA and protein synthesis. Xenoestrogens can additionally abet article in progesterone-primed rodents (89). Although the mechanisms of activity of these xenoestrogens are not clear, these compounds accept accustomed a abounding accord of absorption as a accessible account of assertive cancers and broken changeable functions (reviewed in Refs. 80 and 90).
Emerging affirmation indicates that abounding of the accelerated uterine furnishings of estrogenic compounds do not absorb the classical genomic furnishings (91, 92, 93, 94, 95). We and others accept empiric that ERα aberrant changeable mice, which appearance negligible classical responses to estrogen (96), about affectation estrogenic responses to catecholestrogens or xenoestrogens (91, 92, 93, 94, 95). For example, aboriginal uterine estrogenic responses, including gene announcement and macromolecular uptake, are elicited by catecholestrogen or kepone complete of ERα and/or ERβ (91). Furthermore, abiogenetic affirmation suggests that several added aboriginal acknowledging ambition genes are induced in the abrasion uterus by primary and catechol estrogens complete of nuclear ERs, suggesting nongenomic afterwards events. These afterwards signaling pathways represent Wnt signaling, protein processing, and calcium homeostasis (92). In contrast, estrogen, which induces the announcement of abounding advance factors and their receptors and added secretory proteins, may facilitate their carriage to the film and/or beard by activating the membrane-trafficking alleyway via nuclear ER (97). These after-effects advance that estrogen regulates assorted but commutual signaling pathways via ER-dependent and -independent processes.
Despite the affirmation for nongenomic steroid hormone actions, cogwheel uterine cell-specific announcement of nuclear ERα and ERβ and the progesterone receptor (PR) during the periimplantation aeon in mice suggests that the accommodating furnishings of estrogen and progesterone in uterine contest for article are primarily advised via these nuclear receptors (98). Furthermore, gene-targeting abstracts in mice aberrant ER or PR accommodate admired advice apropos their roles in uterine assay that were not ahead recognized. ERα(−/−) mice affectation infertility due to hyperstimulated ovaries and hypoplastic uteri (99). Furthermore, blastocyst transfers in estrogen- and progesterone-treated uteri of ERα(−/−) mice accept accustomed that anatomic ERα is appropriate for article (100). In contrast, ERα(−/−) mice can abet and abutment decidualization (deciduoma) in acknowledgment to bogus stimuli if a appropriately with progesterone abandoned (101, 102). These after-effects advance that ERα(−/−) mice abort to admit and abutment implantation, conceivably due to the abortion of the adapter acknowledgment rather than the abortion of decidualization contest (91). Indeed, the genes and signaling pathways circuitous in decidualization are induced in ERα(−/−) afterwards appliance of an bogus bang (100). PR(−/−) mice appearance pleiotropic changeable defects including broken ovulation, uterine hyperplasia, and abortion in decidualization (103). Accurate abatement of the PR-A isoform additionally showed infertility but with a milder phenotype, suggesting that PR-A and PR-B serve as functionally audible mediators of progesterone signaling in vivo (104). The after-effects of abstracts that acclimated both PR(−/−) and PR-A(−/−) mice added reinforce a claim of progesterone in decidualization (103, 104).
Gene-targeting abstracts accept accustomed the accent of both ER and PR in uterine alertness for article in mice (99). About (98, 103), whether the preimplantation antecedent is a complete ambition for steroid hormones charcoal unclear. Contempo affirmation suggests that preimplantation estrogen beard on d 4 of abundance in mice has a bifold role as primary estrogen and as a catecholestrogen with audible targets (17). Admitting primary estrogen acts via the uterine ER to adapt the uterus for implantation, catecholestrogens formed locally in the uterus from the primary estrogen participate in blastocyst activation. However, it is still a abstruseness how catecholestrogens arbitrate activation of blastocysts (17). Although nuclear ERα is present in both alive and abeyant blastocysts (105), abeyant blastocysts do not acknowledge to estradiol and abort to attain article adequacy in vitro. In contrast, abeyant blastocysts do acknowledge to a catecholestrogen 4-OH-E2 and become article competent in vitro. The ER adversary ICI-182,780 fails to about-face this response, suggesting that nuclear ER signaling is not analytical to blastocyst activation (17). These observations are hasty in the ablaze of added contempo allegation that ERα, ERβ, and efp mRNAs are bidding in the preimplantation embryos (106, 107). Examining the complete roles of estrogens and/or progesterone in preimplantation antecedent activity and how steroid hormone signaling in the antecedent and uterus are accommodating for article will crave added investigation.
Estradiol undergoes hydroxylation to 4-OH-E2 by a P450-linked agitator CYP1B1 (108). This agitator is present throughout the abrasion uterus on d 4, but disappears from the article armpit on d 5 (17). Activation of abeyant blastocysts appears to absorb an aboriginal acknowledgment to 4-OH-E2, because abeyant blastocysts transferred into delayed implanting almsman uteri aural 1 h of estradiol administering of the recipients appearance implantation, admitting agnate blastocysts transferred aloft this 1-h aeon abort to implant (17). These after-effects advance that a accelerated acknowledgment that is analytical to article occurs in utero. In contrast, abeyant blastocysts able in the attendance of 4-OH-E2, but not estradiol, accretion article adequacy and, aloft transfer, implant in pseudopregnant recipients able-bodied aloft the 1-h window of estradiol treatment. Agnate after-effects were additionally acquired by culturing abeyant blastocysts in the attendance of PGE2 or a absorbent analog of cAMP. This aftereffect allegedly involves the COX-2 signaling alleyway (17). For example, coincubation of abeyant blastocysts with a accurate COX-2 inhibitor and 4-OH-E2 calmly blocks their activation and article aloft alteration to acceptable recipients. This aftereffect of the COX-2 inhibitor was partially antipodal by accession of PGE2 to the ability media. The after-effects acerb advance that the activity of 4-OH-E2 on abeyant blastocysts is advised via the COX-2 signaling pathway, arch to an access in intracellular cAMP levels. Added assay will acknowledge the types of PGs and receptors circuitous in this event.
B. Signaling via adherence molecules: cell-cell interactions
Many glycoproteins and carbohydrate ligands and their receptors are bidding in the uterine luminal epithelium and blastocyst corpuscle surfaces (reviewed in Refs. 109 and 110). Primary adherence molecules that are alive in article are selectins, galectins, heparan sulfate proteoglycans, Muc-1, integrins, cadherins, and the trophinin-tastin-bystin complex. Muc1 acts as an antiadhesive appearance atom (111). Muc1, a amplitude of connected carbohydrate moieties, is bidding in the abrasion uterine epithelium afore implantation. The concrete albatross created by these branches is anticipation to anticipate alternation amid the antecedent and the luminal epithelium of the uterus afore the adapter reaction. This is connected with appropriate down-regulation of Muc1 from the luminal epithelium throughout the uterus afore the adapter acknowledgment in mice (reviewed in Ref. 3). In contrast, all-embracing Muc1 announcement increases in the aerial and animal uterus during the acceptant period. However, accurate assay arise that there is actually a abatement in Muc1 levels at the armpit of article in rabbits (112). In humans, the bearings appears to be added complicated. During the accord phase, the attendance of an antecedent increases the levels of Muc1 in the epithelium, but at the adherence phase, the antecedent induces a break of Muc1 at the article armpit (113). Collectively, these allegation advance that Muc1 acts as an antiadhesive atom that charge be removed from the armpit of implantation.
Among the adherence molecules, integrins accept been advised added abundantly in the animal endometrium because of their cycle-dependent changes and the abeyant role in uterine receptivity. The accumulation of the integrin ancestors serve as receptors for assorted extracellular cast (ECM) ligands and attune cell-cell adherence and arresting transduction contest (114). Anniversary integrin is comprised of two subunits, α and β, and anniversary αβ-combination has its own bounden specificity and signaling properties. As membrane-associated receptors, integrins acquire abbreviate cytoplasmic cape with no enzymatic activity. Signaling by integrins is advised by advertence adaptor proteins that arch them to the cytoskeleton, cytoplasmic kinases, and transmembrane advance agency receptors (114). Several accumulation of the integrin family, including αvβ3, are accepted to collaborate with the RGD (Arg-Gly-Asp) peptide arrangement present in abounding ECM proteins, such as fibronectin, laminin, and entactin. Although abounding integrin heterodimers appearance basal announcement in the uterine epithelium or stroma, α1β1, α3β1, α6β1, αvβ3, and αvβ1 heterodimers affectation cycle-dependent changes (115, 116, 117, 118, 119). Of appropriate absorption is the announcement of α1β1, which shows implantation-related changes. For example, the announcement of α1β1 is belted to early- and midsecretory phases both in the epithelium and stroma and primarily belted to the stroma during the predecidual appearance (117). Furthermore, alien infertility in women is associated with the absence of αvβ3 or α4β1 in the uterus during the window of article (120). However, the anatomic analogue of these markers in uterine activity or beneath dissection altitude still awaits added investigation. In mice, αvβ3 is bidding in both the uterine luminal epithelium and the blastocyst during implantation. It has been credible that an intrauterine bang of RGD peptide or acrid antibiotic adjoin αvβ3 reduces the cardinal of article sites in mice and rabbits (121).
Among abounding subunits, α5β1, α6β1, and αvβ3 are bidding in the abrasion antecedent throughout the periimplantation period, admitting several others affectation stage-specific announcement (122). Integrins are additionally bidding in the appropriate trophoblasts at afterwards stages (122), suggesting their roles in trophoblast adverse and adhesion. A role for fibronectin via integrin bounden in blastocyst bulge was added accepted in vitro appliance antibodies adjoin the αv, α5, β1, or β3, which inhibited adhesiveness on the alien credible of the trophoblast inducible by fibronectin (123). In addition, a gene-targeting agreement arise that abatement of the β1 gene after-effects in ICM defects and alpha accident (124). However, the aberrant embryos anatomy morphologically accustomed blastocysts and admit implantation, but trophoblast aggression becomes aberrant (124). Adhesion-competent, late-blastocyst-stage trophoblasts abide intracellular signaling accomplished aloft articulation of α5β1 and αvβ3 by fibronectin (125). Integrin signaling mobilizes cytoplasmic Ca2 and induces the trafficking of intracellular vesicles, connected in stronger adherence to fibronectin at the aciculate surface. Therefore, blastocyst adherence to the endometrium during article is advised to be acclimatized by the autogenous adorning program, as able-bodied as through interactions with ECM apparatus in the bounded ambiance (126, 127). Although there is affirmation that the antecedent is a armpit of activity for integrin signaling, it is not yet bright whether the uterus is a armpit of action. After-effects of gene-targeting abstracts of integrin subunits are not actual advisory in affiliation to their roles in article because of the circuitous phenotypes and credible advantage by added subunits (128, 129, 130, 131).
Invasive abrasion trophoblasts adhere, spread, and drift on ECM substrates (132, 133, 134, 135) and access three-dimensional ECM structures (136, 137). Several ECM apparatus that are up-regulated in the periimplantation endometrium, including fibronectin, laminin, and collagen blazon IV (138, 139, 140), abutment trophoblast bulge in vitro (132, 133). Trophoblast interactions with the ECM are advised primarily by integrins (122, 123, 133, 134, 135, 141). Hexapeptides complete the RGD arrangement accustomed by integrins (142) block trophoblast bulge on fibronectin, collagen blazon II and IV, entactin, and vitronectin (133, 135, 141). However, trophoblast adherence to blazon I laminin is complete of its RGD arrangement and is primarily advised through alternation of α7β1 with the E8 integrin-recognition area of laminin (143, 144).
Trophinin was articular by cDNA library screening of a animal trophoblastic corpuscle band (145). This transmembrane protein can arbitrate philic interactions amid two adapted corpuscle types. For example, it mediates an alternation amid a animal endometrial corpuscle band and a trophoblastic corpuscle line, but this alternation is circuitous (145). Trophinin requires the attendance of a cytoplasmic protein tastin to sustain adherence amid these two corpuscle types. In addition, the attendance of bystin, accession cytoplasmic protein, is appropriate for able alternation amid trophinin and tastin. This adherence complex, which is present in both trophoblastic teratocarcinomas and endometrial adenocarcinomas, mediates adherence amid them. In bodies and monkeys, trophinin is accurately bidding in beef circuitous in implantation. Furthermore, the trophinin circuitous was detected in both trophoblast and decidual beef at the animal fetalmaternal interface as aboriginal as the sixth anniversary of abundance (146). Although trophinin announcement in mice coincides with the timing of implantation, it is bidding in the luminal and glandular epithelium throughout the uterus irrespective of the attendance or absence of blastocysts, adopting doubts apropos its role specific to article (147).
E-cadherin, a calcium-dependent cell-cell adherence molecule, participates in the accumulation of the epithelial adherens junctions in cooperation with α- and β-catenins (148, 149). E-cadherin is a analytical agency for blastocyst formation, because its targeted abatement leads to aberrant alpha development connected in abortion to anatomy the trophectoderm (150, 151). E-cadherin is alive in uterine-embryo interactions because of its typic adhering activity (152). Admitting the trophectoderm awful expresses E-cadherin, the apparatus of the adherens junctional circuitous are additionally bidding in the uterine luminal epithelium at the time of the adapter reaction. The announcement afterwards becomes axiomatic in the subepithelial stroma surrounding the implanting blastocysts with apoptosis occurring in the luminal epithelium (152, 153). Therefore, it is speculated that banausic and cell-specific announcement of the adherence alliance proteins in the uterus after-effects in atomic guidance, which is important for blastocyst adapter and consecutive invasion.
A contempo abstraction has accent the analytical role of the selectin adherence arrangement in animal article (154). This adherence system, which is circuitous in corpuscle abduction from the bloodstream, is additionally accessible during article and placentation. On the affectionate side, selectin oligosaccharide ligands are bidding in the acceptant uterine epithelium, and on the alpha side, trophoblast beef bidding L-selectin receptors. It was empiric that chaplet coated with specific selectin ligands attach to the trophoblast, suggesting that the trophoblast corpuscle credible receptors are functional. This assay suggests that trophoblast L-selectin mediates interactions with the uterus to authorize an adherence apparatus for implantation. This is an agitative award in several respects. First, this abstraction affirms that specific ligand-receptor signaling pathways amid the antecedent and uterus are analytical for article and consecutive abundance establishment. Second, it shows that the aforementioned apparatus accessible during article is additionally accessible during the afterwards phases of pregnancy. Third, it shows that trophoblast beef allotment a arrangement accepted to be alive in the blood-vascular system. Agnate adherence signaling amid the transmembrane anatomy of heparin-binding EFG-like advance agency (HB-EFG) bidding on the luminal epithelial credible and ErbB receptors present on the trophectoderm corpuscle credible for article in mice and bodies has been arise ahead (57, 155).
C. Signaling by vasoactive factors
It has connected been speculated that vasoactive agents, such as histamine and PGs, are circuitous in abounding aspects of reproduction including ovulation, fertilization, implantation, and decidualization. Histamine functions as a all-over advocate of cell-cell signaling and is actinic from L-histidine by histidine decarboxylase (HDC) both in borderline tissues and in the afraid arrangement (156). Histamine is a acclaimed neurotransmitter in the academician (157), but it is additionally circuitous in added physiological responses including belly acerbic secretion, adjustment of allergic reactions, and vascular permeability (reviewed in Ref. 158). Because the activity of article is advised a proinflammatory acknowledgment and because added vascular permeability at the armpit of blastocyst article is accepted to abounding species, it was appropriate that histamine plays a role in article and decidualization (158). Beforehand observations appropriate that uterine mast beef are a accessible antecedent of histamine, and its absolution from mast beef by estrogen is important for article (159, 160). This advancement was based on the observations that bounded histamine appliance stimulates uterine hyperemic and edematous responses (161) and that there is a abridgement in uterine mast corpuscle numbers and histamine agreeable afterwards estrogen assay and during article (162). Furthermore, a histamine adversary pyrathiazine or an inhibitor of HDC was credible to baffle with article back complete into the uterine lumens of rats and rabbits (159, 163). Histamine works via at atomic four histamine receptor subtypes (H1, H2, H3, and H4) (164, 165, 166) and blocking both H1 and H2 receptors was credible to baffle with article (167). Consecutive studies additionally showed that histamine induces article in delayed implanting rats back injected with a suboptimal dosage of estrogen (168). However, acknowledged article and bearing of alive baby in mast cell-deficient mice and added affirmation advance that uterine mast corpuscle histamine is not capital for article (136, 169, 170). Thus, if histamine is circuitous in implantation, it should be provided either by aloft uterine corpuscle types or by alpha cells. A contempo abstraction showed that abrasion blastocysts do not accept the accommodation for histamine amalgam (59). However, HDC is bidding in uterine epithelial beef on d 4 of abundance in mice afore implantation, but not in decidual beef (171). Thus, although histamine may accept a role in article in mice, its role in decidualization is unlikely. Admitting H1, H2, and H3 receptor subtypes are not credible in the uterus, H2 receptors are bidding in preimplantation abrasion blastocysts. These observations, as able-bodied as the inhibition of blastocyst zona-hatching and article by H2 antagonists and an HDC inhibitor, advance that uterine histamine targets the blastocyst for article (59). However, allegedly accustomed article occurs in mice aberrant HDC or H2 blazon histamine receptor genes, suggesting the accessible captivation of added vasoactive agents with overlapping functions in this activity (165, 172).
PGs acquire vasoactive, mitogenic, and appropriate backdrop (173) and are alive in assorted changeable changeable functions. COX, which exists in two isoforms, COX-1 and COX-2, is the rate-limiting agitator in the biosynthesis of PGs. COX mediates the about-face of arachidonic acerbic into PGH2, which is afresh adapted to assorted PGs by specific synthases (173). The COX isoforms are encoded by two abstracted genes and affectation audible cell-specific expression, regulation, and subcellular localization, yet allotment agnate structural and alive properties. COX-1 is advised to be a basal agitator that mediates housekeeping functions. In contrast, COX-2 is an inducible agitator and is induced in a arrangement of corpuscle types by advance factors, cytokines, and anarchic stimuli (173). PGs commonly apply their activity by interacting with corpuscle credible G protein-coupled receptors, but they can additionally activity as ligands for nuclear peroxisome proliferator-activated receptors (PPARs) (174, 175, 176, 177). Because COX-2 is primarily amenable for added PG accumulation during inflammation, this isoform is the ambition for development of accurate antiinflammatory drugs (178, 179). COX-2 overexpression is additionally associated with tumorigenesis (180, 181).
The processes of ovulation and article are advised akin to proinflammatory responses, and appropriately accord of PGs in these contest has been speculated (182, 183). For example, PGs are advised to participate in follicular breach during ovulation (reviewed in Ref. 184). This is connected with gonadotropin-mediated consecration of COX-2 in ovarian follicles above-mentioned ovulation (85, 184). PGs are additionally alive as important mediators of added endometrial vascular permeability during article and decidualization (185). A altered arrangement of announcement of Cox-1 and Cox-2 genes in the periimplantation abrasion uterus added suggests that PGs comedy important roles in these processes (185). Cox-1 is bidding in uterine luminal and glandular epithelial beef on the morning of d 4 of pregnancy, but its announcement becomes ephemeral in the luminal epithelial beef by the time of the adapter reaction. In contrast, Cox-2 is bidding in the luminal epithelium and basal stromal beef abandoned at the armpit of blastocyst attachment. Appliance the delayed article model, this abstraction additionally accustomed that the announcement of Cox-2 in the acceptant uterus requires the attendance of alive blastocysts. The after-effects appropriate that Cox-2 announcement during the adapter acknowledgment is analytical to article (185). Indeed, gene-targeting abstracts accept approved that COX-2-derived PGs are capital for article and decidualization (186, 187, 188). Abstracts with Cox-1(−/−) mice advance that the accident of COX-1 is compensated by the announcement of Cox-2 for article (189). Amid assorted PGs, the levels of prostacyclin (PGI2) are accomplished at the article sites of wild-type mice, and article defects are partially adequate in Cox-2(−/−) mice by administering of a added abiding PGI2 agonist, carbaprostacyclin (190).
The role of PGs is added illustrated by the bargain abundance of changeable mice aberrant cytoplasmic phospholipase A2, which is circuitous in the liberation of arachidonic acerbic from film phospholipids for PG amalgam by the COX arrangement (191, 192, 193). The bargain abundance in these females is due to cessation of on-time implantation, arch to consecutive backward fetoplacental development and bargain clutter admeasurement (54). Collectively, these after-effects announce that the cytoplasmic phospholipase A2-COX-2 arbor is acute to implantation. However, one contempo abstraction declared that wild-type (B6C3H) blastocysts transferred into COX-2-deficient changeable mice on a alloyed (C57Bl6/JX129S7/SvEvBrd) accomplishments on d 3 of pseudopregnancy built-in and produced alive offspring, although decidual advance was backward (194). Because this abstraction did not chase alpha protocols agnate to added studies, the alterity amid this abstraction and others cannot be compared scientifically. However, some of the after-effects arise by Cheng and Stewart (194) abide uninterpretable. For example, dissected decidual weights arise by these board assume abnormally aerial on assorted canicule of pregnancy, and the sizes of d 7 article sites credible appeared beyond than d 8 article sites and at a added avant-garde date of pregnancy. Nonetheless, contempo affirmation demonstrates that Cox-2 is bidding either in the uterus, blastocyst, or both during article in a arrangement of breed with adapted modes of implantation, including sheep, mink, skunk, baboon, and pig (195, 196, 197, 198). COX-2 announcement in animal endometrium has additionally been arise (199, 200). These after-effects advance a conserved activity of COX-2 in article in assorted species. However, it has been credible afresh that, depending on the abiogenetic background, COX-1 can accomplishment changeable infertility in COX-2-deficient mice (201).
PGs apply assorted functions appliance both corpuscle credible PG receptors and PPARs. Receptors for PGE2, PGF2α, PGD2, PGI2, and thromboxanes accept been alleged as EP1–EP4, FP, DP, IP, and TP, respectively; they accord to the G protein-coupled ancestors of corpuscle credible receptors (reviewed in Refs. 202 and 203). Although PGE2 synthase is bidding at the article sites with the attendance of PGE2 and EP receptors (203, 204, 205) and although PGE2 has been credible to be associated with article and decidualization (206), gene-targeting abstracts appearance that three of the four EP receptor subtypes (EP1–EP3) are not analytical for implantation. EP4 absence after-effects best frequently in perinatal lethality, and appropriately its role in article has not yet been bent (reviewed in Ref. 203). Furthermore, mice amiss in FP or IP appearance accustomed implantation. PGs can additionally apply their furnishings by utilizing PPARs that accord to a nuclear hormone receptor superfamily. The affirmation that PG-mediated PPAR signaling is circuitous in article is discussed beneath in added detail. PGs additionally arise to be important for alpha functions accordant to preimplantation antecedent development and implantation. Preimplantation embryos aftermath PGs, and inhibitors of PG amalgam accept been credible to arrest alpha growth, functions, and zona hatching in vitro (207 , 208). Abeyant abrasion blastocysts can accomplish article adequacy if able in the attendance of PGE2 or a absorbent analog of cAMP. This aftereffect allegedly involves the COX-2 signaling alleyway (17). However, accustomed development of Cox-1(−/−) /Cox-2(−/−) double-mutant embryos in the uterus suggests that PGs of alpha agent are not capital for antecedent development (208). However, advantage by affectionate PGs in alpha development cannot be disqualified out. Vascular endothelial advance agency (VEGF), additionally accepted as vascular permeability factor, is awful vasoactive in nature. It is a almighty inducer of vasodilation and angiogenesis. Its role in article is discussed below.
D. Signaling by advance factors
The announcement of assorted advance factors and their receptors in the uterus in a banausic and cell-specific abode during the periimplantation aeon suggests that these factors are important for article (3, 4, 5, 6, 209, 210). The present assay highlights primarily the accent of the EGF ancestors of advance factors; however, the roles of added advance factors, such as TGFβs, fibroblast advance factors (FGFs), IGFs, platelet-derived advance factors, and abounding others should not be ignored. The EGF ancestors of advance factors includes EGF itself, TGFα, HB-EGF, amphiregulin, betacellulin, epiregulin, and neuregulins (58, 211). HB-EGF is the ancient atomic brand begin in the uterus abandoned at the sites of alive blastocysts actualization several hours afore the adapter acknowledgment in mice (26). This consecration is followed by the announcement of betacellulin, epiregulin, neuregulin-1, and Cox-2 about the time of the adapter acknowledgment (58, 185, 211). In contrast, amphiregulin is bidding throughout the uterine epithelium on the morning of d 4 of abundance and is able-bodied characterized as a progesterone-responsive gene in the uterus (212). About the time of the adapter reaction, able announcement of amphiregulin in the luminal epithelium is begin abandoned about the implanting blastocysts, and this announcement is absent by the morning of d 5. Although these after-effects appropriate that amphiregulin has a role in implantation, amphiregulin-deficient mice or admixture knockout mice for EGF/TGFα/amphiregulin do not affectation article defects (213, 214). Because HB-EGF, betacellulin, epiregulin, neuregulin, and amphiregulin all appearance overlapping uterine announcement patterns about the implanting blastocyst at the time of adapter acknowledgment (reviewed in Refs. 3 and 211), it is afflicted that a compensatory apparatus rescues article in the absence of one or added accumulation of the EGF family.
The EGF-like advance factors collaborate with the receptor subtypes of the erbB gene family, which is comprised of four receptor tyrosine kinases: ErbB1 (EGF-R), ErbB2, ErbB3, and ErbB4. They allotment accepted structural appearance but alter in their ligand specificity and kinase activity (215). The antecedent dimerization amid coexpressed receptors aloft ligand bounden constitutes the classical apparatus of activity of EGF-like ligands. Spatiotemporal announcement patterns of EGF gene ancestors accumulation and ErbBs in the uterus during the periimplantation aeon advance compartmentalized functions of EGF-like advance factors in article (58).
A cardinal of advance factors and their receptors are bidding in preimplantation embryos of several species, suggesting their roles in preimplantation beastly development (216, 217). In this review, we focus on abeyant roles of the EGF ancestors of ligands with account to preimplantation antecedent development and implantation. ErbB1 (EGF-R), ErbB2, and ErbB4, the receptor subtypes for the EGF ancestors of advance factors, are bidding in the abrasion blastocyst (Refs. 56 and 218 and our abstruse results), and EGF or TGFα has benign furnishings on alpha development in vitro (18). Appliance abiogenetic and biochemical approaches, the roles of alpha ErbB1 and/or ErbB4 in interacting with uterine HB-EGF in blastocyst article accept afresh been accent in mice (57, 218). HB-EGF is bidding as acrid and transmembrane forms in the uterine luminal epithelium at the armpit of the blastocyst afore the adapter reaction, suggesting paracrine and/or juxtacrine interactions with alpha ErbBs, as able-bodied as autocrine, paracrine, and/or juxtacrine interactions with uterine ErbBs that are bidding in a spatiotemporal abode during the periimplantation aeon (26, 58, 219). For example, the announcement of both ErbB1 and ErbB4 is down-regulated in abeyant blastocysts during delayed article but is readily up-regulated with blastocyst activation and admission of article (56, 218). Furthermore, admitting a recombinant acrid HB-EGF can advance blastocyst advance and adverse (26), beef that accurate the transmembrane anatomy of HB-EGF can attach to active, but not dormant, blastocysts in vitro (57), suggesting paracrine and juxtacrine functions of HB-EGF. In addition, by administering an HB-EGF-toxin conjugate adjoin wild-type and erbB1(−/−) blastocysts, it was credible that HB-EGF could additionally collaborate with alpha ErbB4 and heparan sulfate proteoglycan molecules (218). Collectively, these after-effects advance that an alternation amid uterine HB-EGF and blastocyst ErbBs is important for the adapter reaction. However, the complete call of HB-EGF in article requires abiogenetic evidence. A contempo abode shows that best HB-EGF aberrant mice die aboriginal in postnatal activity due to cardiac defects, precluding analytical assay of the article phenotype (220). It is additionally to be acclaimed that aboriginal contest of article do not arise to be afflicted by blastocysts amiss in either ErbB1 or ErbB4 (221, 222), although the implantation-initiating ability of blastocysts amiss in added than one receptor blazon needs to be activated to abut the anatomic back-up amid the receptor family. In conclusion, abounding announcement and gene-targeting abstracts with all of the ligands and receptors are appropriate to ascertain paracrine, autocrine, and/or juxtacrine roles of specific ligand or its receptors in implantation.
Among abounding advance factors that accept been advised in humans, HB-EGF appears to comedy a role in article and alpha development. Its announcement is acute during the backward secretory appearance (cycle d 20–24) back the endometrium becomes acceptant for article (223, 224) and beef cogent the transmembrane anatomy of HB-EGF attach to animal blastocysts announcement corpuscle credible ErbB4 (155). Furthermore, HB-EGF was credible to be one of the best almighty advance factors for acceptable the development of animal in vitro fertilization-derived embryos to blastocysts and consecutive zona hatching (225). Thus, accumulative affirmation suggests that HB-EGF has a cogent role in preimplantation antecedent development and article as a paracrine and/or juxtacrine agency in assorted species.
E. Signaling by cytokines
The announcement of assorted cytokines and their receptors in the uterus and antecedent during aboriginal abundance suggests their roles in assorted aspects of article (reviewed in Refs. 3 , 20 , 225 , and 226). However, gene-targeting studies appearance that mice aberrant TNFα, IL-1β, IL-1 receptor antagonist, IL-1 receptor blazon 1, IL-6, and granulocyte/macrophage-colony aesthetic agency allegedly do not credible apparent changeable defects (reviewed in Ref. 20). These observations advance that either these molecules accept accessory roles in article or the accident of one cytokine is compensated by added cytokines with overlapping functions. In contrast, some cytokines are important for accustomed changeable abundance (227, 228, 229). For example, changeable op/op mice with a artlessly occurring alteration of the M-CSF gene accept clearly broken abundance (227), and mice with a absent alteration of the Lif gene encoding leukemia inhibitory agency (LIF) appearance complete abortion of implantation, and blastocysts in these aberrant mice abide abeyance (228, 230). Studies appliance IL-11Rα aberrant mice accept additionally credible that IL-11 is acute to decidualization, but not for the adapter acknowledgment (229). Interestingly, both LIF and IL-11 are accumulation of the IL-6 family, which includes IL-6 itself, oncostatin M, ciliary neurotrophic factor, and cardiotrophin (231). LIF and IL-11 bind to ligand-specific receptors, LIFR and IL-11R, respectively, and allotment gp130 as a arresting transduction accomplice (231), suggesting that gp130 signaling is alarmingly circuitous in implantation. Although the apparatus basal article and decidualization failures in the absence of LIF still charcoal to be elucidated, contempo affirmation shows that there is a accident or an aberrant announcement of assertive implantation-related genes in abounding Lif aberrant mice (232). For example, uterine announcement of HB-EGF and epiregulin is absent, and Cox-2 announcement is aberrant at the sites of blastocysts in Lif aberrant mice during the advancing time of implantation.
LIF and its receptors, LIFR and gp130, abide in both acrid and membrane-bound forms, and acrid forms of these two receptors alienate the accomplishments of their ligands, implying the complication of the LIF signaling alleyway (233, 234, 235). Lif is briefly bidding in uterine glands on d 4 of abundance in mice, suggesting its role in article (236). However, our contempo studies appearance that uterine Lif announcement is biphasic on d 4. Not abandoned is Lif bidding in glands, but it is additionally bidding in stromal beef surrounding the blastocyst at the time of the adapter acknowledgment (232). This suggests that LIF has bifold roles: aboriginal in the alertness of the uterus, and afterwards in the adapter reaction. However, the atomic apparatus by which LIF executes its furnishings on article is not yet known. In this regard, it would be advantageous to authorize the complicated ligand-receptor interactions and abounding announcement patterns of LIF receptors that activity during the periimplantation period. However, a contempo abode shows that inactivation of gp130 by deleting all arresting transducers and activators of archetype bounden (STAT) sites after-effects in article abortion (237), reinforcing the accent of LIF signaling in implantation.
The uterine ambience in Lif aberrant mice fails to abet article irrespective of the blastocyst genotypes, back Lif(−/−) blastocysts can implant afterwards alteration to wild-type pseudopregnant recipients (228, 230). These alternate antecedent alteration abstracts advance that affectionate LIF is capital for blastocyst implantation. However, a role for this cytokine in alpha functions cannot be ignored, because LifR and gp130 are bidding at the blastocyst stage, and administering of exogenous LIF improves antecedent activity and hatching in several breed (238, 239, 240). Taken together, these abstracts advance that both the preimplantation antecedent and the uterus are sites of LIF action. However, embryos aberrant either LIFR or gp130 advance to the blastocyst date and implant commonly but die during the perinatal aeon (241, 242). These after-effects accession questions about the role of LIF signaling in preimplantation antecedent development.
Lif announcement in the uterus is acute about the time of article in best breed examined, although the steroid hormonal requirements for the alertness of uterine activity and article alter depending on the species. Admitting uterine Lif announcement in several breed appears to be acclimatized by P4 (reviewed in Ref. 242), estrogen regulates Lif announcement in the abrasion uterus. This is axiomatic from Lif announcement on d 1 of abundance and during the estrous date of the aeon back the uterus is beneath the access of estrogen dispatch (236, 243, 244). In addition, Lif is not bidding in the uterus during experimentally induced delayed article but is rapidly induced by an bang of estrogen (232, 236). However, it has yet to be abstruse how estrogen induces Lif announcement in the abrasion uterus and the apparatus by which it is acclimatized by progesterone in added species. In humans, Lif is bidding in the endometrium and at college levels in the glandular epithelium of the secretory endometrium (245). Furthermore, LIF absence has been associated with alien alternate abortions and infertility in women (246).
F. Homeobox genes in implantation
Hox genes are archetype factors that accord to a multigene family. They are developmentally acclimatized and allotment a accepted awful conserved arrangement aspect alleged the homeobox that encodes a 61-amino acerbic helix-turn-helix DNA-binding area (247). Hox genes are organized in four clusters (A, B, C, and D) on four adapted chromosomes in mice and bodies and chase a acrimonious arrangement of spatial and banausic colinearity during embryogenesis (247). Several Hox genes at the 5′-end of anniversary array are classified as AbdB-like Hox genes, because of their affinity with the Drosophila AbdB gene. In vertebrates, AbdB-like Hox genes, agnate to their Drosophila ortholog, are bidding in developing genitourinary systems (248). For example, Hoxa-10 and Hoxa-11 are awful bidding in developing genitourinary tracts and the developed changeable changeable tract, suggesting roles in changeable contest (248, 249, 250). Hoxa-10 aberrant mice affectation oviductal transformation of the adjacent one third of the uterus. Furthermore, developed changeable mice amiss in Hoxa-10 appearance failures in blastocyst article and decidualization altered to the oviductal transformation (248). Consecutive studies arise that uterine stromal beef in Hoxa-10-deficient changeable mice appearance bargain admeasurement in acknowledgment to progesterone, arch to decidualization defects (248, 251). The uterus in Hoxa-11-deficient mice is hypoplastic and bare of uterine glands due to adorning defects. Aberrant admeasurement of stromal beef in Hoxa-10(−/−) changeable mice suggests that Hoxa-10 is circuitous in the bounded contest of cellular admeasurement by acclimation corpuscle aeon molecules. Indeed, cyclin D3 is aberrantly bidding in Hoxa-10 aberrant uteri in acknowledgment to a decidualizing bang (252). Furthermore, because several progesterone-responsive genes are dysregulated in the uterine stroma of Hoxa-10 aberrant mice (251), Hoxa-10, as a transcriptional factor, may back progesterone admiration in the uterine stroma by acclimation gene expression. A similar, but added severe, phenotype was additionally acclaimed in Hoxa-11-deficient changeable mice (250).
A contempo abstraction appliance microarray assay added arise that the absence of Hoxa-10 in the uterus in acknowledgment to progesterone is associated with two cellular disturbances (253). First, amid abounding genes that were up-regulated in the Hoxa-10-deficient uteri, two corpuscle aeon molecules, p15 and p57, were notable. These two genes are both cyclin-dependent kinase inhibitors (CKIs), suggesting that the ahead empiric birthmark in stromal corpuscle admeasurement in Hoxa-10 aberrant mice could be associated with this up-regulation of CKIs. Second, the microarray abstracts and aftereffect fluorescence activated corpuscle sorter analyses approved that there was hyperproliferation of T lymphocytes in the Hoxa-10-deficient uterine stroma in acknowledgment to progesterone. These after-effects advance that an aberrant lymphoproliferation has adverse furnishings on article in the Hoxa-10-deficient mice. In humans, both Hoxa-10 and Hoxa-11 genes are clearly up-regulated in the uterus during the midsecretory appearance in steroid hormone-dependent abode (254), suggesting their roles in animal implantation.
There is a homeobox gene family, altered to added beyond classes of homeobox genes, alleged the Hmx ancestors of archetype factors. These genes appearance overlapping announcement during development, but gene-targeting abstracts accept arise a altered role for Hmx3 in changeable reproduction (255). Hmx3 aberrant changeable mice appearance accustomed fertilization and preimplantation antecedent development to blastocysts. However, the blastocysts abort to implant in the uterus and afterwards die. Because Hmx3 is primarily bidding in the myometrium during aboriginal pregnancy, the apparatus of infertility in these mice is adapted from that of Hoxa-10 or Hoxa-11 aberrant mice and has yet to be explored.
G. Ligand-dependent nuclear receptors and coactivators in implantation
The nuclear receptor superfamily of archetype factors modulates announcement of ambition genes by bounden to specific DNA elements. The accumulation of this superfamily bulk from well-characterized steroid hormone receptors to drop nuclear receptors with no accepted ligands. Steroid hormone receptors aside, the PPAR ancestors of nuclear receptors has been alive in changeable changeable events. Three accumulation of the PPAR ancestors are PPARα, PPARγ, and PPARδ. To act as a transcriptional activator, PPARs charge anatomy a heterodimer with a affiliate of the retinoid X receptor (RXR) subfamily (176, 190). As declared below, admitting adorning defects are accepted in PPARδ and PPARγ aberrant mice, no credible changeable phenotype is axiomatic in PPARα aberrant mice.
PGs can act via bifold receptor signaling systems, either via classical corpuscle credible receptors or through nuclear receptor systems. PPARs can acknowledge to a advanced arrangement of ligands including accustomed and constructed eicosanoids, blubbery acids, and hypolipidemic and hypoglycemic drugs (256). There is affirmation that COX-2-derived PGI2 participates in article via activation of PPARδ (190), because the article defects in Cox-2(−/−) mice are capricious by a PGI2 agonist or a aggregate of PPARδ and RXR agonists. PGI2 is the best abounding PG in the aboriginal abounding abrasion uterus and is college at article sites than in interimplantation sites (190). Connected with the award that COX-2-driven uterine PG accumulation is acute to implantation, Cox-2 and prostacyclin synthase (Pgis) are coexpressed at the article site, suggesting the availability of PGI2 anon to uterine cells. In analytic for a ambition receptor for PGI2 in the uterus, the announcement of accepted PGI2 receptors, such as IP, PPARα, and PPARδ, was examined. Amid these, PPARδ was colocalized at agnate regions of the article sites with Cox-2 and Pgis; the announcement of IP and PPARα was actual low to undetectable. The functionality of PPARδ as a PGI2 receptor was added advised in vivo, appliance COX-2-deficient mice as an in vivo model. Administering of cPGI or L-165041 (a accurate PPARδ agonist) to these mice bigger article and decidualization (190). In affiliation with added in vitro evidence, this assignment suggests that PPARδ bidding in the uterine stroma responds to a PGI2 agonist to arbitrate antecedent article (190, 257, 258). Three complete groups accept arise assorted phenotypes of PPARδ knockout mice (259, 260, 261). Because of astringent aboriginal adorning defects of PPARδ aberrant embryos, it is actual difficult to advance this archetypal to anon abode whether the absence of affectionate PPARδ affects article as in COX-2-deficient mice. Therefore, the codicillary knockout abrasion archetypal with uterine-specific abatement of PPARδ is all-important to abode this issue.
PPARγ is able-bodied accepted as a key metaic regulator accommodating in blubber control, diabetes, atherosclerosis, and added processes (262). PPARγ-activating ligands accommodate artlessly occurring compounds, such as 15-deoxy-Δ (12, 14)-PGJ2, and the thiazolidinedione chic of insulin-sensitizing constructed compounds (262). Admitting the roles of PPARγ in several metaic processes accept been able-bodied documented, gene-targeting abstracts acknowledge that PPARγ is additionally appropriate for accustomed development of placental, cardiac, and adipose tissues. PPARγ aberrant mice die about alpha d 10 due to aberrant terminal adverse of the trophoblast and placental vascularization (263). Furthermore, in a abstraction appliance a tissue-specific PPARγ knockout abrasion archetypal generated by cross-breeding of abrasion mammary bump virus-cAMP acknowledgment aspect and codicillary PPARγ-null mice, it was credible that abatement of ovarian PPARγ in changeable mice led to broken article (264). However, the account of uterine dysfunction is not due to the absence of uterine PPARγ, because PPARγ was not deleted in the uterus by this cross-breeding. Added abstraction is appropriate to annotate the basal apparatus of broken uterine activity in the absence of ovarian PPARγ.
3. Transcriptional cofactors.
Many archetype factors including nuclear receptors attune archetype by complete bounden to sequence-specific DNA acknowledgment elements in promoters of ambition genes, connected in activation or repression of archetype in a promoter-specific abode (265, 266). Although biological functions and profiles of activating ligands are acutely diverse, ligand-activated nuclear receptors advance a advancing point of transcriptional cofactors to activate/repress afterwards ambition genes (267). Thus, although abounding cofactors were cloned based on their alternation with a specific nuclear receptor, assorted studies appearance a advanced ambit of administering of cofactors amid the ancestors of nuclear receptors (268), acknowledging the angle of a anatomic aggregation in vivo. Because of the abandoned attributes of transcriptional cofactors, they accept been abundantly advised in affiliation to assorted nuclear receptors. Recently, several gene-targeted abrasion models authenticate that abounding of these cofactors are circuitous in adorning and changeable processes.
a. cAMP acknowledgment aspect bounden protein (CREB)-binding protein (CBP)/p300.
CBP and the accompanying p300 are alleged cointegrators because of their able interactions with nuclear receptors, cofactors, and basal transcriptional accouterment (268). Thus, as a accepted attached cofactor for assorted transcriptional activators and coactivators, CBP allegedly organizes assorted signals into an chip acknowledgment at promoters complete assorted cis-acting elements (268). CBP about exhibits connected levels of announcement in assorted corpuscle curve and in the developing antecedent (269). Furthermore, the gene dosage-dependent role of CBP and p300 is able-bodied approved in abstracts with knockout mice in that CBP(−/−), p300(−/−), and CBP( /−)xp300( /−) bifold heterozygous mice all die in utero during midgestation due to assorted adorning defects (269). This suggests an capital role of cointegrators in alpha development.
b. Steroid receptor coactivator (SRC).
The SRC ancestors consists of three members: SRC-1, transcriptional agent agency 1 (TIF1) (SRC-2/glucocorticoid receptor interacting protein 1), and p/CIP(SRC-3/AlB1/RAC3/ACTR). The SRC ancestors accumulation collaborate with a arrangement of nuclear receptors including ER, PR, and PPAR, advertence their roles in assorted changeable functions (270, 271). The three SRC ancestors accumulation allotment agnate backdrop with account to interacting with nuclear receptors and transcriptional activity, but it is appropriate that these factors affectation assorted announcement patterns and functions (268). Admitting SRC-1-deficient mice are applicable and fertile, they appearance bargain hormone admiration in several ambition organs, including the uterus, prostate, and testis (272). In contrast, abundance of both macho and changeable TIF1(−/−) mice is broken (273). Changeable TIF1(−/−) mice affectation increases in alpha absorption amid d 12.5 and 18.5 gestation, possibly connected from placental hypoplasia. The placental hypoplasia in TIF1(−/−) changeable mice seems to be due to the affectionate absence of TIF1 in decidual stromal cells. Lastly, SRC-3(−/−) mice additionally affectation bargain abundance primarily due to decreased ovulation (274). These after-effects advance that three accumulation of SRC ancestors cofactors comedy assorted roles in changeable processes.
c. PPAR-binding protein (PBP).
PBP was aboriginal articular in a aggrandize two-hybrid screening arrangement as a PPARγ cofactor. This 165-kDa protein was additionally apart cloned by added groups as vitamin D receptor-interacting protein 205 or thyroid hormone receptor (TR)-associated protein 220, anniversary actuality a allotment of a multiunit circuitous for transcriptional activation by vitamin D receptor or TR, appropriately (275, 276). PBP is broadly bidding in assorted abrasion tissues and can collaborate with ER and PPAR (277, 278). Gene-targeting abstracts showed that PBP(−/−) embryos die in utero during midgestation due to poor placental development (279, 280).
d. PPAR-interacting protein (PRIP)/nuclear reaceptor-activating protein 250.
PRIP or nuclear receptor-activating protein 250 was articular as a PPARγ or PPARα cofactor apart (281, 282). PRIP interacts with accumulation of the PPAR, retinoic acerbic receptor and RXR families, as able-bodied as ER and TR. This gene is broadly bidding in assorted tissues including changeable organs (281, 282), and PRIP(−/−) mice affectation astringent adorning defects assuming placental and cardiac hypoplasia (283, 284).
e. Receptor-interacting protein 140 (RIP140).
Two complete groups cloned RIP140 as a cofactor for PPARα or TR2 (an drop receptor) (285, 286). This agency actively competes with SRC-1 in transcriptional assays and accordingly works as a accurate transcriptional corepressor (285). RIP140 is circuitous in changeable fertility, as approved in gene-targeting abstracts (287). RIP140 aberrant changeable mice appearance bargain ovulation that leads to baby clutter size, and a aftereffect abstraction showed that uterine activity in RIP140-deficient mice is accustomed (288).
H. Corpuscle aeon adjustment and signaling in article and decidualization
As declared above, the adverse of the uterus to abutment antecedent development and article is primarily directed by progesterone and estrogen (25, 43). Decidualization is aboriginal accomplished at the antimesometrial armpit area blastocysts implant. This process, characterized by stromal corpuscle admeasurement and adverse into specialized blazon of beef (decidual cells) with polyploidy, is analytical to the enactment of abundance in abounding species. The mechanisms by which the corpuscle aeon contest administer decidualization are ailing understood. The corpuscle aeon is deeply acclimatized at two checkpoints, the G1-S and G2-M phases. Accustomed operation of these phases involves a circuitous coaction of cyclins, cyclin-dependent kinases (cdks), and CKIs. At the alpha of decidualization, the stromal beef anon surrounding the implanting blastocyst breed (50). In mice, stromal beef aing to the antecedent cease to proliferate, initiating the accumulation of the primary decidual area (PDZ) afterwards on d 5 of pregnancy; the PDZ is actually accustomed by d 6. However, stromal corpuscle admeasurement alfresco the PDZ continues, eventually basal the accessory decidual area (SDZ) (30). Beneath accustomed conditions, the bang for decidualization is the implanting blastocyst. However, a agnate activity (deciduoma) can be experimentally induced in the pseudopregnant or hormonally able rodent uterus by intraluminal beverage of assorted agents including oil (30). The development of decidua or deciduoma in rodents is associated with the accumulation of multinucleate and behemothic beef (289, 290, 291). In mice, the decidual beef in the antimesometrial area are characterized by polyploidy and endoreduplication, and best beef in this area eventually enlarge, complete nuclei with as abounding as 64n DNA.
The acclaimed regulators of beastly corpuscle admeasurement are the three D-type cyclins (D1, D2, and D3), additionally accepted as G1 cyclins (292). The D-type cyclins accrue during the G1 phase. Their affiliation with cdk4 or cdk6 is important for basal holoenzymes that facilitate corpuscle access into the S phase. The retinoblastoma protein (Rb) and its ancestors members, p107 and p130, are abrogating regulators of the D-type cyclins. Inactivation of these regulators by phosphorylation is abased on the cyclin/cdk circuitous activity and allows the corpuscle aeon to advance through the G1 appearance (293). Overexpression of D-type cyclins shortens the G1 appearance and allows accelerated access into S appearance (294). In contrast, cyclins A and B are circuitous in the progression from the S through G2-M phase. Bounden of cyclin A or cyclin B to cdk1 induces phosphorylation and activation of the circuitous that is capital to the G2-M appearance transition, admitting the cyclin A/cdk2 circuitous participates during progression in the S phase. In general, the activity of cdks is accountable by at atomic two families of CKI, p16 and p21. The p16 ancestors includes p15, p16, p18, and p19, and they arrest the catalytic ally of D-type cyclins, cdk4 and cdk6. The p21 ancestors consists of p21, p27, and p57, and they arrest cdks with a broader specificity. CKIs accrue in quiescent cells, but are down-regulated with the access of proliferation. Thus, a analytical antithesis amid the absolute and abrogating corpuscle aeon regulators is a key accommodation maker for corpuscle assay (295).
The uterus is a altered and activating physiological archetypal in which cellular proliferation, differentiation, polyploidization, and apoptosis activity in a spatiotemporal abode during the changeable aeon and pregnancy. In the animal uterus, assorted cyclins (A, B1, D1, and E) and cyclin-dependent kinases (cdk1, cdk2, and cdk4) and CKI (p27) are acclimatized during the menstrual aeon or afterwards hormone treatments (57, 58). These molecules are bidding primarily in epithelial and stromal beef during the proliferative phase, suggesting their captivation in adroit admeasurement of these beef (296). During the secretory appearance or afterwards progesterone administration, p27 announcement correlates with progesterone-induced advance aishment in endometrial glands and stromal basalis (297). In rodents, however, the uterine announcement of D- and E-type cyclins and cdks is acclimatized by estrogen and/or progesterone in a banausic abode (298, 299, 300). Progesterone-dependent advance aishment of the endometrium is advised to be advised by decreased cdk activity, which allegedly occurs via decreased levels of cyclins and added affiliation of CKI (p27) with cdks (301). There is additionally affirmation that progesterone inhibition of uterine epithelial corpuscle admeasurement is advised by the inhibition of nuclear about-face of cyclin D1 and cdk4 in affiliation with the activation of cyclins A- and E-dependent cdk2 activity (302). Corpuscle aeon molecules are additionally circuitous in endoreduplication in trophoblast adverse during placentation (303, 304).
In mice, the announcement of cyclin D3 is up-regulated in decidualizing stromal beef at the article armpit and is associated with corpuscle admeasurement (252) (305, 306). Furthermore, cyclin D3 is associated with the ample polyploid beef that are authentic as terminally differentiated stroma. A schematic model, as credible in Fig. 2, illustrates a accessible role for cyclin D3 calm with added corpuscle aeon molecules in the adorning adjustment of stromal corpuscle decidualization and polyploidy. Cyclin D3 about accumulation with cdk4 and/or cdk6 for corpuscle proliferation. The alike announcement of cdk4 and cyclin D3 at the armpit of the antecedent afterwards the access of article in mice on d 5 of abundance suggests that these regulators comedy roles in admeasurement of stromal beef ability decidualization. However, the announcement of p21 with accessory down-regulation of cyclin D3 and cdk4 in the PDZ at the article armpit in the afternoon of d 5 supports the appearance that corpuscle admeasurement activity of cdk4/cyclin D3 ceases with the development of the PDZ. Their announcement in the decidualizing stroma alfresco the PDZ is afresh connected with their role in admeasurement of the stroma at the SDZ. In contrast, down-regulation of cdk4 in the SDZ with assiduous announcement of p21 on d 6 of abundance conceivably directs adverse of stromal beef in this zone. On this day of pregnancy, a about-face from cdk4 to cdk6 with connected announcement of cyclin D3 and p21 in stromal beef aural the SDZ is acclaimed in polyploid decidual cells. The attendance of cyclin E, cyclin A, and cdk2 with accessory down-regulation of cyclin B and cdk1 in these beef supports the appearance that these beef are afterward the endocycle pathway.
The physiological acceptation of stromal corpuscle polyploidy during decidualization is still unclear. The activity bulk of decidual beef during abundance is limited, and their annihilation makes allowance for the rapidly growing embryo. Because best decidual beef become polyploid during their lifetime, it is speculated that polyploidy banned the activity bulk of decidual cells. Furthermore, one of abounding uterine functions is to abutment alpha advance that requires added protein amalgam by decidual cells. The developing polyploidy may ensure added constructed accommodation by accretion the cardinal of gene copies for transcription. In conclusion, a bound allocation of the corpuscle aeon molecules appears to be analytical for uterine corpuscle admeasurement and adverse during article and decidualization.
I. Cast adjustment and angiogenesis during article and decidualization
Tissue adjustment and angiogenesis are two authentication contest during article and decidualization. The alteration endocrine accompaniment of the changeable during the changeable aeon and abundance after-effects in all-encompassing adjustment in the uterine tissue (139, 307). For example, assorted basement film components, such as blazon IV collagen, laminin, fibronectin, and proteoglycans, in the animal uterus abide changes throughout the menstrual aeon and abundance (307). Likewise, the ECM apparatus abide adjustment during abrasion uterine stromal corpuscle decidualization (139). Cast metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are anticipation to be key mediators for cast abasement during article and decidualization (reviewed in Refs. 307, 308, 309). There is affirmation that a antithesis amid a baddest set of MMPs and TIMPs is important for implantation. Mechanisms acclimation the MMP and TIMP genes during the periimplantation aeon are not clear, although advance factors and cytokines including the EGF and TGFβ ancestors accumulation and LIF accept been credible to attune MMPs and TIMPs (reviewed in Ref. 309).
Under physiological conditions, angiogenesis, the activity by which new claret argosy advance from preexisting vessels, primarily occurs in the uterus and ovary of the developed during the changeable aeon and abundance (310). Indeed, added vascular permeability and angiogenesis are acute to acknowledged implantation, decidualization, and placentation (Fig. 3). A cardinal of studies provided aberrant and anecdotic affirmation for the abeyant roles of estrogen and progesterone in these processes in assorted breed (reviewed in Refs. 310, 311, 312). These studies primarily advised the changes in the accomplished uterus of the announcement of a cardinal of gene articles accepted to adapt vascular permeability and angiogenesis, including VEGF and its receptors, afterwards investigating its angiogenic status. Thus, in vivo roles for estrogen and progesterone in uterine angiogenesis are not actually appreciated. VEGF, originally credible as a vascular permeability agency (reviewed in Ref. 313), is additionally a almighty mitogen for endothelial beef and a key authoritative advance agency for vasculogenesis and angiogenesis (314). Targeted disruption of alike one allele of the Vegf gene after-effects in alpha afterlife in utero during midgestation with aberrant claret barge accumulation (315, 316). Cogwheel splicing of the Vegf gene generates several VEGF isoforms in both bodies and mice; VEGF121 and VEGF165 are the absolute isoforms in humans, admitting VEGF120 and VEGF164 are the best abounding isoforms in mice (311, 317).
VEGF furnishings are primarily advised by two tyrosine kinase receptors: VEGFR1 [fms-like tyrosine kinase 1(FLT1)] and VEGFR2 [fetal alarmist kinase 1 (FLK1)/kinase admit domain-containing receptor (KDR)] (318, 319, 320, 321). Although FLT1 activation does not actuate endothelial corpuscle mitosis, targeted disruption of the Flt1 gene produces broken endothelial corpuscle accession into claret argosy and alpha accident (322). FLK1 is the aloft transducer of VEGF signals that abet chemotaxis, actin reorganization, and admeasurement of endothelial beef (314, 323, 324). Targeted abatement of the Flk1 gene in mice produces defects in hematopoietic and endothelial corpuscle development arch to alpha afterlife by d 9.5 (325). Recently, accession multifunctional VEGF receptor has been articular as Neuropilin-1 (NRP1). NRP1 was originally declared as a neuronal transmembrane receptor that participates in axonal advice in the developing afraid arrangement (326, 327) and is a receptor for the collapsin/semaphorin ancestors of proteins (328, 329). It is now accepted that NRP1 functions as a receptor for at atomic bristles adapted ligands, collapsin-1/semaphorin-IIII/D, semaphorin-E, semaphorin-IV, VEGF165, and placental advance agency (PlGF), which are circuitous in adapted biological processes, such as afraid arrangement development, vasculogenesis, and angiogenesis (329, 330). NRP1 is bidding in animal endothelial beef as a VEGF165-specific receptor. Back coexpressed in endothelial beef with FLK1, NRP1 enhances the bounden of VEGF165 to FLK1 and VEGF165-mediated chemotaxis severalfold college than that of FLK1 abandoned (331). Conversely, inhibition of VEGF165 bounden to NRP1 inhibits its bounden to FLK1 and its mitogenic activity in endothelial cells. NRP1-deficient mice appearance borderline afraid arrangement abnormalities and die in midgestation due to yolk sac vascular dearth and adorning anomalies of the cardiovascular arrangement (332). Mice overexpressing NRP1 additionally appearance cardiovascular abnormalities including added cardinal of claret argosy and aberrant hearts (333). Several structurally agnate VEGF ancestors accumulation including PlGF, VEGF-B, VEGF-C, and added VEGF-related proteins accept afresh been identified, and they are audible gene products. VEGF-C and PlGF can bind to FLK1 and FLT1, respectively. VEGF-C can additionally collaborate with a third structurally accompanying tyrosine kinase receptor, FLT4 (reviewed in Ref. 312). Absolute physiological acceptation of these anew articular VEGF-related advance factors in uterine angiogenesis during article warrants added investigation.
We accept afresh credible that the genes encoding murine VEGF isoforms and their receptors, FLT1, FLK1, and NRP1, are differentially bidding in the abrasion uterus in a spatiotemporal abode during article and that the absolute VEGF164 isoform interacts with FLK1 and NRP1 (311, 312). These after-effects advance that the VEGF arrangement is important for uterine vascular permeability and angiogenesis during implantation. Others accept additionally credible the announcement of VEGF and its receptors in the uterus as a accomplished during abundance and in acknowledgment to steroid hormones (313). For example, estrogen rapidly induces uterine vascular permeability and Vegf announcement transcriptionally via nuclear ER (313), and the Vegf gene contains EREs (334). Progesterone additionally up-regulates uterine Vegf announcement via activation of the nuclear PR but at a slower amount (334). Because estrogen rapidly stimulates uterine vascular permeability and Vegf expression, and because vascular permeability is advised a prerequisite for angiogenesis, it is broadly believed that estrogen is a almighty stimulator of uterine angiogenesis during accustomed changeable processes in vivo. However, contempo affirmation appliance molecular, genetic, physiological, and pharmacological approaches shows that estrogen and progesterone accept adapted furnishings in vivo; estrogen promotes uterine vascular permeability but greatly inhibits angiogenesis, admitting progesterone stimulates angiogenesis with little aftereffect on vascular permeability. These furnishings of estrogen and progesterone are advised by cogwheel spatiotemporal announcement of proangiogenic factors in the uterus (335).
VEGF furnishings are complemented and accommodating by accession chic of angiogenic factors, the angiopoietins (336). VEGF acts during the aboriginal stages of barge development (315, 316, 325), admitting angiopoietin-1 (Ang1) acts afterwards to advance angiogenic remodeling, including barge maturation, stabilization, and leakiness (337, 338, 339). In adverse to agonistic functions of Ang1, Ang2 behaves as an antagonist. Thus, Ang1 and Ang2 are artlessly occurring absolute and abrogating regulators of angiogenesis, respectively. They collaborate with an endothelial cell-specific tyrosine kinase receptor Tie2 (340). Two added accumulation of the angiopoietin ancestors accept been articular recently. Ang3, which is bidding in mice, appears to activity as an adversary to Ang1 activation of Tie2 in a appearance agnate to Ang2 (341). In contrast, Ang4, the animal analogue of Ang3, functions as an agonist to Tie2 (341). However, absolute biological functions of Ang3 and Ang4 abide unclear. Our contempo assay shows that admitting VEGF and its receptor Flk1 are primarily important for uterine vascular permeability and angiogenesis afore and during the adapter appearance of the article process, VEGF calm with the angiopoietins and their receptor Tie2 directs angiogenesis during decidualization afterwards article (342). A contempo abode has credible that Ang2 is appropriate for postnatal angiogenic remodeling, and Ang2 in accord with VEGF participates in the development of aqueous vasculature (343).
PGs, because of their roles in angiogenesis, corpuscle proliferation, and adverse in added systems, are additionally acceptable to participate in uterine vascular permeability and angiogenesis during article and decidualization. Indeed, there is now abiogenetic and atomic affirmation that COX-2-derived PGs participate in uterine angiogenesis during article and decidualization (342). Thus, one account of abortion of article and decidualization in Cox-2(−/−) mice is the deregulated vascular contest in the absence of COX-2. The abrasion of uterine angiogenesis in these mice is primarily due to aberrant VEGF signaling rather than the angiopoietin system. Collectively, the after-effects accommodate affirmation that admitting ovarian steroid hormones access uterine vascular permeability and angiogenesis during the preimplantation period, COX-2-derived PGs complete these contest during article and decidualization by differentially acclimation VEGF and angiopoietin signaling (335, 342).
Oxygen homeostasis is capital for corpuscle adaptation and is primarily advised by hypoxia-inducible factors (HIFs). These factors are carefully associated with vascular contest and abet Vegf announcement by bounden to the hypoxia acknowledgment aspect in the Vegf promoter. HIFα isoforms activity by basal heterodimers with the aryl hydrocarbon nuclear translocator (ARNT) (HIF-β) ancestors members. There is actual bound advice on the accord amid HIFs, ARNTs, and VEGF in the uterus during aboriginal pregnancy, although roles of HIFs in acclimation VEGF and angiogenesis in cancers and vasculogenesis during embryogenesis are able-bodied accurate (344). Appliance atomic and physiological approaches, we accept afresh credible that uterine announcement of HIFs and ARNTs does not associate with Vegf announcement during the preimplantation aeon (d 1–4) in mice. In contrast, their announcement follows the localization of uterine Vegf announcement with accretion angiogenesis during the postimplantation aeon (d 5–8). This disparate arrangement of uterine HIFs, ARNTs, and Vegf announcement on d 1–4 of abundance suggests that HIFs accept assorted roles in accession to the adjustment of angiogenesis during the periimplantation period. Appliance pharmacological, molecular, and abiogenetic approaches, we additionally empiric a atypical award that admitting progesterone primarily up-regulates uterine HIF-1α expression, estrogen briefly stimulates that of HIF-2α (345). The absolute role of hypoxia in uterine angiogenesis warrants added investigation.
Studies by the authors congenital in this assay were accurate by National Institutes of Health Grants HD29968, HD12304, HD33994, DA 06668 (to S.K.De.), HD 40810 (to H.L.), HD37830 (to S.K.Da.), HD40221 (to J.R.), and HD37394 (to B.C.P.). S.K.De. is almsman of MERIT Awards from the National Institute of Child Health and Animal Development and the National Institute on Drug Abuse. H.W. is Lalor Foundation postdoctoral fellow.
Abbreviations: 2-AG, 2-Arachidonoylglycerol; Ang1, angiopoietin-1; ARNT, aryl hydrocarbon nuclear translocator; BMP, cartilage morphogenetic protein; CBP, cAMP acknowledgment element-binding protein (CREB)-binding protein; cdk, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitor; COX-2, cyclooxygenase-2; DDRT-PCR, cogwheel affectation RT-PCR; ECM, extracellular matrix; EGF, epidermal advance factor; EGF-R, EGF receptor; ER, estrogen receptor; ERE, estrogen acknowledgment element; FGF, fibroblast advance factor; FLK1, fetal alarmist kinase 1; FLT1, fms-like tyrosine kinase 1; H2, histamine blazon 2 receptor; HB-EGF, heparin-binding EFG-like advance factor; HDC, histidine decarboxylase; HIF, hypoxia-inducible factor; ICM, aing corpuscle mass; IHH, Indian hedgehog; LIF, leukemia inhibitory factor; MMP, matix metalloproteinase; NRP1, Neuropilin-1; 4-OH-E2, 4-hydroxy-17β-estradiol; PBP, PPAR-binding protein; PDZ, primary decidual zone; PG, prostaglandin; PGI2, prostacyclin; PlGF, placental advance factor; PPAR, peroxisome proliferator-activated receptor; PR, progesterone receptor; PRIP, PPAR-interacting protein; PTC, Patched; RGD, Arg-Gly-Asp sequence; RIP, receptor interacting protein; RXR, retinoid X receptor; SAGE, consecutive assay of gene expression; SDZ, accessory decidual zone; SRC, steroid receptor coactivator; TIF, transcriptional agent factor; TIMP, tissue inhibitor of MMPs; TR, thyroid hormone receptor; VEGF, vascular endothelial advance factor.
Fig. 1. A arrangement of signaling networks in embryo-uterine advice during article in mice. Article in mammals actually depends aloft synchronized development of the blastocyst to the date back it is competent to implant and the uterus to the date back it is acceptant to blastocyst advance and implantation. Ovarian estrogen (E2) and progesterone (P4) are the primary effectors that complete the prereceptive uterus to a acceptant accompaniment via a cardinal of locally bidding advance factors, cytokines, archetype factors, and vasoactive mediators in the uterus, admitting uterine-derived catecholestrogen and acclimatized levels of endocannabinoids actuate the blastocyst to an implantation-competent state. During the adapter phase, signaling and adhering contest all-embracing the uterus and the blastocyst advance to implantation. Le, Luminal epithelium; Ge, glandular epithelium; S, stroma; CE, catechol estrogen.
Fig. 2. A proposed archetypal of stromal corpuscle polyploidy and decidualization. The phase-specific corpuscle aeon regulators in the G1 appearance (cyclin D3, p21, cdk4, cdk6, cyclin E, and cdk2) or in the S-G2-M phases (cyclin A, cyclin B, cdk1, and cdk2) are credible with account to their affiliation in mitotic corpuscle aeon vs. endocycle. The alike adjustment of cyclin D3 and cdk4 in decidualizing stromal beef suggests that these regulators comedy roles in proliferation. However, the announcement of p21 with accessory down-regulation of cyclin D3 and cdk4 supports the appearance that corpuscle admeasurement ceases with the development of the PDZ. Furthermore, a about-face from cdk4 to cdk6 with abiding announcement of cyclin D3 and p21 in beef aural the SDZ is connected with the progression through the G appearance for the access of endocycle. This is added accurate by the announcement of cyclin E, cyclin A, and cdk2 in the polyploid beef for acknowledged progression in G and S phases of the endocycle pathway. The absence of cyclin B and cdk1 apparently plays a role to admit the aboriginal endocycle.
Fig. 3. A arrangement assuming angiogenic signaling in the uterus during implantation. Added vascular permeability and angiogenesis at the armpit of the blastocyst are two hallmarks of the article process. The proangiogenic agency VEGF and its receptor Flt1 (VEGFR1) and Flk1 (VEGFR2) are primarily important for uterine vascular permeability and angiogenesis afore and during the adapter appearance of the article process, admitting VEGF in complementation with the angiopoietins (Ang1 and Ang2) and their receptor Tie-2 directs angiogenesis during decidualization. Furthermore, HIFs and COX-2-derived prostaglandins PGs are important for uterine angiogenesis during article and decidualization and primarily ambition the VEGF, but not the angiopoietin, system. Ang1 in accord with VEGF induces barge maturation and maintains barge leakiness, admitting Ang2 induces barge destabilization appropriate for added beginning in the attendance of VEGF. Flk1lacZ mice were acclimated to abstraction angiogenesis during implantation. LacZ-stained (blue) claret argosy are credible at the article armpit on d 8 of pregnancy. EC, Endothelial cells; NO, nitric oxide; bFGF, basal FGF; IFN-α, interferon α.
Fig. 4. A schematic diagram assuming abeyant endocannabinoid signaling in blastocyst activation and implantation. Anandamide and 2-AG are the aloft endocannabinoids that collaborate with G protein-coupled cannabinoid receptors, CB1 and CB2. Acclimatized levels of endocannabinoids in the acceptant uterus and CB1 in activated blastocysts at the time of article are benign for implantation, admitting college levels are adverse to this process. Because COX-2 is bidding in the uterus at the armpit of article and because anandamide and 2-AG can serve as substrates for either COX-2 or FAAH, the angle suggests that uterine endocannabinoids are deeply acclimatized by the accommodating activity of FAAH and COX-2 in the uterus during aboriginal pregnancy. Affirmation suggests that acclimatized uterine levels of endocannabinoids and blastocyst CB1 comedy a physiological role in synchronizing blastocyst adequacy with uterine activity for implantation. Tr, Trophectoderm; ANA, anandamide; CB1, brain-type cannabinoid receptor; FAAH, blubbery acerbic amide hydrolase; IS, article site; Inter-IS, interimplantation site.
TABLE 1. Identification of implantation-related genes in the mouse
TABLE 1. Identification of implantation-related genes in the mouse
TABLE 2. Identification of implantation-related genes in women
TABLE 2. Identification of implantation-related genes in women
TABLE 3. Changeable changeable performances in gene-targeted abrasion models
TABLE 3. Changeable changeable performances in gene-targeted abrasion models
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