Hum. Reprod. Advance Access published online on September 28, 2007
Human Reproduction, doi:10.1093/humrep/dem304
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Prostacyclin receptor signaling and early embryo development in the mouse
1 Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas 77030 USA 2 Obstetrical and Gynecological Associates, Houston, Texas 77030 USA 3 Vascular Biology Research Center and Division of Hematology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas 77030 USA 4 Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA 5 Cardiovascular and Blood Research Center, National Health Research Institutes, Zhunan, Taiwan
6Correspondence address. Tel: +713-500-6382; Fax: +713-500-0586; E-mail: jaou-chen.huang{at}uth.tmc.edu
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Abstract |
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BACKGROUND: Prostacyclin (PGI2) plays an important role in mouse embryo development and implantation. However, it is unclear whether its action is mediated via the I prostaglandin receptor (IP).
METHODS: We compared the preimplantation development of IP deleted (IP–/–) embryos and wild-type (WT) embryos. We also evaluated the effect of iloprost, a stable PGI2 analog, and L-165041, a peroxisome proliferator activated receptor 
(PPAR) ligand, on IP–/– versus WT embryos. Finally, we compared the development of heterozygous IP deficient embryos carrying a normal maternal IP allele versus paternal IP allele.
RESULTS: Development of IP–/– embryos lagged behind WT embryos and was not enhanced by either the PGI2 analog or the PPAR ligand. WT embryos had slightly higher, although statistically not significant, implantation rates than IP–/– embryos. Heterozygous IP deficient embryos carrying a normal maternal IP allele showed better development and responded to the PGI2 analog, unlike those carrying the normal paternal IP allele.
CONCLUSIONS: IP receptors play an important role in preimplantation embryo development and mediate the embryo's response to exogenous PGI2. Early embryo development depends on the oocyte IP receptor.
Key words:
preimplantation embryos/prostaglandins/imprinting/PPAR
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Introduction |
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Development of preimplantation embryos in vivo is promoted by a coordinated program involving soluble factors from embryos, oviducts and uterus (Yeung et al., 1992
; Hardy and Spanos, 2002). The overlapping functions of these factors provide a seamless network which optimizes embryo development to ensure the highest implantation potential. Compared with the development of in vivo embryos, the development of cultured embryos is retarded because they are removed from the protective environment of the oviduct (Cohen, 1991; Hardy, 1997). Prostacyclin (PGI2) is one of the protective factors (Lim et al., 1999; Huang et al., 2003,2004a,b). Our recent work shows supplementing culture media with iloprost, a stable analog of PGI2, enhances mouse blastocyst hatching in vitro (Huang et al., 2003). Cultured embryos preconditioned by iloprost have an enhanced potential for successful implantation and live births when transferred to gestational carriers (Huang et al., 2004b). On the other hand, blocking endogenous PGI2 production by selective cyclooxygenase-2 inhibitors retards embryo hatching (Huang et al., 2004c). Thus, PGI2 is a crucial endogenous factor for optimal embryo development, and its stable analog effectively augments the hatching and the implantation of cultured embryos.
PGI2 was originally identified as a product of vascular cells (Moncada et al., 1976). It inhibits blood platelet aggregation and vascular smooth muscle contraction and is considered to play a crucial role in maintaining vascular homeostasis. The vascular actions of PGI2 are mediated by a G protein-coupled PGI2 receptor (IP), which signals classically via cyclic AMP and protein kinase A (Namba et al., 1994). Other biological actions of PGI2, such as embryo implantation (Lim et al., 1999) and cytoprotection (Tan et al., 2001; Hao et al., 2002; Liou et al., 2006), are proposed to be mediated via a nuclear receptor, peroxisome proliferator activated receptor (PPAR). Several stable PGI2 analogs have been shown to bind PPAR (Forman et al., 1997). Recent work has provided evidence for the involvement of PPAR in the anti-apoptotic action of PGI2 (Tan et al., 2001; Liou et al., 2006). It has been reported that PGI2 up-regulates 14-3-3 
(Liou et al., 2006) and PDK-1 (Di-Poi et al., 2002) via the PPAR pathway. Our recent work indicates that PGI2 enhances preimplantation embryo development in a PPAR-dependent manner (Huang et al., 2007). Furthermore, our data based on PPAR deleted mice have shown that PPAR is essential for blastocyst formation and embryo hatching (Huang et al., 2007). In vitro embryo hatching was completely blocked by PPAR deletion. We have previously shown that the IP is expressed in preimplantation embryos (Huang et al., 2003). However, its role in preimplantation embryo development has not been delineated.
In this study, we investigated the role of IP in blastocyst formation, embryo hatching and implantation using IP deleted (IP–/–) and wild-type (WT) embryos. We also investigated the responses of IP–/– embryos to iloprost, a PGI2 analog.
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Generation of heterozygous IP deficient embryos
The research protocol was approved by the Animal Welfare Committee of the University of Texas Health Science Center, Houston. Unless specified otherwise, all chemicals were purchased from Sigma (St. Louis, MO, USA). The IP–/– mice have been fully backcrossed onto a C57BL6/J background (Cheng et al., 2002
). The heterozygous IP deficient embryos were generated by mating IP–/– mice with WT mice of mixed C3H/HeJ and C57BL/6J backgrounds. Heterozygous IP deficient embryos carrying a deficient maternal allele and a normal paternal allele (designated as IP–/+) were obtained by mating IP–/– females with males of mixed C3H/HeJ and C57BL/6J backgrounds; those carrying a deficient paternal allele and a normal maternal allele (designated as IP+/–) were obtained by mating females of mixed C3H/HeJ and C57BL/6J backgrounds with IP–/– males. Mice were kept in a temperature- and humidity-controlled environment (07:00 light on, 19:00 light off) with free access to food and water.
Embryo harvest and culture
Unless specified otherwise, mouse embryos were harvested and cultured as described previously (Huang et al., 2003). Briefly, ovulation induction was induced in three-week-old females with intra-peritoneal injection of PMSG (5 IU) followed by hCG (5 IU) 42–46 h later. After hCG injection, each female was caged with one fertile male. Two-cell embryos were harvested 44–48 h later and cultured (17–20 per group) at 37°C under 5% CO2 in four-well plates (Nalge Nunc International, Naperville, IL, USA) containing 600 µl media. All, except heterozygous IP deficient embryos, were cultured in HTF media (Sage Biopharma, Bedminster, NJ, USA) during the first 48 h, and 
MEM (Irvine Scientific, Santa Ana, CA, USA) with Earle's salts and 2 mM glutamine during the second 48 h. Heterozygous IP deficient embryos were cultured in Global media (IVF Online, Guelph, Canada), an improved KSOM media, because our ART laboratory changed the culture system when the experiments were conducted. Preliminary experiments were performed to ensure that embryo development was comparable between the two medium systems. Both medium systems were supplemented with 0.5 mg/ml human albumin substitute (IVF Online). After 96 h of culture, embryos were examined for the presence of zona pellucida. Those completely free of the zona pellucida were considered completely hatched. The rate of complete hatching was calculated by dividing the number of completely hatched embryos by the number of total embryos. Complete embryo hatching was chosen as an end point because it is the final developmental stage prior to implantation and correlates with the potentials of implantation and live birth of embryos (Huang et al., 2003,2004b). During the 96-h period, the developmental stages of embryos were recorded every 24 h. Detailed embryo morphology, such as fragmentation or blastomere appearance, was not recorded. Where indicated, experimental embryos received iloprost (1 µM, Cayman Chemical Co. Ann Arbor, MI, USA), L-165041 (1 µM) or GW 501516 (1 µM) and control embryos received vehicle of same concentration (DMSO, 1:10 000) beginning at 24 h of culture. Based on our previous studies (Huang et al., 2003,2007), 1 µM of iloprost and L-165041 enhances maximum embryo hatching.
Embryo transfer and determination of implantation rates
WT and IP–/– embryos were harvested at the two-cell stage and cultured for 48 h. All embryos were transferred to 2.5 Day pseudopregnant gestational carriers (7–12 week old ICR females). The embryo transfer was performed as described previously (Huang et al., 2004b) and is summarized as follows. After adequate anesthesia was attained, each uterine horn was accessed via a 1–1.5 cm flank incision under a dissecting microscope (Olympus SZ-PT, Shinjuku-ku, Tokyo, Japan). An opening was created with a 30-gauge needle on the anti-mesenteric side of the distal uterine horn, while the proximal oviduct was held by a pair of forceps. The opening allowed the entry of transfer pipette which had an inner diameter of 
140 µm. Up to seven embryos in 1.5 µl transfer medium (MEM with 25 mM HEPES and 1% BSA) were transferred to each horn. After each transfer, the content of the transfer pipette was examined under a stereomicroscope to identify retained embryos. Each gestational carrier received only one type of embryos in order to prevent mixing of embryos (Dr Andreas Zimmer, University of Bonn, Germany, MGI-List, the Jackson Laboratory). Embryo transfer was performed by one individual (J-.C.H.) following the same protocol to ensure consistency. Seventy-two hour after embryo transfer, the implantation rates were determined based on a previously described method with modifications (Paria et al., 1993). Briefly, 3 min before euthanasia, 0.1 ml of Chicago blue (1%) was injected via the tail vein. After the carrier was euthanized, the blue bands over the uteri were counted and confirmed with the number of gestation sacs inside the uterine horns. The implantation rate was expressed as the number of gestational sacs divided by the number of embryos transferred.
Statistical analysis
GraphPad InStat® (Version 3.05, GraphPad Software Inc., San Diego, USA) software was used for statistical analysis. Two-tailed Fisher's exact test or Chi square test was used to compare the rates. A P < 0.05 was considered statistically significant.
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IP–/– embryos showed retarded development and were unresponsive to PGI2
We used complete embryo hatching as a surrogate of embryo development in vitro to compare the development of WT and IP–/– embryos because it correlates with enhanced implantation and live birth (Huang et al., 2004b
). Our results show the development of IP–/– embryos was retarded: the number of hatched IP–/– embryos was 56% that of WT embryos (P = 0.02, Fig. 1). We have previously shown that iloprost enhances embryo hatching (Huang et al., 2003). In this study, we evaluated the effect of iloprost on IP–/– and WT embryos. Similar to previous report, iloprost (1 µM) increased WT embryo hatching from 31 to 49% (P = 0.013, Fig. 1). In contrast, iloprost did not enhance the hatching of IP–/– embryos (Fig. 1). Surprisingly, L-165041, a PPAR ligand, which enhanced WT embryo hatching (Fig. 1) as reported previously (Huang et al., 2007), also failed to enhance IP–/– embryo hatching (Fig. 1). We confirmed these unexpected findings with another synthetic PPAR ligand, GW501516. GW501516 also failed to enhance IP–/– embryo hatching: eight and ten out of 81 embryos receiving DMSO and GW501516, respectively, hatched completely, P = 0.8).
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We next determined if the progression of IP–/– embryos to blastocysts, as compared with the progression of WT embryos, was retarded. After two-cell staged embryos had been cultured for 48 h they were categorized as ‘
blastocysts’ and ‘<blastocysts’ to include those embryos that had progressed to blastocyst stage (and beyond) and those that had not, respectively. Our results show that the early development of IP–/– embryos was retarded. Compared with WT embryos, approximately half as many IP–/– embryos reached the blastocyst stage (and beyond) after 48 h (P < 0.001, Table I). Consistent with our earlier observation (Fig. 1), the number of hatched IP–/– embryos was 60% that of WT embryos (P = 0.019). It is worth mentioning that extending the duration of culture to 120 h did not result in more hatched IP–/– embryos. The majority of blastocysts that did not hatch completely at 96 h became collapsed during the additional 24-h period.
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IP–/– embryos had normal implantation potential
Although the development of IP–/– embryos was significantly slower than that of WT embryos (Table I), IP–/– mice have not been reported to have smaller litters than WT mice (Murata et al., 1997
; Cheng et al., 2002). Therefore, we used a previously described embryo transfer model (Huang et al., 2004b) to compare the implantation potential of WT and IP–/– embryos. At the time of embryo transfer, IP–/– embryos remained largely at the morula stage (67 versus 40% of WT embryos, Table II), more than half of WT embryos had progressed to the blastocyst stage (54 versus 16% of IP–/– embryos) and three times more IP–/– embryos than WT embryos (18 versus 6%) had not reached the morula stage. Despite these striking differences in embryo development, the implantation rates of WT and IP–/– embryos were not significantly different (Fig. 2). Exposure to iloprost between 24–48 h neither augmented embryo development (Table II) nor increased implantation rates (Fig. 2).
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IP–/+ embryos (IP–/–
x WT 
), but not IP+/– embryos (WT x IP–/– ), showed retarded developmentWe generated heterozygous IP deficient embryos from male or female IP–/– mice and compared their development in vitro to test the hypothesis that IP deficiency during oogenesis affects early embryo development. Our results show IP+/– embryos (Table III), similar to WT embryos (Table I), exhibited normal development during the first 48 h. In contrast, IP–/+ embryos (Table III), similar to IP–/– embryos (Table I), exhibited retarded development. However, at 96 h, the percentage of completely hatched IP+/– embryos decreased to the same level as that of IP–/– embryos, whereas the percentage of completely hatched IP–/+ embryos was higher than that of IP+/– embryos (Table III).
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PGI2 enhanced the development of IP–/+ (IP–/–
x WT ) but not IP+/– (WT x IP–/– ) embryosThe above results show that two-cell IP–/+ embryos have a reduced developmental potential during the first 48 h of culture. A previous report reveals that the ‘window’ of response to PGI2, in terms of enhanced embryo development, is between 24 and 42 h after harvest of two-cell embryos (Huang et al., 2003
). Therefore, we exposed IP+/– embryos and IP–/+ embryos to iloprost beginning at 24 h and compared embryo hatching at 96 h to determine the extent to which IP deficiency in oocytes affected embryo's response to PGI2. Our results show that iloprost enhanced IP+/– embryo hatching (Fig. 3) to an extent similar to that of WT embryos (Fig. 1). On the other hand, iloprost did not increase IP–/+ embryo hatching (Fig. 3).
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Discussion |
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Our results indicate that IP receptors are involved in blastocyst formation and embryo hatching and that the enhancing effects of iloprost in preimplantation embryos require IP receptors. Deletion of IP receptors results in
50% reduction of two-cell embryos reaching the blastocyst stage at 48 h and 40% reduction of completely hatched blastocysts at 96 h. As PGI2 is produced by cultured embryos (Huang et al., 2004c), these findings suggest that basal PGI2 promotes the development of preimplantation embryos in part through IP-mediated signal transduction. We showed previously that iloprost, an exogenous PGI2 analog, enhances embryo development in vitro (Huang et al., 2003). The present study shows iloprost no longer enhances embryo hatching when IP receptors are deleted. These findings provide strong evidence that IP receptors play a crucial role in the in vitro development of preimplantation embryos.
Our results suggest that a cross-talk between IP receptor and PPAR signaling pathways may occur in the preimplantation embryos. We previously reported that embryo development in vitro is completely retarded when PPAR is genetically deleted and that L-165041, a PPAR selective ligand which enhances embryo hatching in vitro, completely loses this effect on PPAR–/– embryos (Huang et al., 2007). As L-165041 does not have any known effect on IP receptors, we were surprised to see that L-165041 (and another PPAR selective ligand, GW501516) also did not enhance IP–/– embryo development. The reason for this phenomenon is not apparent. However, it may be speculated that PPAR activation is modulated by signaling pathways activated by IP receptors. In fact, the retarded development of IP–/– embryos (which have intact PPAR) may be attributed to the loss of IP-mediated, post-translational modification of PPAR, which contributes to 40–50% of in vitro embryo development. Post-translational modification of both PPAR and PPAR
has previously been reported (Blanquart et al., 2003).
Understanding IP signaling pathways in the preimplantation embryos may benefit IVF. Although gross reproductive failure was not one of the reported phenotypes of IP–/– mice (Murata et al., 1997; Cheng et al., 2002), the litter sizes of WT and IP–/– mice have not been compared. Nevertheless, the data presented in one of the reports (Murata et al., 1997) suggest that WT and IP–/– embryos may have subtle differences in reproduction. The genotypic distribution of pups born to heterozygous IP deficient parents shows a small, but significant (P = 0.029) deviation from the Mendelian distribution: 27% WT (78/281), 54% heterozygous IP deficient (152/281) and 18% IP–/– (51/281) (Murata et al., 1997). The above distribution suggests that IP–/– embryos may have inherent flaws such that fewer than expected pups are born. The magnitude of difference (7%) is similar to what we observed in embryo transfer experiments: 6% fewer IP–/– embryos implant successfully than WT embryos (Fig. 3). Therefore, the deviation from the Mendelian distribution may be partly attributed to the decreased development and implantation potentials of IP–/– embryos. It is worth noting that the large difference in embryo hatching between WT and IP–/– embryos (36 versus 22%, Table I) was not reflected in implantation (54 versus 48%, Fig. 3). This suggests that the loss-of-function due to IP deletion was almost fully compensated by uterine factors. It may be argued that as far as reproduction is concerned, the IP signaling pathway is not biologically relevant because IP deletion does not lead to gross reproductive failure. Nonetheless, information gained from studying IP–/– embryos in vitro may be used to enhance IVF success, because IVF embryos spent a brief but critical time in vitro.
Our results indicate that an intact IP signaling pathway is required to produce oocytes with normal developmental potential. First, significantly more WT than IP–/– embryos reached blastocyst stage after 48 h (Table I). Second, more two-cell staged IP+/– embryos (WT x IP–/– ) than IP–/+ embryos (IP–/– x WT ) reached blastocyst stage after 48 h (Table III). Third, a similar proportion of IP–/– embryos (Table I) and IP–/+ embryos (Table III) reached the blastocyst stage after 48 h. And finally, comparable numbers of WT and IP+/– embryos reached the blastocyst stage at 48 h (P = 0.28). These results are consistent with the notion that genetic signals required for initial zygote development derive from the oocytes (Seydoux, 1996). Although the network of signaling pathways in the oocytes governing embryo development remains to be established, our results indicate that IP is a key components of early embryo development.
The development patterns of IP+/– and IP–/+ embryos suggest that the maternal IP allele may be silenced (imprinted) after the embryonic genome activation. Although IP+/– embryos showed more advanced development than IP–/+ embryos at 48 h, their rates of complete hatching at 96 h were slightly lower than those of IP–/+ embryos (Table III). Furthermore, the complete hatching of IP–/+ and IP+/– embryos was not different from that of IP–/– embryos and was 60–70% that of WT embryos. One possible explanation is that embryo-derived PGI2 (Huang et al., 2004c) activates the IP to optimize embryo development throughout the preimplantation period and that normal maternal and paternal IP alleles are required for IP expression in oocytes/early embryos and late embryos, respectively. As a result, despite the early delay, IP–/+ embryos were able to ‘catch up’ with IP+/– embryos after the activation of the embryonic genome, because the former had normal paternal IP allele. It should be noted that a PGI2 analog did not augment IP–/+ embryo development because IP–/+ embryos had developmental delay during the first 48 h (details below). On the other hand, although IP+/– embryos have an early developmental advantage, they lost the momentum after the oocyte–embryo transition because the inherited maternal IP mRNA degraded and they had a knock out paternal IP allele. Thus, normal maternal and paternal IP alleles ensure PGI2 can provide a continuous (or basal) impetus to propel the progression of preimplantation embryos ensuring successful and ‘on-time’ completion of every developmental stage.
Our results suggest that oocytes produced in an IP deficient environment had diminished early developmental potentials, which, in turn, reduced their responsiveness to PGI2 analogs. Iloprost did not enhance IP–/+ embryo development (Table I), but enhanced IP+/– embryo development to an extent comparable to WT embryos (Fig. 3). It has been reported (Huang et al., 2003) that the enhancing effect of PGI2 has a narrow window: between 24 and 42 h after the harvest of two-cell embryos (corresponding to the eight-cell to morular stage transition). Although the existence of this narrow window of responsiveness could be explained by the timing of IP and PPAR expression (IP and PPAR become detectable by immunohistochemistry at the morular and two-cell stages, respectively), the true reason is unclear. Based on the results presented here, one possible explanation is that embryo-derived PGI2, which exert its effects via oocyte-derived IP receptors in early cultured embryos, may be limited. As a result, an exogenous PGI2 analog such as iloprost may enhance the development of cultured embryos via the same signaling pathway. Further studies are needed to resolve this complex issue.
In conclusion, IP receptors have an important role in preimplantation embryo development and mediate the embryo's response to exogenous PGI2. Normal early embryo development requires intact IP receptors in the oocytes. Information gained from studying IP signaling in the preimplantation embryos may be used to enhance IVF success.
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Supported by National Institute of Health K12-HD01277 (to J-C Huang), HL62250 (to G. A. FitzGerald), and HL 50675 (to K. K. Wu). G. A. FitzGerald is the McNeil Professor of Translational Medicine and Therapeutics.
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Submitted on June 20, 2007; resubmitted on August 13, 2007; accepted on August 28, 2007.
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