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Biomedical subjects

S K Dey

Publications and source records attributed to S K Dey.

At least 55 records · Page 3Linked to original sources
PubMed2000

Implantation and decidualization defects in prolactin receptor (PRLR)-deficient mice are mediated by ovarian but not uterine PRLR.

PRL and its homologs accomplish their biological effects through the PRL receptor (PRLR). We evaluated the expression and function of PRLR in the embryo and uterus during the periimplantation period because PRLR deficiency results in implantation failure. In wild-type mice, PRLR expression was localized to undecidualized stromal cells in the antimesometrial border on days 6-8 of pregnancy. A small population of PRLR-expressing cells was observed adjacent to the ectoplacental cone in the mesometrial stroma. Low levels of PRLR expression were also detected in the developing embryo on days 6-8. To determine the significance of PRLR expression in this distribution, we examined implantation and decidualization in PRLR-/- mice. Progesterone (P4) administration rescued infertility in PRLR-/- mice from the periimplantation period to midgestation. Artificially induced decidualization was absent in pseudopregnant PRLR-/- mice but was identical to wild-type in P4-treated PRLR-/- mice. Furthermore, wild-type and P4-treated PRLR-/- mice had similar expression of the implantation-specific genes, LIF, amphiregulin, HB-EGF, COX-1, COX-2, PPARdelta, Hoxa-10, cyclin-D3, VEGF, and its receptors, Flk-1 and neuropilin-1. Together, these results show that luteal P4 production via ovarian PRLR signaling is required for implantation and early pregnancy. The function of uterine PRLR remains unclear. However, the eventual loss of pregnancy in P4-treated PRLR-/- mice suggests that uterine PRLR may be essential for the support of late gestation.

Animals↗
PubMed2000

Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice.

Various mediators, including cytokines, growth factors, homeotic gene products, and prostaglandins (PGs), participate in the implantation process in an autocrine, paracrine, or juxtacrine manner. However, interactions among these factors that result in successful implantation are not clearly understood. Leukemia inhibitory factor (LIF), a pleiotropic cytokine, was shown to be expressed in uterine glands on day 4 morning before implantation and is critical to this process in mice. However, the mechanism by which LIF executes its effects in implantation remains unknown. Moreover, interactions of LIF with other implantation-specific molecules have not yet been defined. Using normal and delayed implantation models, we herein show that LIF is not only expressed in progesterone (P4)-primed uterine glands before implantation in response to nidatory estrogen, it is also induced in stromal cells surrounding the active blastocyst at the time of the attachment reaction. This suggests that LIF has biphasic effects: first in the preparation of the receptive uterus and subsequently in the attachment reaction. The mechanism by which LIF participates in these events was addressed using LIF-deficient mice. We observed that while uterine cell-specific proliferation, steroid hormone responsiveness, and expression patterns of several genes are normal, specific members of the EGF family of growth factors, such as amphiregulin (Ar), heparin-binding EGF-like growth factor (HB-EGF), and epiregulin, are not expressed in LIF(-/-) uteri before and during the anticipated time of implantation, although EGF receptor family members (erbBs) are expressed correctly. Furthermore, cyclooxygenase-2 (COX-2), an inducible rate-limiting enzyme for PG synthesis and essential for implantation, is aberrantly expressed in the uterus surrounding the blastocyst in LIF(-/-) mice. These results suggest that dysregulation of specific EGF-like growth factors and COX-2 in the uterus contributes, at least partially, to implantation failure in LIF(-/-) mice. Since estrogen is essential for uterine receptivity, LIF induction, and blastocyst activation, it is possible that the nidatory estrogen effects in the P4-primed uterus for implantation are mediated via LIF signaling. However, we observed that LIF can only partially resume implantation in P4-primed, delayed implanting mice in the absence of estrogen, suggesting LIF induction is one of many functions that are executed by estrogen for implantation.

Animals↗
PubMed2000

Blastocyst H(2) receptor is the target for uterine histamine in implantation in the mouse.

The process of implantation is a 'two-way' interaction between the blastocyst and uterus. It has long been suspected that histamine is an important mediator in embryo-uterine interactions during implantation, but its source, targets and mechanism of actions remained undefined. We have recently demonstrated that uterine epithelial cells are the source of histamine, which peaks on day 4 of pregnancy (the day of implantation) in the mouse. In searching for its target and site of action, we discovered that preimplantation blastocysts, which express histamine type 2 receptor (H(2)), is the target for histamine action. Using multiple approaches, we demonstrate herein that uterine-derived histamine interacts with embryonic H(2) receptors in a paracrine fashion to initiate the process of implantation.

Animals↗
PubMed2000

Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation.

The mechanism(s) by which localized vascular permeability and angiogenesis occur at the sites of implantation is not clearly understood. Vascular endothelial growth factor (VEGF) is a key regulator of vasculogenesis during embryogenesis and angiogenesis in adult tissues. VEGF is also a vascular permeability factor. VEGF acts via two tyrosine kinase family receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). Recent evidence suggests that neuropilin-1 (NRP1), a receptor involved in neuronal cell guidance, is expressed in endothelial cells, binds to VEGF(165) and enhances the binding of VEGF(165) to VEGFR2. We examined the spatiotemporal expression of vegf isoforms, nrp1 and vegfr2 as well as their interactions in the periimplantation mouse uterus. We observed that vegf(164) is the predominant isoform in the mouse uterus. vegf(164) mRNA accumulation primarily occurred in epithelial cells on days 1 and 2 of pregnancy. On days 3 and 4, the subepithelial stroma in addition to epithelial cells exhibited accumulation of this mRNA. After the initial attachment reaction on day 5, luminal epithelial and stromal cells immediately surrounding the blastocyst exhibited distinct accumulation of vegf(164) mRNA. On days 6-8, the accumulation of this mRNA occurred in both mesometrial and antimesometrial decidual cells. These results suggest that VEGF(164) is available in mediating vascular changes and angiogenesis in the uterus during implantation and decidualization. This is consistent with coordinate expression of vegfr2, and nrp1, a VEGF(164)-specific receptor, in uterine endothelial cells. Their expression was low during the first 2 days of pregnancy followed by increases thereafter. With the initiation and progression of implantation (days 5-8), these genes were distinctly expressed in endothelial cells of the decidualizing stroma. Expression was more intense on days 6-8 at the mesometrial pole, the presumptive site of heightened angiogenesis and placentation. However, the expression was absent in the avascular primary decidual zone immediately surrounding the implanting embryo. Crosslinking experiments showed that (125)I-VEGF(165) binds to both NRP1 and VEGFR2 present in decidual endothelial cells. These results suggest that VEGF(164), NRP1 and VEGFR2 play a role in VEGF-induced vascular permeability and angiogenesis in the uterus required for implantation. genesis 26:213-224, 2000.

Animals↗
PubMed1999

Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta.

We have demonstrated previously that cyclo-oxygenase-2 (COX2), the rate-limiting enzyme in the biosynthesis of prostaglandins (PGs), is essential for blastocyst implantation and decidualization. However, the candidate PG(s) that participates in these processes and the mechanism of its action remain undefined. Using COX2-deficient mice and multiple approaches, we demonstrate herein that COX2-derived prostacyclin (PGI2) is the primary PG that is essential for implantation and decidualization. Several lines of evidence suggest that the effects of PGI2 are mediated by its activation of the nuclear hormone receptor PPARdelta, demonstrating the first reported biologic function of this receptor signaling pathway.

Animals↗
PubMed1999

COX-2 compensation in the uterus of COX-1 deficient mice during the pre-implantation period.

Prostaglandins (PGs) produced by cyclooxygenase (COX) participate in many aspects of female reproduction. The two isoforms of cyclooxygenase, COX-1 and COX-2, have distinct expression patterns in the mouse uterus during the peri-implantation period and suggest their independent contribution to uterine PGs. Using wild type and COX-1(-/-) mice, we examined the role of COX-1-derived PGs on day 4 of pregnancy, when its expression is maximal. Uterine vascular permeability was measured by 125I-labeled bovine serum albumin (BSA) uptake, and PG content was measured by gas chromatography-mass spectrometry. Vascular permeability and PG concentrations were reduced in COX-1(-/-) mice, but by less than the expected amount. After ovariectomy, uterine vascular permeability declined in both groups, but returned to baseline in wild type and was exaggerated in COX-1(-/-) females after treatment with ovarian steroids. Most importantly, COX-1(-/-) uteri displayed COX-2 expression on the morning of day 4, when COX-2 is normally absent. This hybridization pattern resembles the native expression of COX-1, and may partially offset the loss of COX-1-derived PGs. These data indicate that COX-1-derived PGs are important during uterine preparation for implantation, and that COX-2 compensation occurs in the absence of COX-1.

Animals↗
PubMed1999

Zonula occludens-1 and E-cadherin are coordinately expressed in the mouse uterus with the initiation of implantation and decidualization.

Two-way interactions between the blastocyst trophectoderm and the uterine luminal epithelium are essential for implantation. The key events of this process are cell-cell contact of trophectoderm cells with uterine luminal epithelial cells, controlled invasion of trophoblast cells through the luminal epithelium and the basement membrane, transformation of uterine stromal cells surrounding the blastocyst into decidual cells, and protection of the "semiallogenic" embryo from the mother's immunological responses. Because cell-cell contact between the trophectoderm epithelium and the luminal epithelium is essential for implantation, we investigated the expression of zonula occludens-1 (ZO-1) and E-cadherin, two molecules associated with epithelial cell junctions, in the mouse uterus during the periimplantation period. Preimplantation uterine epithelial cells express both ZO-1 and E-cadherin. With the initiation and progression of implantation, ZO-1 and E-cadherin are expressed in stromal cells of the primary decidual zone (PDZ). As trophoblast invasion progresses, these two molecules are expressed in stroma in advance of the invading trophoblast cells. These results suggest that expression of these adherence and tight junctions molecules in the PDZ serves to function as a permeability barrier to regulate access of immunologically competent maternal cells and/or molecules to the embryo and provide homotypic guidance of trophoblast cells in the endometrium.

Animals↗
PubMed1999

Homeopathy in HIV infection: a trial report of double-blind placebo controlled study.

OBJECTIVE: This study was aimed to evaluate the immuno-modulator role of homeopathic remedies in Human Immunodeficiency Virus (HIV) infection. METHODOLOGY: A randomised double blind clinical trial was conducted to compare the effect of homeopathic remedies with placebo, on CD4+ve T-lymphocytes in HIV infected individuals, conforming to Centres for Disease Control (CDC) stage II & III. 100 HIV+ve individuals between 18-50 y (71% males) were included in the study. 50 cases conformed to CDC stage II--Asymptomatic HIV infection, and 50 cases to CDC stage III--Persistent Generalised Lymphadenopathy (PGL). Cases were stratified according to their clinical status and CD4+ve lymphocyte counts. The randomisation charts were prepared much before the start of the trial by randomly assigning placebo and verum codes to registration numbers from 1 to 50. A single individualised homeopathic remedy was prescribed in each case and was followed up at intervals of 15 d to one month. A six months study was performed for each registered case. Assessment of progress was made by evaluation of CD+ve lymphocyte counts, which was the prospectively-defined main outcome measure of the study; the results were compared with the base line immune status. RESULTS: In PGL, a statistically significant difference was observed in CD+ve T-lymphocyte counts between pre and post trial levels in verum group (P < 0.01). In the placebo group a similar comparison yielded non-significant results. (P = 0.91). Analysis of change in the pre and post trial counts of CD4+ve cells between groups was also statistically significant (P = 0.04). In asymptomatic HIV infection, differences in absolute CD4+ve lymphocyte counts between pre and post trial levels were not significant. Analysis of changes in pre and post trial CD4 levels of placebo and verum groups for combined strata of asymptomatic and PGL groups was also not significant. CONCLUSION: The study suggests a possible role of homeopathic treatment in HIV infection in symptomatic phase, as evidenced by a statistically significant elevation of base line immune status in persistent generalised lymphadenopathy.

Adolescent↗
PubMed1999

Changes in uterine expression of leukemia inhibitory factor during pregnancy in the Western spotted skunk.

Mutation of the leukemia inhibitory factor (LIF) gene results in reproductive failure in LIF -/- mice due to an inability to implant their blastocysts. This condition is reversed by infusion of LIF or by transferral of embryos to pseudopregnant, wild-type mice. This led us to hypothesize that embryonic diapause in the spotted skunk is due to insufficient uterine expression of LIF whereas resumption of development and implantation are associated with increased LIF expression. We also investigated the hormonal control of LIF expression. Uterine concentrations of LIF mRNA were determined by quantitative reverse transcription-polymerase chain reaction. Changes in cell-specific localization of LIF mRNA and protein were determined by in situ hybridization and immunocytochemistry. LIF mRNA was detected but was not abundant during embryonic diapause; it then increased when blastocysts resumed development and remained elevated prior to implantation. LIF mRNA and protein could not be localized in the uterus during embryonic diapause but were quite apparent in luminal and glandular epithelium during blastocyst activation. Prolactin, progesterone, and estradiol failed to increase uterine concentrations of LIF mRNA above those in ovariectomized controls. These data are consistent with the initial hypothesis and suggest that LIF may somehow be involved in preparing the uterus for implantation in the spotted skunk.

Animals↗
PubMed1999

Stage-specific excitation of cannabinoid receptor exhibits differential effects on mouse embryonic development.

Anandamide (N-arachidonoylethanolamine), an arachidonic acid derivative, is an endogenous ligand for both the brain-type (CB1-R) and spleen-type (CB2-R) cannabinoid receptors. We have previously demonstrated that preimplantation mouse embryos express mRNA for these receptors and that the periimplantation uterus contains the highest level of anandamide yet discovered in a mammalian tissue. We further demonstrated that 2-cell mouse embryos exposed to low levels of anandamide (7 nM) or other known cannabinoid agonists in culture exhibit markedly compromised embryonic development to blastocysts and that this effect is mediated by CB1-R. In contrast, the present study demonstrates that blastocysts exposed in culture to the same low levels of cannabinoid agonists exhibited accelerated trophoblast differentiation with respect to fibronectin-binding activity and trophoblast outgrowth. Again, these effects resulted from activation of embryonic CB1-R. There was a differential concentration-dependent effect of cannabinoids on the trophoblast, with an observed inhibition of differentiation at higher doses. These results provide evidence for the first time that cannabinoid effects are differentially executed depending on the embryonic stage and cannabinoid levels in the environment. Since uterine anandamide levels are lowest at the sites of implantation and highest at the interimplantation sites, the new findings imply that site-specific levels of anandamide and/or other endogenous ligands in the uterus may regulate implantation spatially by promoting trophoblast differentiation at the sites of blastocyst implantation.

Animals↗
PubMed1999

Spatiotemporal expression of cyclooxygenase 1 and cyclooxygenase 2 during delayed implantation and the periimplantation period in the Western spotted skunk.

Embryonic development in the western spotted skunk is arrested after blastocyst formation for about 200 days. This developmental arrest is believed to be due to insufficiency of uterine conditions to support continuous development. Implantation and decidualization are defective in cyclooxygenase 2 (Cox2)-, but not Cox1-, deficient mice. We therefore used Northern and in situ hybridization to investigate changes in uterine expression of Cox1 and Cox2 genes during various stages of pregnancy in the spotted skunk. Cox1 was constitutively expressed at all stages of pregnancy examined, but it did exhibit localized up-regulation in the trophoblast and necks of uterine glands at early implantation sites. Cox2 expression was highly regulated with little or no expression during delayed implantation. Cox2 expression was first detected in the uterus and trophoblast prior to blastocyst attachment and remained detectable for 5-6 days after blastocyst attachment. Cox2 expression was also localized in the luminal and glandular epithelia of uterine segments located between implantation chambers. Changes in Cox expression were not correlated with the abrupt increase in uterine weight that occurs simultaneously with renewed embryonic development but was correlated with an influx of serum proteins into the uterus observed in a previous study.

Animals↗
PubMed1999

Fatty-acid amide hydrolase is expressed in the mouse uterus and embryo during the periimplantation period.

Arachidonoylethanolamide (anandamide) is an endogenous ligand for cannabinoid receptors. We demonstrated previously that the periimplantation mouse uterus has high levels of anandamide and can synthesize and hydrolyse anandamide. In the present investigation, we examined the expression of the recently identified fatty-acid amide hydrolase (FAAH) gene, which is involved in hydrolyzing anandamide to arachidonic acid and ethanolamine, in the periimplantation mouse embryo and uterus. As previously reported, Northern blot hybridization detected a transcript of approximately 2.5 kilobases of FAAH mRNA in whole uterine poly(A)+ RNA samples. The levels of this mRNA were higher in the liver and brain than in the uterus. In the uterus, higher accumulation of FAAH mRNA occurred on Days 1-4 followed by declines on later days (Days 5-8) of pregnancy. In situ hybridization detected this mRNA primarily in uterine luminal and glandular epithelial cells on Days 1-4 of pregnancy. With the progression of implantation (Days 5-8), accumulation of this mRNA was retained in the luminal and glandular epithelia. In addition, implanting blastocysts showed accumulation of this mRNA. FAAH mRNA accumulation was absent or minimal in the myometrium during this period. Western blotting detected an approximately 60-kDa protein in uterine membrane preparations. In preimplantation embryos, FAAH mRNA was present in one-cell and two-cell embryos but was absent in embryos at the eight-cell/morula stage. However, this mRNA was again detected in Day 4 blastocysts. The presence of FAAH mRNA in one- and two-cell embryos reflects accumulation of maternal message, while its presence in blastocysts reflects embryonic gene activation. Collectively, our present and previous results provide evidence that FAAH is expressed in the mouse uterus and embryo during early pregnancy to modulate local levels of anandamide that could be important for embryo development and implantation.

Amidohydrolases↗
PubMed1999

Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse.

The present investigation examined the spatiotemporal expression of estrogen receptors (ER-alpha and ER-beta) and progesterone receptor (PR) in the periimplantation mouse uterus (days 1-8). ER-alpha messenger RNA (mRNA) was detected at much higher levels in the periimplantation uterus compared with that of ER-beta mRNA, the levels of which were very low in all uterine cells during this period. Results of in situ hybridization demonstrated expression of ER-alpha mRNA primarily in the luminal and glandular epithelia on days 1 and 2 of pregnancy. On days 3 and 4, the accumulation was localized primarily in stromal cells in addition to its presence in the epithelium. Following implantation on day 5, the accumulation of this mRNA was more condensed in the luminal and glandular epithelia, but declined in the subluminal epithelial stroma at the sites of implanting embryos. On days 6-8, the accumulation of ER-alpha mRNA was primarily localized in the secondary decidual zone (SDZ) with more intense localization in the subepithelial cells at the mesometrial pole. In contrast, signals were very low to undetectable in the primary decidual zone (PDZ), and no signals were detected in implanting embryos. The undifferentiated stroma underneath the myometrium also showed positive signals. The immunolocalization of ER-alpha protein correlated with the mRNA localization. Western blot analysis showed down-regulation of ER-alpha in day 8 decidual cell extracts consistent with the down-regulation of ER-alpha mRNA in decidual cells immediately surrounding the embryo on this day. The expression pattern of PR was also dynamic in the periimplantation uterus. On day 1, the accumulation of PR mRNA was very low to undetectable, whereas only a modest level of accumulation in the epithelium was noted on day 2. On days 3 and 4, the accumulation of this mRNA was detected in both the epithelium and stroma. In contrast, the expression was restricted only to the stroma with increased signals at the sites of implantation on day 5. On days 6-8, PR mRNA accumulation increased dramatically throughout the deciduum. The localization of immunoreactive PR correlated with the mRNA distribution in the periimplantation uterus. Taken together, the results demonstrate that the expression of ER-alpha, ER-beta, and PR is differentially regulated in the periimplantation mouse uterus. This compartmentalized expression of ER and PR provides information regarding the sites of coordinated effects ofestrogen and progesterone in the preparation of the uterus for implantation and decidualization during early pregnancy.

Animals↗
PubMed1999

Expression of cyclooxygenase-1 and -2 in the baboon endometrium during the menstrual cycle and pregnancy.

Cyclooxygenase (COX) is the rate-limiting enzyme in the biosynthesis of PGs. PGs together with ovarian steroids play important regulatory roles in the establishment and maintenance of pregnancy in a number of different species. In the primate, little is known about the role of PGs in these processes. In this study, the uterine expression of COX-1 and COX-2 throughout the menstrual cycle [late follicular, day 5 postovulation (PO), day 10 PO, and day 14 PO] and pregnancy (days 12-18, day 39, day 51, and near term) was analyzed using semiquantitative RT-PCR, in situ hybridization, and immunocytochemistry. During the menstrual cycle, the highest expression of COX-1 occurred in luteal phase endometrium and was localized to the surface and glandular epithelium. The stromal cells did not express detectable levels of COX-1 at any time. COX-2 messenger RNA (mRNA) expression, as measured by RT-PCR, was evident at all stages of the menstrual cycle, and in situ hybridization showed specific localization for this mRNA in the epithelial cells during the cycle. Treatment of animals with the antiprogestin (ZK 137.316) for 9 days (beginning on the day of the LH surge) inhibited COX-1 expression in the epithelium when the tissue was analyzed on day 10 PO, whereas COX-2 expression disappeared in the epithelium and increased in the stroma. With the onset of pregnancy, COX-1 expression in epithelial cells decreased dramatically. In contrast, COX-2 continued to be detected on the surface epithelium and was also strongly expressed specifically in the stromal cells at the site of implantation. Immunocytochemical staining for COX-2 showed the same pattern of expression for the protein as the message. Finally, near-term decidua expressed very little COX-1 or COX-2 mRNA. These studies suggest that in the baboon endometrium, COX-1 expression is regulated primarily by progesterone, whereas regulation of COX-2 expression may involve additional mediators of embryonic origin at the site of implantation.

Animals↗
PubMed1999

Uterine decidual response occurs in estrogen receptor-alpha-deficient mice.

Embryo-uterine interactions leading to the attachment reaction is followed by stromal cell proliferation and differentiation into decidual cells (decidualization) at the sites of blastocyst apposition. In rodents, decidualization is also induced by application of an artificial stimulus (intraluminal oil infusion) in a pseudopregnant uterus, or to one that has been appropriately prepared by exogenous progesterone (P4) and estrogen. The process of decidualization is under the control of these steroids in the presence of blastocysts or deciduogenic stimuli. Although it is well known that estrogen is required for the induction of progesterone receptors in the uterus, the functional importance of estrogen in the process of decidualization is poorly understood. To better understand the role of estrogenic actions in decidualization, we used wild-type and estrogen receptor-alpha knock-out (ERKO) mice for induction of decidualization employing a defined steroid hormonal treatment schedule. Our results demonstrate that P4 alone induces decidualization in ovariectomized wild-type or ERKO mice in response to intraluminal oil infusion in the absence of estrogen. A combined treatment of either estradiol-17beta (E2) or its catecholmetabolite 4-hydroxyestradiol-17beta(4-OH-E2) with P4 does not potentiate the decidual response produced by P4 treatment alone in either ovariectomized wild-type or ERKO mice. The induction of decidual response was associated with up-regulation of decidual cell marker genes, such as progesterone receptor, metallothionein-1, and cyclooxygenase-2. The results suggest that the stromal cell sensitivity to decidualization is critically dependent on P4-regulated events, and estrogenic induction of progesterone receptor via classical nuclear ER-alpha is not critical for this process.

Animals↗
PubMed1999

Multiple roles for heparin-binding epidermal growth factor-like growth factor are suggested by its cell-specific expression during the human endometrial cycle and early placentation.

Embryonic expression of the epidermal growth factor (EGF) receptor as well as embryonic and steroid-dependent uterine secretion of its ligand, heparin-binding EGF-like growth factor (HB-EGF), are temporally associated with the period of blastocyst implantation. We examined the temporal cell type-specific expression of HB-EGF in human endometrium during the menstrual cycle by immunohistochemistry and in situ hybridization. Early first trimester implantation sites were also examined to determine HB-EGF protein levels in decidual and fetal tissues. In the endometrial stroma, HB-EGF protein expression increased markedly during the late proliferative phase and then decreased in the early secretory phase. By contrast, luminal and glandular epithelial cells as well as blood vessel endothelium accumulated the protein between midcycle and cycle day 20, with peak expression observed during the period of uterine receptivity for implantation. HB-EGF expression decreased dramatically at the end of the cycle, before menses. Spatiotemporal expression of HB-EGF messenger ribonucleic acid demonstrated a similar pattern. During early pregnancy, HB-EGF immunostaining was noted in the decidua and in both villous and extravillous trophoblast populations. These findings suggest that HB-EGF promotes implantation and trophoblast invasion through paracrine and autocrine signaling as cells penetrate the stroma and displace the arteriole endothelium.

Adolescent↗
PubMed1999

Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse.

Hoxa-10 is an AbdominalB-like homeobox gene that is expressed in the developing genitourinary tract during embryogenesis and in the adult uterus during early pregnancy. Null mutation of Hoxa-10 in the mouse causes both male and female infertility. Defective implantation and decidualization resulting from the loss of maternal Hoxa-10 function in uterine stromal cells is the cause of female infertility. However, the mechanisms by which Hoxa-10 regulates these uterine events are unknown. We have identified two potential mechanisms for these uterine defects in Hoxa-10(-/-) mice. First, two PGE2 receptor subtypes, EP3 and EP4, are aberrantly expressed in the uterine stroma in Hoxa-10(-/-) mice, while expression of several other genes in the stroma (TIMP-2, MMP-2, ER, and PR) and epithelium (LIF, HB-EGF, Ar, and COX-1) are unaffected before implantation. Further, EP3 and EP4 are inappropriately regulated by progesterone (P4) in the absence of Hoxa-10, while PR, Hoxa-11 and c-myc, three other P4-responsive genes respond normally. These results suggest that Hoxa-10 specifically mediates P4 regulation of EP3 and EP4 in the uterine stroma. Second, since Hox genes are implicated in local cell proliferation, we also examined steroid-responsive uterine cell proliferation in Hoxa-10(-/-) mice. Stromal cell proliferation in mutant mice in response to P4 and 17beta-estradiol (E2 was significantly reduced, while epithelial cell proliferation was normal in response to E2. These results suggest that stromal cell responsiveness to P4 with respect to cell proliferation is impaired in Hoxa-10(-/-) mice, and that Hoxa-10 is involved in mediating stromal cell proliferation. Collectively, these results suggest that Hoxa-10 mutation causes specific stromal cell defects that can lead to implantation and decidualization defects apparently without perturbing epithelial cell functions.

Animals↗