BMP7 coordinates endometrial epithelial cell receptivity for blastocyst implantation through the endoglin pathway in cell lines and a mouse model

Yuan,Caixia; Li,Xianlian; Song,Haixia; Fan,Lingling; Su,Shili; Dong,Baihua

doi:10.3892/etm.2019.7265

BMP7 coordinates endometrial epithelial cell receptivity for blastocyst implantation through the endoglin pathway in cell lines and a mouse model

Authors:
- Caixia Yuan
- Xianlian Li
- Haixia Song
- Lingling Fan
- Shili Su
- Baihua Dong
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Affiliations: Department of Gynecology and Obstetrics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, Department of Reproductive Medicine, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
Published online on: February 13, 2019 https://doi.org/10.3892/etm.2019.7265
Pages: 2547-2556
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bone morphogenetic protein (BMP) expression has been observed in the uterus in previous studies. However, the influence of BMP7 on blastocyst implantation remains unclear. Blastocysts first act on luminal endometrial epithelial cells during implantation. The purpose of the present study was to explore the influence of BMP7 on endometrial epithelial cells. A pregnancy animal model, and mouse and human endometrial epithelial cells were used in the present study. Transient knockdown, immunofluorescence assay, in vitro embryo implantation, BMP7 silencing, reverse transcription‑quantitative polymerase chain reaction, western blotting, immunoprecipitation and Rac1 function assay were also performed. It was revealed that BMP7 concentration was increased in endometrial epithelial cells during the final pre‑receptive and receptive stages of receptivity in the mouse endometrium. Additionally, BM7 acted on the transforming growth factor‑β receptor, endoglin. Endoglin expression was detected in both stromal and endothelial cells apart from trophoblast expression. Following knockdown of BMP7, Rac‑GTP was decreased in endometrial epithelial cells and the uterus. Knockdown of endoglin by small interfering RNA decreased the number of blastocysts and implantation regions. Additionally, BMP7 silencing and endoglin suppression of Ishikawa cells led to impaired JAr spheroid attachment. These findings suggest that BMP7 is associated with receptivity of the endometrium, indicating that BMP7 regulates receptivity of endometrial epithelial cells for implantation of blastocysts via the endoglin pathway.

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1	Yoshinaga K: Research on blastocyst implantation essential factors (BIEFs). Am J Reprod Immunol. 63:413–424. 2010. View Article : Google Scholar : PubMed/NCBI
2	Haouzi D and Hamamah S: The acquisition of the human endometrial receptivity phenotype: Lessons from proteomic studies. Reproductomics Elsevier. 303–314. 2018.
3	Propst AM, Hansard L, Silverberg K, Hegtvedt M, Burger NZ and Vaughn TC: Endometrial receptivity and pregnancy rates are higher after 7 days of progesterone in medicated FET cycles. Fertil Steril. 108:e357–e358. 2017. View Article : Google Scholar
4	Kumar V, Soni UK, Maurya VK, Singh K and Jha RK: Integrin beta8 (ITGB8) activates VAV-RAC1 signaling via FAK in the acquisition of endometrial epithelial cell receptivity for blastocyst implantation. Sci Rep. 7:18852017. View Article : Google Scholar : PubMed/NCBI
5	Achache H and Revel A: Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 12:731–746. 2006. View Article : Google Scholar : PubMed/NCBI
6	Aghajanova L, Hamilton AE and Giudice LC: Uterine receptivity to human embryonic implantation: Histology, biomarkers, and transcriptomics. Semin Cell Dev Biol. 19:204–211. 2008. View Article : Google Scholar : PubMed/NCBI
7	Hill CR, Sanchez NS, Love JD, Arrieta JA, Hong CC, Brown CB, Austin AF and Barnett JV: BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFbeta receptor to promote invasion. Cell Signal. 24:1012–1022. 2012. View Article : Google Scholar : PubMed/NCBI
8	Christensen ST, Morthorst SK, Mogensen JB and Pedersen LB: Primary cilia and coordination of receptor tyrosine kinase (RTK) and transforming growth factor β (TGF-β) signaling. Cold Spring Harb Perspect Biol. 9(pii): a0281672017. View Article : Google Scholar : PubMed/NCBI
9	Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, Zhang Q, Ye J, Yan Z, Denduluri S, et al: Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis. 1:87–105. 2014. View Article : Google Scholar : PubMed/NCBI
10	López-Rovira T, Chalaux E and Massagué J: Rosa JL and Ventura F: Direct binding of Smad1 and Smad4 to two distinct motifs mediates bone morphogenetic protein-specific transcriptional activation of Id1 gene. J Biol Chem. 277:3176–3185. 2002. View Article : Google Scholar : PubMed/NCBI
11	Frum T and Ralston A: Cell signaling and transcription factors regulating cell fate during formation of the mouse blastocyst. Trends Genet. 31:402–410. 2015. View Article : Google Scholar : PubMed/NCBI
12	Velasco S, Alvarez-Munoz P, Pericacho M, Dijke PT, Bernabéu C, López-Novoa JM and Rodríguez-Barbero A: L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. J Cell Sci. 121:913–919. 2008. View Article : Google Scholar : PubMed/NCBI
13	Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM and ten Dijke P: Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J. 23:4018–4028. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ruiz-Llorente L, Gallardo-Vara E, Rossi E, Smadja DM, Botella LM and Bernabeu C: Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert Opin Ther Targets. 21:933–947. 2017. View Article : Google Scholar : PubMed/NCBI
15	Pece-Barbara N, Vera S, Kathirkamathamby K, Liebner S, Di Guglielmo GM, Dejana E, Wrana JL and Letarte M: Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta1 with higher affinity receptors and an activated Alk1 pathway. J Biol Chem. 280:27800–27808. 2005. View Article : Google Scholar : PubMed/NCBI
16	Maurya VK, Jha RK, Kumar V, Joshi A, Chadchan S, Mohan JJ and Laloraya M: Transforming growth factor-beta 1 (TGF-B1) liberation from its latent complex during embryo implantation and its regulation by estradiol in mouse. Biol Reprod. 89:842013. View Article : Google Scholar : PubMed/NCBI
17	St-Jean G, Boyer A, Zamberlam G, Godin P, Paquet M and Boerboom D: Targeted ablation of Wnt4 and Wnt5a in Müllerian duct mesenchyme impedes endometrial gland development and causes partial Müllerian agenesis. Biol Reprod. Jul 13–2018.(Epub ahead of print). doi: 10.1093/biolre/ioy160.
18	Richardson KA, Hannon PR, Johnson-Walker YJ, Myint MS, Flaws JA and Nowak RA: Di (2-ethylhexyl) phthalate (DEHP) alters proliferation and uterine gland numbers in the uteri of adult exposed mice. Reprod Toxicol. 77:70–79. 2018. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Leone DP, Srinivasan K, Brakebusch C and McConnell SK: The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain. Dev Neurobiol. 70:659–678. 2010.PubMed/NCBI
21	Grijelmo C, Rodrigue C, Svrcek M, Bruyneel E, Hendrix A, de Wever O and Gespach C: Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells. Cell Signal. 19:1722–1732. 2007. View Article : Google Scholar : PubMed/NCBI
22	Tan SY, Hang F, Purvarshi G, Li MQ, Meng DH and Huang LL: Decreased endometrial vascularity and receptivity in unexplained recurrent miscarriage patients during midluteal and early pregnancy phases. Taiwan J Obstet Gynecol. 54:522–526. 2015. View Article : Google Scholar : PubMed/NCBI
23	Bollum LK, Huse K, Oksvold MP, Bai B, Hilden VI, Forfang L, Yoon SO, Wälchli S, Smeland EB and Myklebust JH: BMP-7 induces apoptosis in human germinal center B cells and is influenced by TGF-β receptor type I ALK5. PLoS One. 12:e01771882017. View Article : Google Scholar : PubMed/NCBI
24	Akiyama I, Yoshino O, Osuga Y and Yano T: Bone morphogenetic protein-7(BMP-7) might contribute to folliculogenesis by promoting angiogenesis. Fertil Steril. 98 (Suppl):S2002012. View Article : Google Scholar
25	Ying Y and Zhao GQ: Detection of multiple bone morphogenetic protein messenger ribonucleic acids and their signal transducer, Smad1, during mouse decidualization. Biol Reprod. 63:1781–1786. 2000. View Article : Google Scholar : PubMed/NCBI
26	Chadchan SB, Kumar V, Maurya VK, Soni UK and Jha RK: Endoglin (CD105) coordinates the process of endometrial receptivity for embryo implantation. Mol Cell Endocrinol. 425:69–83. 2016. View Article : Google Scholar : PubMed/NCBI
27	Monsivais D, Clementi C, Peng J, Fullerton PT Jr, Prunskaite-Hyyryläinen R, Vainio SJ and Matzuk MM: BMP7 induces uterine receptivity and blastocyst attachment. Endocrinology. 158:979–992. 2017. View Article : Google Scholar : PubMed/NCBI
28	Tu Z, Wang Q, Cui T, Wang J, Ran H, Bao H, Lu J, Wang B, Lydon JP, DeMayo F, et al: Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice. Cell Death Differ. 23:169–181. 2016. View Article : Google Scholar : PubMed/NCBI
29	Rossi E, Lopez-Novoa JM and Bernabeu C: Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1). Front Genet. 5:4572014.PubMed/NCBI
30	Chadchan SB, Kumar V, Maurya VK, Soni UK and Jha RK: Endoglin (CD105) coordinates the process of endometrial receptivity for embryo implantation. Mol Cell Endocrinol. 425:69–83. 2016. View Article : Google Scholar : PubMed/NCBI
31	Ma Y, Zou H, Zhu XX, Pang J, Xu Q, Jin QY, Ding YH, Zhou B and Huang DS: Transforming growth factor β: A potential biomarker and therapeutic target of ventricular remodeling. Oncotarget. 8:53780–53790. 2017.PubMed/NCBI
32	Bradshaw FJ and Bradshaw D: Progesterone and reproduction in marsupials: A review. Gen Comp Endocrinol. 170:18–40. 2011. View Article : Google Scholar : PubMed/NCBI
33	Wang W, Ju YY, Zhou QX, Tang JX, Li M, Zhang L, Kang S, Chen ZG, Wang YJ, Ji H, et al: The Small GTPase rac1 contributes to extinction of aversive memories of drug withdrawal by facilitating GABAA receptor endocytosis in the vmPFC. J Neurosci. 37:7096–7110. 2017. View Article : Google Scholar : PubMed/NCBI